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Interaction between food antigens and the immune system: Association with autoimmune disorders
Abstract
It has been shown that environmental factors such as infections, chemicals, and diet play a major role in autoimmune diseases; however, relatively little attention has been given to food components as the most prevalent modifiers of these afflictions. This review summarizes the current body of knowledge related to different mechanisms and associations between food proteins/peptides and autoimmune disorders. The primary factor controlling food-related immune reactions is the oral tolerance mechanism. The failure of oral tolerance triggers immune reactivity against dietary antigens, which may initiate or exacerbate autoimmune disease when the food antigen shares homology with human tissue antigens. Because the conformational fit between food antigens and a host's self-determinants has been determined for only a few food proteins, we examined evidence related to the reaction of affinity-purified disease-specific antibody with different food antigens. We also studied the reaction of monoclonal or polyclonal tissue-specific antibodies with various food antigens and the reaction of food-specific antibodies with human tissue antigens. Examining the assembled information, we postulated that chemical modification of food proteins by different toxicants in food may result in immune reaction against modified food proteins that cross-react with tissue antigens, resulting in autoimmune reactivity. Because we are what our microbiome eats, food can change the gut commensals, and toxins can breach the gut barrier, penetrating into different organs where they can initiate autoimmune response. Conversely, there are also foods and supplements that help maintain oral tolerance and microbiome homeostasis. Understanding the potential link between specific food consumption and autoimmunity in humans may lay the foundation for further research about the proper diet in the prevention of autoimmune diseases.
... Among the various mechanisms that drive autoimmunity, molecular mimicry is the most reported 11,16,31,32 . Actually, SARS-CoV-2-associated autoimmunity is suggested to operate through molecular mimicry with self-epitopes 33,34 . ...
... Those three interrelated pathways are the basis for our current novel hypothesis, whereby, two very common environmental domains, plants and microbes, and gluten and mTG, respectively, are joining together to induce autoimmunity and other gluten-dependent in ammatory diseases 4,7,9,22,26,27,32,39,41 . ...
... To demonstrate cross-reactivity between mTG and various human target tissue antigens, the steps for the ELISA method were extracted from various manuscripts published by Vojdani et al. 4,32,[125][126][127][128][129][130][131] . ...
Microbial transglutaminase (mTG) is a bacterial survival factor, frequently used as a food additive to glue processed nutrients. As a result, new immunogenic epitopes are generated that might drive autoimmunity. Presently, its contribution to autoimmunity through epitope similarity and cross-reactivity was investigated. Emboss Matcher was used to perform sequence alignment between mTG and various antigens implicated in many autoimmune diseases. Monoclonal and polyclonal antibodies made specifically against mTG were applied to 77 different human tissue antigens using ELISA. Six antigens were detected to share significant homology with mTG immunogenic sequences, representing major targets of common autoimmune conditions.
Polyclonal antibody to mTG reacted significantly with 17 out of 77 tissue antigens. This reaction was most pronounced with mitochondrial M2, ANA, and extractable nuclear antigens. The results indicate that sequence similarity and cross-reactivity between mTG and various tissue antigens are possible, supporting the relationship between mTG and the development of autoimmune disorders. 150W
... (6) Unhealthy diets may lead to a disturbed gut microbiome and breached intestinal barriers, allowing undigested food proteins into the circulatory system and activating the immune response. (8) Antibodies formed against food-specific antigens could then cross-react with human tissues leading to the development of extra-intestinal autoimmune diseases. (8,9) In a recent study, antibodies against food antigens commonly found in industrial processed foods including wheat (gluten), milk, peanuts, soy, egg and corn all demonstrated cross-reactivity with human tissue proteins. ...
... (8) Antibodies formed against food-specific antigens could then cross-react with human tissues leading to the development of extra-intestinal autoimmune diseases. (8,9) In a recent study, antibodies against food antigens commonly found in industrial processed foods including wheat (gluten), milk, peanuts, soy, egg and corn all demonstrated cross-reactivity with human tissue proteins. (8) Anti-gluten antibodies may have sequence homologies and cross-react with brain antigens, pointing to a possible pathway between Western diets and neurodegenerative, neuropsychiatric and neuroinflammatory diseases. ...
... (8,9) In a recent study, antibodies against food antigens commonly found in industrial processed foods including wheat (gluten), milk, peanuts, soy, egg and corn all demonstrated cross-reactivity with human tissue proteins. (8) Anti-gluten antibodies may have sequence homologies and cross-react with brain antigens, pointing to a possible pathway between Western diets and neurodegenerative, neuropsychiatric and neuroinflammatory diseases. (10) Gluten also appears to contribute to the tight junction dysfunction and intestinal permeability associated with initiation of the autoimmune cascade. ...
Introduction
Previous studies have reported that patients affected by systemic lupus erythematosus (SLE) are interested in using diet to treat fatigue, cardiovascular disease and other symptoms. However, to date, there is insufficient information regarding the ways for patients to modify their diet to improve SLE symptoms. We investigated the relationship between the eating patterns of SLE patients and their self-reported disease symptoms and general aspects of health.
Methods
A UK-based, online survey was developed, in which patients with SLE were asked about their attitudes and experiences regarding their SLE symptoms and diet.
Results
The majority (>80%) of respondents that undertook new eating patterns with increased vegetable intake and/or decreased intake of processed food, sugar, gluten, dairy and carbohydrates reported benefiting from their dietary change. Symptom severity ratings after these dietary changes were significantly lower than before (21.3% decrease, p<0.0001). The greatest decreases in symptom severity were provided by low/no dairy (27.1% decrease), low/no processed foods (26.6% decrease) and vegan (26% decrease) eating patterns (p<0.0001). Weight loss, fatigue, joint/muscle pain and mood were the most cited symptoms that improved with dietary change.
Conclusion
SLE patients who changed their eating patterns to incorporate more plant-based foods while limiting processed foods and animal products reported improvements in their disease symptoms. Thus, our findings show promises in using nutrition interventions for the management of SLE symptoms, setting the scene for future clinical trials in this area. Randomised studies are needed to further test whether certain dietary changes are effective for improving specific symptoms of SLE.
... Based on earlier studies about the cross reactivity of food components and human tissue antigens [7,[45][46][47][48][49], the present study explored the reactivity of aSN antibody with 180 different commonly used food products. ...
... Molecular mimicry between food antigens and self-tissue proteins is one of the possible mechanisms in the initiation of autoimmune diseases [7,8,[45][46][47][48][49]58,59]. Intriguingly, based on this mechanism, several aspects of neuroinflammation and autoimmunity have been described in PD [60,61]. ...
... Interestingly, in addition to the luminal aSN [34,[36][37][38], another frequently ingested nutrient, namely, gluten, was recently suggested as a potential driver of neurodegeneration [100]. The anti-gluten antibodies cross-reactivity [7,46,47,59] and the numerous epitope sequence homologies with human central nervous system peptides [102] direct to the possible pathophysiological pathway of molecular mimicry, operating in neurodegenerative diseases. The food-gut-brain axis might represent an additional avenue, operating in neurodegenerative disease evolvement. ...
Introduction:
Parkinson's disease is characterized by non-motor/motor dysfunction midbrain neuronal death and α-synuclein deposits. The accepted hypothesis is that unknown environmental factors induce α-synuclein accumulation in the brain via the enteric nervous system.
Material and methods:
Monoclonal antibodies made against recombinant α-synuclein protein or α-synuclein epitope 118-123 were applied to the antigens of 180 frequently consumed food products. The specificity of those antibody-antigen reactions was confirmed by serial dilution and inhibition studies. The Basic Local Alignment Search Tool sequence matching program was used for sequence homologies.
Results:
While the antibody made against recombinant α-synuclein reacted significantly with 86/180 specific food antigens, the antibody made against α-synuclein epitope 118-123 reacted with only 32/180 tested food antigens. The food proteins with the greatest number of peptides that matched with α-synuclein were yeast, soybean, latex hevein, wheat germ agglutinin, potato, peanut, bean agglutinin, pea lectin, shrimp, bromelain, and lentil lectin. Conclusions: The cross-reactivity and sequence homology between α-synuclein and frequently consumed foods, reinforces the autoimmune aspect of Parkinson's disease. It is hypothesized that luminal food peptides that share cross-reactive epitopes with human α-synuclein and have molecular similarity with brain antigens are involved in the synucleinopathy. The findings deserve further confirmation by extensive research.
... Based on earlier studies about the cross reactivity of food components and human tissue antigens [7,[45][46][47][48][49], the present study explored the reactivity of aSN antibody with 180 different commonly used food products. ...
... Molecular mimicry between food antigens and self-tissue proteins is one of the possible mechanisms in the initiation of autoimmune diseases [7,8,[45][46][47][48][49]58,59]. Intriguingly, based on this mechanism, several aspects of neuroinflammation and autoimmunity have been described in PD [60,61]. ...
... Interestingly, in addition to the luminal aSN [34,[36][37][38], another frequently ingested nutrient, namely, gluten, was recently suggested as a potential driver of neurodegeneration [100]. The anti-gluten antibodies cross-reactivity [7,46,47,59] and the numerous epitope sequence homologies with human central nervous system peptides [102] direct to the possible pathophysiological pathway of molecular mimicry, operating in neurodegenerative diseases. The food-gut-brain axis might represent an additional avenue, operating in neurodegenerative disease evolvement. ...
Parkinson’s disease is characterized by nonmotor/motor dysfunction, midbrain dopaminergic neuronal death, and α-synuclein (aSN) deposits. The current hypothesis is that aSN accumulates in the enteric nervous system to reach the brain. However, invertebrate, vertebrate, and nutritional sources of aSN reach the luminal compartment. Submitted to local amyloidogenic forces, the oligomerized proteins’ cargo can be sensed and sampled by a specialized mucosal cell to be transmitted to the adjacent enteric nervous system, starting their upward journey to the brain. The present narrative review extends the current mucosal origin of Parkinson’s disease, presenting the possibility that the disease starts in the intestinal lumen. If substantiated, eliminating the nutritional sources of aSN (eg, applying a vegetarian diet) might revolutionize the currently used dopaminergic pharmacologic therapy.
... Cross-reactive antibodies between self-components and environmental epitopes are a well described biologic phenomenon, as schematically illustrated in Figure 1. In this regards, molecular mimicry between anti-wheat/gluten and brain tissue component were shown by cross-reactive antibodies [8][9][10]78,79]. For example, when autistic children were checked, an eight amino acids sequence similarity of gliadin and cerebellar neural tissue was detected [8]. ...
... More so, when anti-food antibody derived from six common foods were checked against 65 different tissue antigens, anti-wheat antibody cross-reacted with 15 tissue antigens. Concentrating on brain components, the anti-wheat antibodies reacted against dopamine receptor, neurotropin, alpha enolase and not surprisingly also against tTG which is the autoantigen of CD [10,79]. Interestingly, anti-gliadin antibodies also reacted against glutamic acid decarboxylase (GAD65), an enzyme involved in the production of γ-aminobutyric acid (GABA), which is a prime inhibitory neurotransmitter that, when dysregulated, is implicated in both depression and anxiety [65,78]. ...
... Although, the potential pathogenic role of SYN1-cross-reactive anti-gliadin antibodies is still unclear [7,9], increasing evidence substantiated the relevance of alterations in synapsins as a major determinant in many neurological disorders, including AD, MS, bipolar disorder, psychosis, schizophrenia, depressive Amyloid-beta precursor protein is a key protein in AD and is considered one of the main components and inducers of the built-up plaque in the brain. Autoantibodies against this protein are detected in patients with AD and have been shown to cause neuronal degeneration in individuals with compromised blood brain barrier [10,85,93,106]. • Alpha-synuclein is a neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release. This protein is a pathogenic hallmark of PD, and related to dementia with Lewy bodies, and multiple system atrophy [94]. ...
Wheat is a most favored staple food worldwide and its major protein is gluten. It is involved in several gluten dependent diseases and lately was suggested to play a role in non-celiac autoimmune diseases. Its involvement in neurodegenerative conditions was recently suggested but no cause-and-effect relationship were established. The present narrative review expands on various aspects of the gluten-gut-brain axes events, mechanisms and pathways that connect wheat and gluten consumption to neurodegenerative disease. Gluten induced dysbiosis, increased intestinal permeabillity, enteric and systemic side effects, cross-reactive antibodies, and the sequence of homologies between brain antigens and gluten are highlighted. This combination may suggest molecular mimicry, alluding to some autoimmune aspects between gluten and neurodegenerative disease. The proverb of Hippocrates coined in 400 BC, “let food be thy medicine,” is critically discussed in the frame of gluten and potential neurodegeneration evolvement.
... Том 23, № 7 (2024) | | 89 ОБЗОРЫ Известно, что экзогенные молекулы способны нарушать толерантность к аутоантигенам и стимулировать иммунные клетки в основном за счет молекулярного сходства экзогенного антигена с антигенами тканей человека (молекулярной мимикрии). Свойством мимикрии под антигены тканей человека обладают как вирусные и микробные антигены, так и эпитопы пищевых пептидов [29][30][31][32]. Перекрестная реактивности экзогенных антигенов с антигенами собственных тканей организма способствует запуску аутоимму нного процесса. ...
... Наиболее изученной является перекрестная реактивность животных и растительных пищевых антигенов с антигенами островковых клеток поджелудочной железы, тканей щитовидной железы и нейрональными антигенами. Так, белки коровьего молока имеют молекулярное сходство с миелин-олигодендроцитарным гликопротеином, а астроцитарный аквапорин-4 -с пищевыми аквапоринами и серпинами бобовых, содержащимися в сое, кукурузе и других овощах [29]. Примечательно, что пищевые антигены способны не только служить триггерами аутоиммунитета с антиген-индуцированным синтезом антител или активацией Т-лимфоцитов, но и поддерживать аутовоспалительный процесс с помощью активации врожденных иммунных реакций, что характерно, например, для глютена [33]. ...
Aim. A synthesis of scientific literature data on the association of autism spectrum disorders (ASD) with gastrointestinal dysfunction and disturbances of the intestinal microbiota. Key points. ASDs belong to a group of neurodevelopmental disorders associated with genetic, epigenetic and environmental factors, and include conditions that are heterogeneous in clinical presentation and severity of psychopathological symptoms. ASD is often comes with various symptoms of gastrointestinal tract dysfunction referred to impaired intestinal barrier permeability. The consequence is the pervasion of external agents (food antigens, toxins, bacterial metabolites) into the blood and initiation or maintenance of the inflammatory process, which is the most important pathophysiological link in ASD. Particular attention is paid to the analysis of the mechanisms of impaired intestinal barrier permeability. It is necessary to develop strategies aimed at reducing the level of inflammation in complex therapy of patients with ASD. Conclusion. Patients with ASD, in addition to psychoneurological symptoms, often present somatic problems, which, however, may not be timely recognized due to their nonspecificity and the difficulty of differentiating behavioral reactions either associated with the disorder or being just a reaction to somatic ill-being.Moreover, the whole complex of clinical manifestations is mediated by a single systemic dysregulation of immunological and metabolic reactions and is inherently a different reflection of one process, requiring profound multidisciplinary treatment and the use of various therapy approaches. Keywords: autism spectrum disorders, neuroinflammation, microbiome, intestinal permeability.
... It affects epigenetics, influences the microbiome, and increases intestinal permeability [45]. Most recently, antibody's cross-reactivity and sequence homology were demonstrated between gluten/wheat and human body antigens, thus reinforcing gluten as a food additive with potential multiple molecular mimicries repertoire [46][47][48]. Those findings further extend the list of food components that express autoimmunogenic capacities. ...
... However, there are some dark sides to those colorants. Their consumption can drive the inflammatory cascade, enhance intestinal permeability to larger antigenic molecules, and induce human self-cross-reactive antibodies with the colorants, thus pushing toward autoimmunogenesis [48,132]. Even neurobehavioral disorders such as attention-deficit disorder and attention-deficit/hyperactivity disorder are attributed to colorant's intake [132,133]. ...
... It seems that the mTG-gluten-human self-epitopes axis is interactive and auto-immunogenic. Those three interrelated pathways are the basis for our current novel hypothesis, whereby, two very common environmental domains, plants and microbes, and gluten and mTG, respectively, are joining together to induce autoimmunity and other gluten-dependent inflammatory diseases 4,7,9,22,26,27,32,39,41 . Interestingly, gluten avoidance was recently reported to alleviate symptoms and disease activity of non-celiac ADs 81,82,102-106 , although, gluten withdrawal is not devoid of side effects [107][108][109] . ...
... To demonstrate cross-reactivity between mTG and various human target tissue antigens, the steps for the ELISA method were extracted from various manuscripts published by Vojdani et al. 4,32,[125][126][127][128][129][130][131] . ...
Microbial transglutaminase (mTG) is a bacterial survival factor, frequently used as a food additive to glue processed nutrients. As a result, new immunogenic epitopes are generated that might drive autoimmunity. Presently, its contribution to autoimmunity through epitope similarity and cross-reactivity was investigated. Emboss Matcher was used to perform sequence alignment between mTG and various antigens implicated in many autoimmune diseases. Monoclonal and polyclonal antibodies made specifically against mTG were applied to 77 different human tissue antigens using ELISA. Six antigens were detected to share significant homology with mTG immunogenic sequences, representing major targets of common autoimmune conditions. Polyclonal antibody to mTG reacted significantly with 17 out of 77 tissue antigens. This reaction was most pronounced with mitochondrial M2, ANA, and extractable nuclear antigens. The results indicate that sequence similarity and cross-reactivity between mTG and various tissue antigens are possible, supporting the relationship between mTG and the development of autoimmune disorders 150W.
... On the other hand, a high intake of dairy products may increase the risk of type 1 diabetes in children [4]. This is possibly attributed to the strong antigenicity of cow's milk and the molecular mimicry between cow's milk proteins and proteins in the islets of Langerhans [9]. Regarding the risk of autoimmune diabetes with adult-onset, such as type 1 diabetes or latent autoimmune diabetes in adults (LADA), a potential association with OCFA concentrations or dairy product intake has not been addressed. ...
... This contrasts with previous findings for type 1 diabetes in children that suggested an elevated risk with a higher intake of cow's milk products [4]. Although a biological mechanism linking dairy consumption to type 1 diabetes has yet to be discovered, it has been hypothesised that due to structural similarities with islet cell proteins, cow's milk proteins, which are known dietary antigens, may promote autoimmune diabetes in susceptible individuals [9]. This might be particularly relevant in infancy and childhood when immune-mediated reactions to cow's milk proteins are more common [32] and may explain why dairy intake was neither associated with GAD65Ab positivity at baseline nor with progression to adult-onset diabetes in our study. ...
Aims/hypothesis
Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes.
Methods
We used the European EPIC-InterAct case–cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected individuals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive individuals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP).
Results
Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) individuals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive individuals (HR 0.97 [95% CI 0.79, 1.18]).
Conclusions/interpretation
Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes.
Graphical Abstract
... Although it is known that food protein oxidation impairs its functional properties, including solubility and digestibility [21,23,25], few articles evaluate the effect of carbonylation of animal food proteins and allergenicity; Fenaille et al. (2005) reported that resistance to digestion is associated with protein carbonylation may be related to the increase of food allergens [21]. Likewise, Vojdani et al. (2020) and Corsini et al. (2013), in their works, establish that post-translational modification of proteins such as carbonylation can generate their recognition and stimulation of the immune system [45,46]. On the other hand, Nagai et al. (2008) demonstrated in their study the elevation in the content of carbonylated proteins in sputum of asthmatic patients compared to controls, finding that proteins such as albumin and α1-antitrypsin were specifically carbonylated in allergic inflammation in humans and mice, demonstrating a relationship between these two phenomena [47]. ...
... Although it is known that food protein oxidation impairs its functional properties, including solubility and digestibility [21,23,25], few articles evaluate the effect of carbonylation of animal food proteins and allergenicity; Fenaille et al. (2005) reported that resistance to digestion is associated with protein carbonylation may be related to the increase of food allergens [21]. Likewise, Vojdani et al. (2020) and Corsini et al. (2013), in their works, establish that post-translational modification of proteins such as carbonylation can generate their recognition and stimulation of the immune system [45,46]. On the other hand, Nagai et al. (2008) demonstrated in their study the elevation in the content of carbonylated proteins in sputum of asthmatic patients compared to controls, finding that proteins such as albumin and α1-antitrypsin were specifically carbonylated in allergic inflammation in humans and mice, demonstrating a relationship between these two phenomena [47]. ...
This work aimed to evaluate the effect of carbonylation induced by tetracyclines, β-lactams, fluoroquinolones, and pyrethroids in caseins of bovine origin on their immunoreactivity and allergenicity. Using a spectrophotometric method, ELISA, dot-blot, and an IgE-mediated milk allergy mouse model, we confirmed that antibiotics and pesticides at their maximum residue limit, promoted the in vitro carbonylation of caseins (among 5.0 ± 0.01 and 67.5 ± 0.70 nmol of carbonyl/mg of protein); furthermore, carbonylations greater than 19 nmol significantly increase the in vitro IgE immunoreactivity of caseins (average OD among 0.63 - 1.50) regarding the negative control (average OD: 0.56). On the other hand, sensitized mice exposed to oxidized caseins showed increased clinical scores (2-5), positive skin tests, and footpad swelling (0.28 - 0.59 mm) compared to the negative control (1-2; negative skin tests; 0.1 mm, respectively), denoting increased allergenicity. These results suggest that casein carbonylation increases their IgE immunoreactivity and allergenicity, a fact that could be explained by the resistance to the digestion promoted by carbonylation and by conformational changes in the random coil casein structure, which can expose cryptic epitopes or neoepitopes.
... Most recently, Vojdani et al. [66] postulated that the chemical modification of food proteins by diverse food toxicants might result in immune reactions that involve cross-reactions with tissue antigens, resulting in autoimmune reactivity. Leaky gut in patients with ASD, of course, can help toxins to cross the gut barrier, penetrating into different organs, where they can initiate autoimmune responses. ...
... This might be the reason for the atypical eating behaviors observed in autistic children with leaky gut and autoimmunity. This might help to inform clinicians early enough so that they can identify autistic patients and develop evidence-based intervention strategies [66]. ...
Background
Innovative research highlighted the probable connection between autism spectrum disorder (ASD) and gut microbiota as many autistic individuals have gastrointestinal problems as co-morbidities. This review emphasizes the role of altered gut microbiota observed frequently in autistic patients, and the mechanisms through which such alterations may trigger leaky gut.
Main body
Different bacterial metabolite levels in the blood and urine of autistic children, such as short-chain fatty acids, lipopolysaccharides, beta-cresol, and bacterial toxins, were reviewed. Moreover, the importance of selected proteins, among which are calprotectin, zonulin, and lysozyme, were discussed as biomarkers for the early detection of leaky gut as an etiological mechanism of ASD through the less integrative gut–blood–brain barriers. Disrupted gut–blood–brain barriers can explain the leakage of bacterial metabolites in these patients.
Conclusion
Although the cause-to-effect relationship between ASD and altered gut microbiota is not yet well understood, this review shows that with the consumption of specific diets, definite probiotics may represent a noninvasive tool to reestablish healthy gut microbiota and stimulate gut health. The diagnostic and therapeutic value of intestinal proteins and bacterial-derived compounds as new possible biomarkers, as well as potential therapeutic targets, are discussed.
... Lectins are carbohydrate-binding proteins that perform important biological roles and are common in food plants but are somewhat digestion-resistant [85]. Based on the hypothesis that lectins can bind gut bacteria and epithelial cells, releasing endotoxins that induce intestinal permeability and allow lectins to penetrate the digestive barrier and bind to body tissue inducing inflammatory and autoimmune responses [85]. ...
... Lectins are carbohydrate-binding proteins that perform important biological roles and are common in food plants but are somewhat digestion-resistant [85]. Based on the hypothesis that lectins can bind gut bacteria and epithelial cells, releasing endotoxins that induce intestinal permeability and allow lectins to penetrate the digestive barrier and bind to body tissue inducing inflammatory and autoimmune responses [85]. There is scant evidence for dietary lectin involvement in FD aetiology or symptom induction, but dietitians need to be familiar with the concept due to the popularity of dietary lectin restriction as a management approach to auto-immune and 'leaky gut' conditions despite a lack of evidence of efficacy. ...
Functional dyspepsia (FD) is a common disorder of gut-brain interaction, characterised by upper gastrointestinal symptom profiles that differentiate FD from the irritable bowel syndrome (IBS), although the two conditions often co-exist. Despite food and eating being implicated in FD symptom induction, evidence-based guidance for dietetic management of FD is limited. The aim of this narrative review is to collate the possible mechanisms for eating-induced and food-related symptoms of FD for stratification of dietetic management. Specific carbohydrates, proteins and fats, or foods high in these macronutrients have all been reported as influencing FD symptom induction, with removal of ‘trigger’ foods or nutrients shown to alleviate symptoms. Food additives and natural food chemicals have also been implicated, but there is a lack of convincing evidence. Emerging evidence suggests the gastrointestinal microbiota is the primary interface between food and symptom induction in FD, and is therefore a research direction that warrants substantial attention. Objective markers of FD, along with more sensitive and specific dietary assessment tools will contribute to progressing towards evidence-based dietetic management of FD.
... The characterization of such modifications will allow a better understanding of the interplay between bioactive dietary components and dietrelated diseases [82,83]. For e.g., nutriproteomics could help in elucidating the possible relationships between food antigens and autoimmune disorders [84]. Tsuda et al. (2015) have demonstrated that monoclonal autoantibodies derived from RA patients cross-react not only with various autoantigens but also with numerous food proteins. ...
... The authors proposed that such dietary proteins may trigger the generation of RA-specific autoantibodies to induce autoimmunity in at risk individuals [85]. Interestingly, it has been also hypothesized that chemical alterations of food proteins by different toxic agents in food may lead to immune reaction against altered food proteins that cross-react with tissue antigens, causing autoimmune reactions [84]. Understanding the possible link between specific food consumption and autoimmunity in humans may lead to prevention of autoimmune diseases through precise dietary advices in at risk individuals. ...
Modern high-throughput ‘omics’ science tools (including genomics, transcriptomics, proteomics, metabolomics and microbiomics) are currently being applied to nutritional sciences to unravel the fundamental processes of health effects ascribed to particular nutrients in humans and to contribute to more precise nutritional advice. Diet and food components are key environmental factors that interact with the genome, transcriptome, proteome, metabolome and the microbiota, and this life-long interplay defines health and diseases state of the individual. Rheumatoid arthritis (RA) is a chronic autoimmune disease featured by a systemic immune-inflammatory response, in genetically susceptible individuals exposed to environmental triggers, including diet. In recent years increasing evidences suggested that nutritional factors and gut microbiome have a central role in RA risk and progression. The aim of this review is to summarize the main and most recent applications of ‘omics’ technologies in human nutrition and in RA research, examining the possible influences of some nutrients and nutritional patterns on RA pathogenesis, following a nutrigenomics approach. The opportunities and challenges of novel ‘omics technologies’ in the exploration of new avenues in RA and nutritional research to prevent and manage RA will be also discussed.
... In particular, autoimmune illnesses can be prevented and treated in large part by cultivating self-tolerance. Immune cells may wrongly target their own tissues when tolerance is lost, which can result in autoimmune illnesses including diabetes type 1 and multiple sclerosis [19]. ...
The immune system comprises various regulators and effectors that elicit immune responses against various attacks on the body. The pathogenesis of autoimmune diseases is derived from the deregulated expression of cytokines, the major regulators of the immune system. Among cytokines, interleukins have a major influence on immune-mediated diseases. These interleukins initiate the immune response against healthy and normal cells of the body, resulting in immune-mediated disease. The major interleukins in this respect are IL-1, IL-3, IL-4, IL-6, IL-10 and IL-12 which cause immune responses such as excessive inflammation, loss of immune tolerance, altered T-cell differentiation, immune suppression dysfunction, and inflammatory cell recruitment. Systemic Lupus Erythematosus (SLE) is an autoimmune illness characterized by dysregulation of interleukins. These immune responses are the signs of diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, type I diabetes, and multiple sclerosis.
... In addition, biologically active components of wheat include dietary fibers, phytochemicals such as carotenoids and polyphenols, phenolic acids, flavonoids and lignans, and vitamins. [1,2] At the same time, wheat grains (rye, barley, wheat) contain proteins rich in proline and glutamine-prolamins, the consumption of which in some people can initiate gluten-dependent diseases such as celiac disease, wheat allergy, asthma, anaphylaxis [3,4]. ...
The paper describes the fact of the presence of a proteolytic enzyme in the leaves of the natural hybrid variety of grape - Isabella (Vitis Labrusca L.) and the perspective of its practical application for breaking down wheat gluten. As our research has shown, this enzyme effectively degradates the constituent components of the protein fraction of wheat flour-the gluten fraction. It is known that the wheat gluten is a strong allergen for many people, which can initiate a disease such as celiac disease. Protease from Isabella leaves carries out deep hydrolysis of gluten to low molecular weight soluble peptides and amino acids. This effect can be successfully used in the production of gluten-free bread products.
... Nagyon gyakori, hogy időről időre emésztési problémákat vagy más, az elfogyasztott táplálékkal kapcsolatos panaszokat tapasztalunk. (Vojdani et al., 2020) "Te pedig súlyos betegségbe, bélbajba esel, mindaddig, míg a te béled naponként kimegy a betegség miatt." (2Krón,21 19.) Az élelmiszer-túlérzékenység egy összefoglaló kifejezés az élelmiszerekre adott, egyént érintő kóros reakciókra. ...
A tápcsatorna hatékonyan dolgozza fel az étrendi összetevőket, a legtöbb esetben megakadályozva a kóros immunválaszok vagy más kóros reakciók kialakulását. A nemkívánatos étkezési reakciók előfordulása azonban folyamatosan növekszik. Jelen írás célja rövid áttekintést adni az immun- és nem immun-hátterű reakciókról, hangsúlyozva a két kategória közötti alapvető különbségeket.
... Various cells can be bound by such lectins, such as connective tissue, liver, pancreas, thyroid, cardiac muscle, prostate, breast, brain, etc., and thereby induce the expression of class II antigens on these cells, which ordinarily do not do so. Alternatively, if a dietary lectin escapes, it may also cause the release of endotoxins such as lipopolysaccharides (LPSs), which increase gut permeability and release lectins, food antigens, and bacterial toxins into the circulatory system [79]. The LPS released from the gram-negative bacterial wall leaks into the bloodstream to the connective tissues, where it causes systemic inflammation through the inflammasome NLRP3. ...
Beans, vegetables, fruits, and mushrooms offer a delightful array of fragrances and an abundance
of nutrients, including essential vitamins, minerals, protein rich in vital amino acids, and omega-3
fatty acids. However, they may also contain lectins, carbohydrate-binding proteins with potential
health risks. While some lectins exhibit stability and resistance to digestion, posing threats to
gastrointestinal integrity and immune function, others, such as those from butterfly peas and pink
bauhinia, show immunomodulatory properties that could bolster immune responses. While some
lectins, such as phytohemagglutinin, have been associated with inflammatory responses and
autoimmune disorders, others, such as wheat lectin, have shown potential benefits in nutrient
absorption. Additionally, mushroom lectins, while generally nontoxic, exhibit immunomodulatory
properties with implications for immune health. Despite their potential benefits, challenges
remain in understanding lectin dosages, administration routes, and mechanisms of action. Further
research is needed to elucidate the intricate roles of dietary lectins in immune function and autoimmune disorders. This review surveys the immunomodulatory effects of dietary lectins from
plants and mushrooms, shedding light on their mechanisms of action. From inflammation modulation
to potential autoimmune implications, the diverse roles of dietary lectins have been explored, highlighting avenues for future investigations and therapeutic exploration.
... The structural resemblance of gluten peptides to gut self-antigens may provoke an immune response, resulting in damage to intestinal tissue [79]. In type 1 diabetes, certain milk proteins are suspected of imitating pancreatic beta-cell antigens, possibly inciting an autoimmune response against these cells [80]. Furthermore, the role of the gut microbiome in molecular mimicry must be considered [81]. ...
Purpose of Review
Autoimmune diseases manifest as an immune system response directed against endogenous antigens, exerting a significant influence on a substantial portion of the population. Notably, a leading contributor to morbidity and mortality in this context is cardiovascular disease (CVD). Intriguingly, individuals with autoimmune disorders exhibit a heightened prevalence of CVD compared to the general population. The meticulous management of CV risk factors assumes paramount importance, given the current absence of a standardized solution to this perplexity. This review endeavors to address this challenge from a nutritional perspective.
Recent Findings
Emerging evidence suggests that inflammation, a common thread in autoimmune diseases, also plays a pivotal role in the pathogenesis of CVD. Nutritional interventions aimed at reducing inflammation have shown promise in mitigating cardiovascular risk.
Summary
The integration of nutritional strategies into the management plans for patients with autoimmune diseases offers a holistic approach to reducing cardiovascular risk. While conventional pharmacological treatments remain foundational, the addition of targeted dietary interventions can provide a complementary pathway to improve cardiovascular outcomes.
... The mucosal immunity of the intestine is also influenced by the diet and food-related antigens [26]. Forkhead box P3 (Foxp3) and retinoid orphan receptor (ROR)γt are transcription factors that influence polarization of T cells to either regulatory T cells (Tregs) or Th17 cells [27]. ...
Background:
The intestinal ecosystem, including epithelium, immune cells, and microbiota, are influenced by diet and timing of food consumption. The purpose of this study was to evaluate various dietary protocols after ad libitum high fat diet (HFD) consumption on intestinal morphology and mucosal immunity.
Methods:
C57BL/6 male mice were fed a 45% high fat diet (HFD) for 6 weeks and then randomized to the following protocols; (1) chow, (2) a purified high fiber diet known as the Daniel Fast (DF), HFD consumed (3) ad libitum or in a restricted manner; (4) caloric-restricted, (5) time-restricted (six hours of fasting in each 24 h), or (6) alternate-day fasting (24 h fasting every other day). Intestinal morphology and gut-associated immune parameters were investigated after 2 months on respective protocols.
Results:
Consuming a HFD resulted in shortening of the intestine and reduction in villi and crypt size. Fasting, while consuming the HFD, did not restore these parameters to the extent seen with the chow and DF diet. Goblet cell number and regulatory T cells had improved recovery with high fiber diets, not seen with the HFD irrespective of fasting.
Conclusion:
Nutritional content is a critical determinant of intestinal parameters associated with gut health.
... Пшеница, которую мы сегодня потребляем повсеместно, генетически сильно отличается от того простого зерна, которое человек ел ранее. Как и большинство современных пищевых растений, пшеница эволюционировала в ходе генно-инженерных воздействий, направленных на повышение продуктивности, урожайности, квоты питательных веществ и продолжительности хранения [2,3]. Состав зерна варьирует в зависимости от генотипа зерновых, что приводит к методологическим проблемам при исследовании пищевых аллергенов и выборе генотипа при селекции по качеству. ...
Food safety all over the world is largely dependent on production of grains that are cultivated in 60% of agricultural lands. Wheat is the main food for millions of people and one of the three most commonly cultivated grain cultures worldwide, along with corn and rice. Modern wheat is a product of gene engineering interventions aimed at increased productivity, yields, nutrient quota, and storage time, as well as immunogenic properties. However, the consumption of gluten, a proline and glutamine-rich wheat, rye and barley protein, triggers gluten-dependent disorders, such as celiac disease, wheat allergy, baker's asthma and wheat-dependent exercise-induced anaphylaxis. This group of disorders are curable provided the correct diagnosis has been made and strict lifelong gluten-free diet is implemented. Continuous patient's adherence to the gluten-free diet is associated with a number of medical and paramedical challenges, and the adherence level of the most compliant patients does not exceed 80%. The paper discuss other treatment strategies to improve the nutrition of people with gluten-sensitive disorders, in particular, the reduction grain gluten content, gluten sequestration in the gut before its digestion, prevention of gluten absorption and subsequent immune cell activation, and administration of tissue transglutaminase 2 inhibitors.
... Inappropriate activation of immune cells residing in the lymphatics to food and self-antigens can result in both acute inflammation and chronic inflammatory disorders and auto-immune disease [57]. IBD is the term commonly used to describe Crohn's disease and ulcerative colitis. ...
Targeted drug delivery to the intestinal lymphatic system has emerged as an important goal in drug development for the treatment of a number of clinical indications. These include, cancers, inflammatory disorders and infectious diseases. Following oral administration, small molecule drugs with specific physiochemical properties, have been shown to associate with lipoproteins called chylomicrons in the enterocytes of the small intestine. Chylomicron associated drugs then bypass hepatic uptake and enter the mesenteric lymph nodes (MLN). Oral coadministration of highly lipophilic small molecule drugs with lipids had subsequently been identified as an effective mechanism for delivering highly lipophilic small molecule drugs to the MLN in high concentrations. One example is Cannabidiol (CBD), which was shown to undergo lymphatic transport following oral administration with lipids and has received significant research interest for the treatment of inflammatory disorders. The overarching aim of this thesis was to determine how small molecule drugs distribute in the lymphatic system following oral delivery. More specifically, work in this thesis was divided into two main research questions; 1) where within the cellular structures of lymph nodes drugs distribute and 2) which specific individual lymph nodes can be targeted. For the purposes of this thesis, CBD was selected as a model drug, with which drug distribution in the lymphatics was investigated. Lymph nodes are comprised of distinct anatomical and function regions. The flow of lymph and lymph bourn molecules within lymph nodes is highly regulated. This aids appropriate immune surveillance. Based on this, it was hypothesised that small molecule drugs, such as CBD, may preferentially distribute in some regions of lymph nodes more than others. Mass spectrometry imaging (MSI) has been adapted over recent years to enable detailed tissue analysis. However, so far, MSI had only been applied to image drug distribution in tissues at mg/g concentrations, following topical administration. A method using a hybrid instrument comprising a time-of-flight analyser with an Orbitrap mass spectrometer, termed OrbiSIMS, to image CBD in MLN tissues at in vivo relevant concentrations was described. The estimated limit of sensitivity for the [M-H]- ion of CBD was in the range of 5-10 µg/g, which correlates to concentrations observed in vivo. Subsequently, OrbiSIMS imaging of sectioned MLNs from rats dosed orally with CBD in sesame oil was performed. Critically, CBD could be visualised primarily in the paracortex of the lymph node, which is known to be dominated by T-cells. This work represents the first evidence of label- and matrix-free imaging of drug distribution at the time of peak absorption into intestinal lymph nodes. Although imaging reproducibility and drug-cell interaction would need to be confirmed, this work may therefore support the hypothesis that CBD exerts its immunoregulatory effects in vivo primarily through T-cells. This is likely aided through cross- talk with conduit resident dendritic cells of the paracortex. Assuming other lipophilic small molecule drugs are also distributed in the paracortex, this finding could have wider clinical implications for diseases where T-cells are primarily involved. The MLNs are a large group of lymph nodes which drain lymph from the small intestine. Lipid uptake is understood to vary across the length of the small intestine. Based on this it was also hypothesised that individual nodes within the chain of MLNs may be exposed to differing concentrations of orally administered drugs entering the lymphatics via chylomicron association. In addition, following collection in the MLN, lymph is understood to drain into the retroperitoneal lymph nodes (RPLN) before entering the cisterna chyli and ultimately systemic circulation. Subsequently, it was also hypothesised that the RPLN may also be exposed to drugs undergoing lymphatic transport. The second major research question of this project, relating to which specific lymph nodes can be targeted following oral delivery and to what extent, was addressed using two main approaches. Firstly, in a rat model, CBD concentrations in individual lymph nodes from animals dosed orally with CBD were determined using high-performance liquid chromatography (HPLC). It was shown that, at the time of peak absorption, drug concentrations were significantly higher in the upper middle nodes of the mesenteric chain and distribution was therefore non-uniform within the MLNs. Another key finding was that the RPLN could also be targeted. Moreover, at time points after 2 hours post administration, at which absorption into the MLN reaches a peak, concentrations were similar in RPLN and MLN. Concentrations in RPLN were also more than 20 times higher than previously reported in plasma, indicating lymphatic transport of drug rather than redistribution from systemic circulation. This widespread delivery of drugs to multiple groups of lymph nodes following oral administration had not previously been demonstrated and indicates the clinical potential of oral drug administration for diseases where lymphatic involvement is widespread. This includes inflammatory diseases and cancer metastases. Finally, the question of which lymph nodes can be targeted using orally delivered lipid-based formulations was assessed in a human setting. It was hypothesised that MRI may be used to identify changes in lymph nodes as dietary lipids are absorbed. Subsequently, these changes could be used to map lipid uptake into individual lymph nodes and thus which nodes may be exposed to chylomicron associated drugs. An assessment of the feasibility of a label free, non-invasive MRI method for this indication was also performed. Repeated identification of individual lymph nodes at baseline and following a high fat meal was achieved in 3 healthy human volunteers. In all participants, the apparent diffusion coefficient (ADC) of lymph nodes was shown to increase following a high fat meal. The timings of these changes correlated with expected lymphatic lipid uptake. Based on this, increases in ADC may represent a novel measurable indicator for lipid tracking in the intestinal lymphatics in future work. In conclusion, the work in this thesis has provided preliminary evidence that the paracortex is the predominant target following oral delivery of small molecule drugs. In addition, novel data support the notion that the MLN are differentially exposed to lymph associated drugs and that the RPLN may also be targeted.
... In support hereof, a large RCT that compared weaning to extensively hydrolyzed formula versus cows milk-based formula failed to find beneficial effects [34]. On the other hand, proteins found in cow's milk contain amino acids with similar structure to human tissues, including the pancreatic islets, and they may enter the circulatory system undigested and trigger autoimmune response [35]. This might explain the observed associations between cow's milk consumption in childhood and risk of T1D and IA. ...
Background
Numerous dietary components have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D); however, no associations are firmly established. This systematic review and meta-analysis aimed to synthesize current knowledge on diet and incidence of IA and T1D.
Methods
Literature search was performed in Medline, Embase, and Cochrane Library, from inception until October 2020. Eligible studies had IA or T1D as outcome; any dietary exposure; case-control, cohort, or randomized controlled trial design; and hazard, risk, or odds ratios as measures of association. Summary relative risks (RR) and 95% confidence intervals (CI) were estimated with random-effects models. Certainty of evidence was assessed with GRADE. PROSPERO registration number: CRD42020212505.
Findings
Among 5935 identified records, 96 were eligible, and pooled estimates could be produced for 26 dietary factors. Evidence with moderate/high certainty indicated lower risk of T1D in relation to longer (≥6-12 vs <6-12 months, RR: 0⋅39, CI: 0⋅26-0⋅58, I²=43%) and exclusive (≥2-3 vs <2-3 months, RR: 0⋅68, CI: 0⋅58-0⋅80, I²=0%) breastfeeding, later introduction to gluten (3-6 vs <3-5 months, RR: 0⋅36, CI: 0⋅17-0⋅75, I²=0%), cow's milk (≥2-3 vs <2-3 months, RR: 0⋅69, CI: 0⋅59-0⋅81, I²=0%), and fruit (4-6 vs <4-5 months, RR: 0⋅47, CI: 0⋅25-0⋅86, I²=0%). Higher childhood intake of cow's milk was associated with increased risk of both IA (per 2-3 portions/day, RR: 1⋅25, CI: 1⋅06-1⋅47, I²=0%) and T1D (≥2-3 vs <2-3 glasses/day, RR: 1⋅81, CI: 1⋅12-2⋅91, I²=31%). For the remaining dietary factors investigated, there was no association, or the evidence was of low certainty.
Interpretation
This study suggests that breastfeeding and late introduction of gluten, fruit, and cow's milk may reduce the risk of T1D, whereas high childhood cow's milk intake may increase it.
Funding
Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare (FORTE), Novo Nordisk Foundation, and Swedish Diabetes Foundation.
... The highest cross-reactivity was between anti-wheat antibodies, while the CD associated anti-supra-molecule alpha gliadin 33mer reacted moderately to ENO [101]. The molecular mimicry between food specific antigens and tissue components based on the cross-reactivity of their corresponding antibodies associated with autoimmunity induction was recently reported [102,103]. Zooming on ENO1 and CD, the topic of specific anti food antibodies reacting to ENO1 in CD patients should further be explored. The fact that gluten might be involved in neurodegeneration [104] adds a new potential pathophysiological mechanism relaying the enolases to extraintestinal manifestations of CD. ...
Celiac disease is a life-long intestinal autoimmune disease, characterized by the gluten intolerance and chronic enteric inflammation. Traditionally presented by intestinal manifestations, however, a shift toward extra intestinal presentation is taking place. One of the affected organs is the nervous systems presented by neuropsychiatric manifestations, hence the mechanism and pathways are not clear. The presence of neuronal and alpha-enolases and their corresponding antibodies were noticed in the mucosa and serum of celiac disease patients, as well as in other various autoimmune diseases with psycho-neurological manifestations. The aims of the present review are to screen the literature on different isoforms of enolase, mainly alpha enolase, and their specific antibodies and to suggest their potential pathophysiological mechanisms relaying the enolases to intestinal or extraintestinal celiac disease manifestations. The shared aspects between the enolases and celiac disease and the cross-talks between alpha-enolase and tissue transglutaminase suggest new potential pathophysiological mechanisms that might drive celiac disease evolvement.
... Due to molecular mimicry of food items sharing the sequence homology with human tissue can induce the autoimmune disorder. [29] Due to lack of absorption and improper intake of food which ultimately weakens the immune system in older adults have been identified to be more prone to infections. Micronutrients deficiencies have been identified in deterioration of immunity. ...
The basic concept of immunity is well explained under the heading Vyadhi-kshamatva in classical texts of Ayurveda. A clear and comprehensive understanding of the relationship between immunity and lifestyle such as daily activities, seasonal regimens, diet, emotional factors, and psychological factors is documented in ancient literature. According to Ayurveda, the most important contributing factors for the normal immune functioning of the body include Agni (digestive factors), Ahara (food), Nidra (sleep), Vyayama (physical activity/exercise), Satva (mental stability), and Rasayana (rejuvenators). In the present work, these factors influencing immunity were compiled from classical texts of Ayurveda and presented systematically with the help of published scientific literature. It is observed that good immunity in an individual will be due to effect of active and healthy functioning of the digestive system. It depends mainly on the type of food consumed. Higher diet quality is associated with the positive health of the body. Quality diet, required quantity and balanced food, is the base for the proper digestion and in turn for the development of a strong immune system. Exercises improve metabolic health which in turn provides a good immune system. Even sleep affects the immune system. Good sleep provides strong immune responses; it results in the formation of antibodies which along with white blood cells cellular immune system of body and fight against the disease. A significant relationship is also reported between mental resilience and perceived immune functioning and health. Psychological well-being also can increase living comfort. Rasayana provides a defense mechanism against diseases ( Vyadhi ) in the body. Proper understanding and application of these concepts in clinical practice can be a preventive strategy for a number of diseases.
... Studies have shown that resveratrol can reduce intestinal damage and improve the intestinal barrier integrit (Sandoval-Ramírez et al. 2020). The small intestine epithelium, as a medium for the internal and external environment of the intestine and an important part of the body's immune barrier, has a variety of biological functions, such as digestion, absorption, and secretion (Allaire et al. 2018;Vojdani et al. 2020). Resveratrol is not easily absorbed from the gut it is likely that it may act on endocannabinoid and light, odor, and taste receptors located in the gut, which, in turn, convey their messages to the various organs via vagus nerve (Repossi et al. 2020). ...
Resveratrol has a variety of biological functions, however, a limited number of studies have assessed its interaction with cell surface receptors. In this study, a sandwich-type rat small intestine tissue sensor (RSIT-sensor) was fabricated to detect the response current from receptor stimulation by different resveratrol concentrations via electrochemical workstation. The results showed that with detection limit of 1 × 10–13 mol/L, the maximum rate of change of the response current was found at the concentration of 8.5 × 10–12 mol/L, indicating that the resveratrol-related receptor was saturated. With comparing the response values of prepared biosensor and bare electrode with resveratrol, it can be concluded that the response value of small intestinal cells to resveratrol has obviously been amplified by the intracellular signal transmission system, and its magnification was about 100 times. In the current research, for the first time, kinetics of the interaction between resveratrol and its receptors and the transmission of signals to the body could be quantitatively measured by a biosensor. Our findings may provide new ideas for resveratrol-related receptor analysis, separation and purification, signal transmission, and evaluation of biological function.
... Metabolites of food and other exogenous substances in the gastrointestinal tract not only provide energy and substrates but also play important roles in the regulation of the immune, nervous, and endocrine systems [4,5]. Indeed, gut metabolites have been recognized as key bridges of the gut-liver, gut-lung and gut-brain axes [6e8]. ...
Although SARS-CoV-2 can invade the intestine, though its effect on digestion and absorption is not fully understood. In the present study, 56 COVID-19 patients and 47 age- and sex-matched healthy subjects were divided into a discovery cohort and a validation cohort. Blood, faeces and clinical information were collected from the patients in the hospital and at discharge. The faecal metabolome was analysed using gas chromatography-mass spectrometry, and Spearman's correlation analyses of clinical features, the serum metabolome, and the faecal micro- and mycobiota were conducted. The results showed that, the faeces of COVID-19 patients were enriched with important nutrients that should be metabolized or absorbed, such as sucrose and 2-palmitoyl-glycerol; diet-related components that cannot be synthesized by humans, such as 1,5-anhydroglucitol and D-pinitol; and harmful metabolites, such as oxalate, were also detected. In contrast, purine metabolites such as deoxyinosine and hypoxanthine, low-water-soluble long-chain fatty alcohols/acids such as behenic acid, compounds rarely occurring in nature such as D-allose and D-arabinose, and microbe-related compounds such as 2,4-di-tert-butylphenol were depleted in the faeces of COVID-19 patients. Moreover, these metabolites significantly correlated with altered serum metabolites such as oxalate and gut microbesincluding Ruminococcaceae, Actinomyces, Sphingomonas and Aspergillus. Although levels of several faecal metabolites, such as sucrose, 1,5-anhydroglucitol and D-pinitol, of discharged patients were not different from those of healthy controls (HCs), those of oxalate and 2-palmitoyl-glycerol did differ. Therefore, alterations in the faecal metabolome of COVID-19 patients may reflect malnutrition and intestinal inflammation and warrant greater attention. The results of present study provide new insights into the pathogenesis and treatment of COVID-19.
The chapter delves into the intricate relationship between the immune system and food in the context of autoimmune diseases. Recent research has shown that dietary components, such as gluten, dairy proteins, and certain food additives, can cause abnormal immune responses in vulnerable individuals. Symbiosis is linked to the deterioration of immunological tolerance and the emergence of autoimmune disorders, with the gut microbiota acting as a major mediator in the immunomodulatory effects of food. The chapter also discusses molecular imitation, where food antigens can trigger cross-reactive immune responses and prolong autoimmune inflammation by physically resembling self-antigens. Current research has clarified how epigenetic changes mediate the effect of food exposures on immune function, offering new directions for therapeutic intervention. The chapter emphasizes the need for tailored strategies based on immunological, microbiological, and genetic profiling to develop customized dietary interventions and targeted therapeutic strategies for autoimmune disorders.
Gluten has multiple harmful effects that compromise human health, not only in gluten-dependent diseases but also in non-gluten-affected chronic inflammatory conditions. After consumption, the indigestible gluten peptides are modified by luminal microbial transglutaminase or transported through the gut epithelium to interact with the highly populated mucosal immune cells. As a disruptor of gut permeability, gluten peptides compromise tight junction integrity, allowing foreign immunogenic molecules to reach internal compartments. Gliadin peptides are distributed systemically to remote organs, where they encounter endogenous tissue transglutaminase. Following post-translational deamidation or transamidation, the peptides become immunogenic and pro-inflammatory, inducing organ dysfunction and pathology. Cross-reactivity and sequence homology between gluten/gliadin peptides and human epitopes may contribute to molecular mimicry in autoimmunity induction. A gluten-free diet can prevent these phenomena through various mechanisms. As proof of concept, gluten withdrawal alleviates disease activity in chronic inflammatory, metabolic, and autoimmune conditions, and even in neurodegeneration. We recommend combining the gluten-free and Mediterranean diets to leverage the advantages of both. Before recommending gluten withdrawal for non-gluten-dependent conditions, patients should be asked about gut symptomatology and screened for celiac-associated antibodies. The current list of gluten-induced diseases includes celiac disease, dermatitis herpetiformis, gluten ataxia, gluten allergy, and non-celiac gluten sensitivity. In view of gluten being a universal pro-inflammatory molecule, other non-celiac autoinflammatory and neurodegenerative conditions should be investigated for potential gluten avoidance.
The long-term value of efficient antigen discovery includes gaining insights into the variety of potential cancer neoantigens, effective vaccines lacking adverse effects, and adaptive immune receptor (IR) targets for blocking adaptive IR-antigen interactions in autoimmunity. While the preceding goals have been partially addressed via big data approaches to HLA (human leukocyte antigen)-epitope binding, there has been little such progress in the big data setting for adaptive IR-epitope binding. This delay in progress for the latter is likely due to, among other things, the much more complicated adaptive IR repertoire in an individual compared to individual HLA alleles. Thus, results described here represent the application of an algorithm for efficient assessment of immunoglobulin heavy chain complementarity determining region-3 (IGH CDR3)-gliadin epitope interactions, with a focus on epitopes known to be associated with an immune response in celiac disease. The hydrophobic, chemical complementarity between celiac case IGH CDR3s and known celiac epitopes was found to be greater in comparison to the hydrophobic, chemical complementarity between the same celiac case IGH CDR3s and a series of control epitopes. Thus, the approaches indicated here likely offer guidance for the development of conveniently applied algorithms for antigen verification and discovery.
Much of nutrition research has been conventionally based on the use of simplistic in vitro systems or animal models, which have been extensively employed in an effort to better understand the relationships between diet and complex diseases as well as to evaluate food safety. Although these models have undeniably contributed to increase our mechanistic understanding of basic biological processes, they do not adequately model complex human physiopathological phenomena, creating concerns about the translatability to humans. During the last decade, extraordinary advancement in stem cell culturing, three‐dimensional cell cultures, sequencing technologies, and computer science has occurred, which has originated a wealth of novel human‐based and more physiologically relevant tools. These tools, also known as “new approach methodologies,” which comprise patient‐derived organoids, organs‐on‐chip, multi‐omics approach, along with computational models and analysis, represent innovative and exciting tools to forward nutrition research from a human‐biology‐oriented perspective. After considering some shortcomings of conventional in vitro and vivo approaches, here we describe the main novel available and emerging tools that are appropriate for designing a more human‐relevant nutrition research. Our aim is to encourage discussion on the opportunity to explore innovative paths in nutrition research and to promote a paradigm‐change toward a more human biology‐focused approach to better understand human nutritional pathophysiology, to evaluate novel food products, and to develop more effective targeted preventive or therapeutic strategies while helping in reducing the number and replacing animals employed in nutrition research.
Irritable bowel syndrome (IBS), one of the most prevalent functional gastrointestinal disorders, is characterized by recurrent abdominal pain and abnormal defecation habits, resulting in a severe healthcare burden worldwide. The pathophysiological mechanisms of IBS are multi‐factorially involved, including food antigens, visceral hypersensitivity reactions, and the brain–gut axis. Numerous studies have found that gut microbiota and intestinal mucosal immunity play an important role in the development of IBS in crosstalk with multiple mechanisms. Therefore, based on existing evidence, this paper elaborates that the damage and activation of intestinal mucosal immunity and the disturbance of gut microbiota are closely related to the progression of IBS. Combined with the application prospect, it also provides references for further in‐depth exploration and clinical practice.
Tolerance to food antigens is essential for body’s sustainable development under constant antigenic load. Specific IgG against food antigens have been extensively studied in the literature over the recent years. The presence of those associated with various disorders and introduction of elimination diets for certain food products result in good treatment outcomes related not only to the gastrointestinal tract. Investigation of the impact of the long-term IgG-mediated hypersensitivity to food antigens associated with the increased blood-brain barrier permeability is also relevant when studying pathogenesis of the central nervous system disorders. However, identification of specific IgG in the generally healthy people having no history of allergy or inflammation currently provides no clear understanding of their nature and functional significance. Specific IgG are of great interest in terms of predicting the development of functional disorders, remission and treatment of disorders, changes in susceptibility to food antigens at certain age. The results of specific IgG studies are equivocal, which confirms the need to study their structure, epitopes capable of activating autoimmune processes considering the combined effects of medication, environmental conditions and social living conditions. The paper provides the analysis of the currently available research focused on studying specific IgG against food antigens. The data on identification of specific IgG in individuals with various disorders are provided, as well as the gender-related and age-related differences in antibody detection, the relationship between the antibody levels and the rate of food product consumption.
The microbiome plays a crucial role in integrating environmental factors into host physiology, potentially linking it to autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. All autoimmune liver diseases are associated with reduced diversity of the gut microbiome and altered abundance of certain bacteria. However, the relationship between the microbiome and liver diseases is bidirectional and varies over the course of the disease. This makes it challenging to dissect whether such changes in the microbiome are initiating or driving factors in autoimmune liver diseases, secondary consequences of disease and/or pharmacological intervention, or alterations that modify the clinical course that patients experience. Potential mechanisms include the presence of pathobionts, disease-modifying microbial metabolites, and more nonspecific reduced gut barrier function, and it is highly likely that the effect of these changes is during the progression of the disease. Recurrent disease after liver transplantation is a major clinical challenge and a common denominator in these conditions, which could also represent a window to disease mechanisms of the gut-liver axis. Herein, we propose future research priorities, which should involve clinical trials, extensive molecular phenotyping at high resolution, and experimental studies in model systems. Overall, autoimmune liver diseases are characterized by an altered microbiome, and interventions targeting these changes hold promise for improving clinical care based on the emerging field of microbiota medicine.
Parkinson’s disease (PD) is a complex progressive neurodegenerative disease associated with aging. Its main pathological feature is the degeneration and loss of dopaminergic neurons related to the misfolding and aggregation of α-synuclein. The pathogenesis of PD has not yet been fully elucidated, and its occurrence and development process are closely related to the microbiota-gut-brain axis. Dysregulation of intestinal microbiota may promote the damage of the intestinal epithelial barrier, intestinal inflammation, and the upward diffusion of phosphorylated α-synuclein from the enteric nervous system (ENS) to the brain in susceptible individuals and further lead to gastrointestinal dysfunction, neuroinflammation, and neurodegeneration of the central nervous system (CNS) through the disordered microbiota-gut-brain axis. The present review aimed to summarize recent advancements in studies focusing on the role of the microbiota-gut-brain axis in the pathogenesis of PD, especially the mechanism of intestinal microbiome dysregulation, intestinal inflammation, and gastrointestinal dysfunction in PD. Maintaining or restoring homeostasis in the gut microenvironment by targeting the gut microbiome may provide future direction for the development of new biomarkers for early diagnosis of PD and therapeutic strategies to slow disease progression.
It has been shown that SARS-CoV-2 shares homology and cross-reacts with vaccines, other viruses, common bacteria and many human tissues. We were inspired by these findings, firstly, to investigate the reaction of SARS-CoV-2 monoclonal antibody with different pathogens and vaccines, particularly DTaP. Additionally, since our earlier studies have shown immune reactivity by antibodies made against pathogens and autoantigens towards different food antigens, we also studied cross-reaction between SARS-CoV-2 and common foods. For this, we reacted monoclonal and polyclonal antibodies against SARS-CoV-2 spike protein and nucleoprotein with 15 different bacterial and viral antigens and 2 different vaccines, BCG and DTaP, as well as with 180 different food peptides and proteins. The strongest reaction by SARS-CoV-2 antibodies were with DTaP vaccine antigen, E. faecalis, roasted almond, broccoli, soy, cashew, α+β casein and milk, pork, rice endochitinase, pineapple bromelain, and lentil lectin. Because the immune system tends to form immune responses towards the original version of an antigen that it has encountered, this cross-reactivity may have its advantages with regards to immunity against SARS-CoV-2, where the SARS-CoV-2 virus may elicit a “remembered” immune response because of its structural similarity to a pathogen or food antigen to which the immune system was previously exposed. Our findings indicate that cross-reactivity elicited by DTaP vaccines in combination with common herpesviruses, bacteria that are part of our normal flora such as E. faecalis, and foods that we consume on a daily basis should be investigated for possible cross-protection against COVID-19. Additional experiments would be needed to clarify whether or not this cross-protection is due to cross-reactive antibodies or long-term memory T and B cells in the blood.
Autoimmune diseases affect 5–9% of the world’s population. It is now known that genetics play a relatively small part in the pathophysiology of autoimmune disorders in general, and that environmental factors have a greater role. In this review, we examine the role of the exposome, an individual’s lifetime exposure to external and internal factors, in the pathophysiology of autoimmune diseases. The most common of these environmental factors are toxic chemicals, food/diet, and infections. Toxic chemicals are in our food, drink, common products, the air, and even the land we walk on. Toxic chemicals can directly damage self-tissue and cause the release of autoantigens, or can bind to human tissue antigens and form neoantigens, which can provoke autoimmune response leading to autoimmunity. Other types of autoimmune responses can also be induced by toxic chemicals through various effects at the cellular and biochemical levels. The food we eat every day commonly has colorants, preservatives, or packaging-related chemical contamination. The food itself may be antigenic for susceptible individuals. The most common mechanism for food-related autoimmunity is molecular mimicry, in which the food’s molecular structure bears a similarity with the structure of one or more self-tissues. The solution is to detect the trigger, remove it from the environment or diet, then repair the damage to the individual’s body and health.
Context:
A gluten-free diet (GFD) is the recommended treatment for gluten-dependent disease. In addition, gluten withdrawal is popular and occasionally is suggested as a treatment for other autoimmune diseases (ADs).
Objective:
The current systematic review summarizes those entities and discusses the logic behind using a GFD in classical non-gluten-dependentADs.
Data sources:
A search for medical articles in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo published between 1960 and 2020 was conducted, using the key words for various ADs and GFDs.
Data exxtraction:
Eight-three articles were included in the systematic review (using PRISMA guidelines).
Data analysis:
Reduction in symptoms of ADs after observance of a GFD was observed in 911 out of 1408 patients (64.7%) and in 66 out of the 83 selected studies (79.5%). The age of the patients ranged from 9 months to 69 years. The duration of the GFD varied from 1 month to 9 years. A GFD can suppress several harmful intraluminal intestinal events. Potential mechanisms and pathways for the action of GFD in the gut - remote organs' axis have been suggested.
Conclusion:
A GFD might represent a novel nutritional therapeutic strategy for classical non-gluten-dependent autoimmune conditions.
Since the start of the “modern era”, characterized by the increase in urbanization, a progressive attention to hygiene and autoimmune conditions has considerably grown. Although these diseases are often multifactorial, it was demonstrated that environment factors such as pollution, diet and lifestyles may play a crucial role together with genetic signature. Our research, based on the newest and most significant literature of this topic, highlights that the progressive depletion of microbes and parasites due to increased socioeconomic improvement, may lead to a derangement of immunoregulatory mechanisms. Moreover, special attention was given to the complex interplay between microbial agents, as gut microbiome, diet and vitamin D supplementation with the aim of identifying promising future therapeutic options. In conclusion, autoimmunity cannot be limited to hygiene-hypothesis, but from the point of view of precision medicine, this theory represents a fundamental element together with the study of genomics, the microbiome and proteomics, in order to understand the complex functioning of the immune system.
Group A Streptococcus (GAS) is a bacteria that manifests itself in a variety of diseases, from strep throat to neuroautoimmune psychiatric disorders, such as pediatric acute-onset neuropsychiatric syndrome (PANS) or pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). Dopamine 1 and dopamine 2 (D1 and D2) receptors and asialoganglioside (GM1) are used commercially as biomarkers in assessing neuropsychiatric diseases. However, some studies have found these antibodies in healthy subjects. Since previous research has shown cross-reactivity between foods and tissue antigens, we sought to determine whether or not cross-reactivity exists between GAS, D1, D2 receptors, GM1 and commonly consumed foods, and whether the presence of food antibodies may be responsible for the false positivity. We reacted antibodies against GAS, D1, D2 receptors, and GM1 with the antigens of 180 foods using the ELISA method. Anti-GAS antibodies had significant cross-reactivity with 17/180 foods, anti-D1 antibody with 26/180 foods, anti-D2 antibody with 20/180 foods, and anti-GM1 antibody with 47/180 foods. Our results indicate that the presence in blood of antibodies to GAS, D1, D2 and GM1 that cross-react with food antigens may not only interfere with the accurate measurement of these biomarkers of PANS and PANDAS, but show that these patients with these antibodies in their blood may not have these conditions at all, but just have innocuous antibodies against food antigens.
Autoimmunity is on the rise around the globe. Diet has been proposed as a risk factor for autoimmunity and shown to modulate the severity of several autoimmune disorders. Yet, the interaction between diet and autoimmunity in humans remains largely unstudied. Here, we systematically interrogated commonly consumed animals and plants for peptide epitopes previously implicated in human autoimmune disease. A total of fourteen species investigated could be divided into three broad categories regarding their content in human autoimmune epitopes, which we represented using a new metric, the Gershteyn-Ferreira index (GF index). Strikingly, pig contains a disproportionately high number of unique autoimmune epitopes compared to all other species analyzed. This work uncovers a potential new link between pork consumption and autoimmunity in humans and lays the foundation for future studies on the impact of diet on the pathogenesis and progression of autoimmune disorders.
Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by a broad spectrum of clinical and serological manifestations. This may reflect a complex and multifactorial etiology involving several identified genetic and environmental factors, though not explaining the full risk of SLE. Established SLE risk genotypes are either very rare or with modest effect sizes and twin studies indicate that other factors besides genetics must be operative in SLE etiology. The exposome comprises the cumulative environmental influences on an individual and associated biological responses through the lifespan. It has been demonstrated that exposure to silica, smoking and exogenous hormones candidate as environmental risk factors in SLE, while alcohol consumption seems to be protective. Very few studies have investigated potential gene-environment interactions to determine if some of the unexplained SLE risk is attributable hereto. Even less have focused on interactions between specific risk genotypes and environmental exposures relevant to SLE pathogenesis. Cohort and case-control studies may provide data to suggest such biological interactions and various statistical measures of interaction can indicate the magnitude of such. However, such studies do often have very large sample-size requirements and we suggest that the rarity of SLE to some extent can be compensated by increasing the ratio of controls. This review summarizes the current body of knowledge on gene-environment interactions in SLE. We argue for the prioritization of studies that comprise the increasing details available of the genome and exposome relevant to SLE as they have the potential to disclose new aspects of SLE pathogenesis including phenotype heterogeneity.
Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus (EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.
The enzyme microbial transglutaminase is heavily used in the food processing industries to ameliorate food qualities and elongate the products' shelf life. As a protein's glue, it cross-links gliadin peptides, creating neo-complexes that are immunogenic and potentially pathogenic to celiac disease communities. Even lacking sequence identity, it imitates functionally the endogenous tissue transglutaminase, known to be the autoantigen of celiac disease and representing an undisputable key player in celiac disease initiation and progress. The present review expend on the enzyme characteristics, exogenous intestinal sources, its cross-linking avidity to gluten or gliadin, turning naïve protein to immunogenic ones. Several observation on microbial transglutaminase cross linked complexes immunogenicity in celiac patients are reviewed and its pathogenicity is summarized. Warnings on its potential risks for the gluten dependent conditions are highlighted. When substantiated, it might represent a new environmental factor of celiac disease genesis. It is hoped that the presented knowledge will encourage further research to explore the mechanism and the pathogenic pathways taken by the gliadin cross linked enzyme in driving celiac disease.
Objective:
To present the evidence for nutritional lifestyle changes recommended for gout patients; an explicit focus will be on the evidence for weight loss in overweight gout patients based on a recent systematic review and to describe methodological details for a coming weight loss trial.
Methods:
We did a pragmatic but systematic search in MEDLINE for current guidelines that had made an attempt to make nutritional recommendations for gout. The quality of the evidence for the nutritional recommendations was evaluated based on the guidelines' own ratings and converted into a common simple version based on the GRADE system. The recently published systematic review on weight loss for gout, was based on six databases from which longitudinal studies that had quantified the effects following weight loss were included. The internal validity was assessed with the ROBINS-I tool and the quality of the evidence was assessed with the GRADE approach. Based on the results of the systematic review, a trial was designed, adhering to the principles of evidence based research.
Results:
We included 17 guidelines. Most guidelines recommend avoiding or limiting alcohol intake (15; i.e. 88%), lose weight if relevant (12; 71%), and reduce fructose intake (11; 65%). The majority of the evidence for the nutritional recommendations was rated Moderate/Low or Very Low quality. Our recent systematic review on weight loss included 10 studies and found that the available evidence indicates beneficial effects of weight loss for overweight and obese gout patients, but the evidence is of low to moderate quality. As a consequence, researchers from the Parker Institute are launching a randomized trial to explore the short-term effects related to a diet-induced weight loss in obese gout patients.
Conclusions:
The nutritional recommendations for gout are generally based on low quality evidence. In terms of weight loss as a management strategy, the available evidence is in favor of weight loss for overweight/obese gout patients. However, since the current evidence consists of only a few studies (mostly observational) of low methodological quality, the Parker Institute are now initiating a rigorous exploratory randomized trial. Similar efforts are needed for other nutritional management strategies for gout.
The earliest autoantibodies in lupus are directed against the RNA binding autoantigen Ro60, but the triggers against this evolutionarily conserved antigen remain elusive. We identified Ro60 orthologs in a subset of human skin, oral, and gut commensal bacterial species and confirmed the presence of these orthologs in patients with lupus and healthy controls. Thus, we hypothesized that commensal Ro60 orthologs may trigger autoimmunity via cross-reactivity in genetically susceptible individuals. Sera from human anti-Ro60-positive lupus patients immunoprecipi-tated commensal Ro60 ribonucleoproteins. Human Ro60 autoantigen-specific CD4 memory T cell clones from lupus patients were activated by skin and mucosal Ro60-containing bacteria, supporting T cell cross-reactivity in humans. Further, germ-free mice spontaneously initiated anti-human Ro60 T and B cell responses and developed glomerular immune complex deposits after monocolonization with a Ro60 ortholog-containing gut commensal, linking anti-Ro60 commensal responses in vivo with the production of human Ro60 autoantibodies and signs of autoimmunity. Together, these data support that colonization with autoantigen ortholog-producing commensal species may initiate and sustain chronic autoimmunity in genetically predisposed individuals. The concept of commensal ortholog cross-reactivity may apply more broadly to autoimmune diseases and lead to novel treatment approaches aimed at defined commensal species.
Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity.
Significance
Studies using experimental models have indicated that multiple sclerosis (MS)-like disease can be triggered in the gut following interactions of brain autoimmune T lymphocytes with local microbiota. Here we studied the gut microbiota from monozygotic human twin pairs discordant for multiple sclerosis. When we transferred human-derived microbiota into transgenic mice expressing a myelin autoantigen-specific T cell receptor, we found that gut microbiota from multiple sclerosis-affected twins induced CNS-specific autoimmunity at a higher incidence than microbiota from healthy co-twins. Our results offer functional evidence that human microbiome components contribute to CNS-specific autoimmunity.
Many hypothyroid and autoimmune thyroid patients experience reactions with specific foods. Additionally, food interactions may play a role in a subset of individuals who have difficulty finding a suitable thyroid hormone dosage. Our study was designed to investigate the potential role of dietary protein immune reactivity with thyroid hormones and thyroid axis target sites. We identified immune reactivity between dietary proteins and target sites on the thyroid axis that includes thyroid hormones, thyroid receptors, enzymes, and transport proteins. We also measured immune reactivity of either target specific monoclonal or polyclonal antibodies for thyroid-stimulating hormone (TSH) receptor, 5′deiodinase, thyroid peroxidase, thyroglobulin, thyroxine-binding globulin, thyroxine, and triiodothyronine against 204 purified dietary proteins commonly consumed in cooked and raw forms. Dietary protein determinants included unmodified (raw) and modified (cooked and roasted) foods, herbs, spices, food gums, brewed beverages, and additives. There were no dietary protein immune reactions with TSH receptor, thyroid peroxidase, and thyroxine-binding globulin. However, specific antigen-antibody immune reactivity was identified with several purified food proteins with triiodothyronine, thyroxine, thyroglobulin, and 5′deiodinase. Laboratory analysis of immunological cross-reactivity between thyroid target sites and dietary proteins is the initial step necessary in determining whether dietary proteins may play a potential immunoreactive role in autoimmune thyroid disease.
Dietary management of autoimmune diabetes includes low glycemic foods classified from the glycemic index, but it does not consider the role that immunoreactive foods may play with the immunological etiology of the disease. We measured the reactivity of either monoclonal or polyclonal affinity-purified antibodies to insulin, insulin receptor alpha, insulin receptor beta, zinc transporter 8 (ZnT8), tyrosine phosphatase-based islet antigen 2 (IA2), and glutamic acid decarboxylase (GAD) 65 and 67 against 204 dietary proteins that are commonly consumed. Dietary protein determinants included unmodified (raw) and modified (cooked and roasted) foods, herbs, spices, food gums, brewed beverages, and additives. There was no immune reactivity between insulin or insulin receptor beta and dietary proteins. However, we identified strong to moderate immunological reactivity with antibodies against insulin receptor alpha, ZnT8, IA2, GAD-65, and GAD-67 with several dietary proteins. We also identified 49 dietary proteins found in foods classified as low glycemic foods with immune reactivity to autoimmune target sites. Laboratory analysis of immunological cross-reactivity between pancreas target sites and dietary proteins is the initial step necessary in determining whether dietary proteins may play a potential immunoreactive role in autoimmune diabetes.
The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a “leaky gut.” In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease. Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer term studies are still required. Conversely, pathogenic bacteria that can facilitate a leaky gut and induce autoimmune symptoms can be ameliorated with the use of antibiotic treatment. Therefore, it is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals.
Usage of the herbicide glyphosate on core crops in the USA has increased exponentially over the past two decades, in step with the exponential increase in autoimmune diseases including autism, multiple sclerosis, inflammatory bowel disease, type 1 diabetes, coeliac disease, neuromyelitis optica and many others. In this paper we explain how glyphosate, acting as a non-coding amino acid analogue of glycine, could erroneously be integrated with or incorporated into protein synthesis in place of glycine, producing a defective product that resists proteolysis. Whether produced by a microbe or present in a food source, such a peptide could lead to autoimmune disease through molecular mimicry. We discuss similarities in other naturally produced disease-causing amino acid analogues, such as the herbicide glufosinate and the insecticide L-canavanine, and provide multiple examples of glycine-containing short peptides linked to autoimmune disease, particularly with respect to multiple sclerosis. Most disturbing is the presence of glyphosate in many popular vaccines including the measles, mumps and rubella (MMR) vaccine, which we have verified here for the first time. Contamination may come through bovine protein, bovine calf serum, bovine casein, egg protein and/or gelatin. Gelatin sourced from the skin and bones of pigs and cattle given glyphosate-contaminated feed contains the herbicide. Collagen, the principal component of gelatin, contains very high levels of glycine, as do the digestive enzymes: pepsin, trypsin and lipase. The live measles virus could produce glyphosate-containing haemagglutinin, which might induce an autoimmune attack on myelin basic protein, commonly observed in autism. Regulatory agencies urgently need to reconsider the risks associated with the indiscriminate use of glyphosate to control weeds.
Anti-citrullinated protein antibodies are primarily associated with a progressive course in the autoimmune disease rheumatoid arthritis, a disease with a chronic and inflammatory nature. These antibodies do not appear to have any strict dependency for reactivity except from the presence of the non-genetically encoded amino acid citrulline, which is the result of a posttranslational modification, catalyzed by calcium-dependent peptidylarginine deiminase enzymes. Nevertheless, several amino acids surrounding the citrulline residue notably influence antibody reactivity, especially with a central-Cit-Gly-motif being essential for antibody reactivity. Most importantly, these antibodies have been proposed to be divided into two groups, based on their ability to recognize multiple citrullinated peptides. Thus, an “overlapping” antibody group, which appears to recognize several citrullinated peptides, and a “non-overlapping” antibody group, which only recognizes a limited number of citrullinated peptides, have been proposed. Based on these findings, we suggest that antibodies recognizing several citrullinated targets, also referred to as cross-reactive antibodies, primarily are backbone-dependent, whereas less cross-reactive antibodies primarily depend on the side chains of the amino acids comprising the epitopes for stable antibody-antigen interactions, which reduces the degree of cross-reactivity significantly. Clarifying the reactivity pattern of anti-citrullinated protein antibodies may contribute to determining their true nature of origin.
U24 is a protein found in both roseoloviruses Human Herpes Virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminus that is rich in prolines (PY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that the interaction between U24 and WW domains is important for endocytic recycling of T-cell receptors, but a cognate ligand was never identified. In this contribution, data was obtained from pull-downs, ITC, NMR and molecular dynamics simulations to show that a specific interaction exists between U24 and Nedd4 WW domains. ITC experiments were also carried out for U24 from HHV-6A phosphorylated at Thr6 (pU24-6A) and a peptide containing the PY motif from Nogo-A, a protein implicated in both the initial inflammatory and the neurodegenerative phases of multiple sclerosis (MS). The results suggest that phosphorylation of U24 from HHV-6A may be crucial for its potential role in MS.
The broadband herbicide glyphosate (N-[phosphonomethyl]-glycine) and its main metabolite aminomethylphosphonic acid (AMPA) were analyzed by GC-MS-MS in 24 h-urine samples cryo-archived by the German Environmental Specimen Bank (ESB). Samples collected in 2001, 2003, 2005, 2007, 2009, 2011, 2012, 2013, 2014, and 2015 were chosen for this retrospective analysis. All urine samples had been provided by 20 to 29 years old individuals living in Greifswald, a city in north-eastern Germany. Out of the 399 analyzed urine samples, 127 (=31.8 %) contained glyphosate concentrations at or above the limit of quantification (LOQ) of 0.1μg/L. For AMPA this was the case for 160 (=40.1 %) samples. The fraction of glyphosate levels at or above LOQ peaked in 2012 (57.5 %) and 2013 (56.4 %) after having discontinuously increased from 10.0% in 2001. Quantification rates were lower again in 2014 and 2015 with 32.5 % and 40.0 %, respectively. The overall trend for quantifiable AMPA levels was similar. Glyphosate and AMPA concentrations in urine were statistically significantly correlated (spearman rank correlations coefficient=0.506, p≤0.001). Urinary glyphosate and AMPA levels tended to be higher in males. The possible reduction in exposure since 2013 indicated by ESB data may be due to changes in glyphosate application in agricultural practice. The ESB will continue monitoring internal exposures to glyphosate and AMPA for following up the time trend, elucidating inter-individual differences, and contributing to the ongoing debate on the further regulation of glyphosate-based pesticides
Both animal model and human studies indicate that commensal bacteria may modify type 1 diabetes (T1D) development. However, the underlying mechanisms by which gut microbes could trigger or protect from diabetes are not fully understood, especially the interaction of commensal bacteria with pathogenic CD8 T cells. In this study, using islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8 T cell receptor NY8.3 transgenic nonobese diabetic mice, we demonstrated that MyD88 strongly modulates CD8(+) T cell-mediated T1D development via the gut microbiota. Some microbial protein peptides share significant homology with IGRP. Both the microbial peptide mimic of Fusobacteria and the bacteria directly activate IGRP-specific NY8.3 T cells and promote diabetes development. Thus, we provide evidence of molecular mimicry between microbial antigens and an islet autoantigen and a novel mechanism by which the diabetogenicity of CD8(+) T cells can be regulated by innate immunity and the gut microbiota.
Reported values in the literature on the number of cells in the body differ by orders of magnitude and are very seldom supported by any measurements or calculations. Here, we integrate the most up-to-date information on the number of human and bacterial cells in the body. We estimate the total number of bacteria in the 70 kg "reference man" to be 3.8·1013. For human cells, we identify the dominant role of the hematopoietic lineage to the total count (≈90%) and revise past estimates to 3.0·1013 human cells. Our analysis also updates the widely-cited 10:1 ratio, showing that the number of bacteria in the body is actually of the same order as the number of human cells, and their total mass is about 0.2 kg.
T cells target peptide combos
One of the enduring mysteries of autoimmunity is the identity of the specific proteins targeted by autoimmune T cells. Delong et al. used mass spectrometry to elucidate the peptide targets of autoimmune T cells isolated from a mouse model of type 1 diabetes. T cells targeted hybrid peptides formed by the covalent linking of a peptide derived from pro-insulin to other peptides derived from proteins found in pancreatic beta cells. T cells isolated from the pancreatic islets of two individuals with type 1 diabetes also recognized such hybrid peptides, suggesting that they may play an important role in driving disease.
Science , this issue p. 711
A huge increase in the incidence and prevalence of chronic diseases has been reported in the United
States (US) over the last 20 years. Similar increases have been seen globally. The herbicide
glyphosate was introduced in 1974 and its use is accelerating with the advent of herbicide-tolerant
genetically engineered (GE) crops. Evidence is mounting that glyphosate interferes with many
metabolic processes in plants and animals and glyphosate residues have been detected in both.
Glyphosate disrupts the endocrine system and the balance of gut bacteria, it damages DNA and is a
driver of mutations that lead to cancer.
In the present study, US government databases were searched for GE crop data, glyphosate
application data and disease epidemiological data. Correlation analyses were then performed on a
total of 22 diseases in these time-series data sets. The Pearson correlation coefficients are highly
-5
significant (< 10 ) between glyphosate applications and hypertension (R = 0.923), stroke (R = 0.925),
diabetes prevalence (R = 0.971), diabetes incidence (R = 0.935), obesity (R = 0.962), lipoprotein
metabolism disorder (R = 0.973), Alzheimer’s (R = 0.917), senile dementia (R = 0.994), Parkinson's (R
= 0.875), multiple sclerosis (R = 0.828), autism (R = 0.989), inflammatory bowel disease (R = 0.938),
intestinal infections (R = 0.974), end stage renal disease (R = 0.975), acute kidney failure (R = 0.978),
cancers of the thyroid (R = 0.988), liver (R = 0.960), bladder (R = 0.981), pancreas (R = 0.918), kidney
(R = 0.973) and myeloid leukaemia (R = 0.878).
-4
The Pearson correlation coefficients are highly significant (< 10 ) between the percentage of GE corn
and soy planted in the US and hypertension (R = 0.961), stroke (R = 0.983), diabetes prevalence (R =
0.983), diabetes incidence (R = 0.955), obesity (R = 0.962), lipoprotein metabolism disorder (R =
0.955), Alzheimer’s (R = 0.937), Parkinson's (R = 0.952), multiple sclerosis (R = 0.876), hepatitis C (R
= 0.946), end stage renal disease (R = 0.958), acute kidney failure (R = 0.967), cancers of the thyroid
(R = 0.938), liver (R = 0.911), bladder (R = 0.945), pancreas (R = 0.841), kidney (R = 0.940) and
myeloid leukaemia (R = 0.889). The significance and strength of the correlations show that the effects
of glyphosate and GE crops on human health should be further investigated.
Activated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune-privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen. Our findings not only have implications for the etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes might be a more common trigger of autoimmune diseases than is currently appreciated.
Copyright © 2015 Elsevier Inc. All rights reserved.
Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. Key Messages: Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLA-DQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this absence does not significantly affect these patients' incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk.
The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives. © 2015 S. Karger AG, Basel.
The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption. The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them. Glucose, salt, emulsifiers, organic solvents, gluten, microbial transglutaminase, and nanoparticles are extensively and increasingly used by the food industry , claim the manufacturers, to improve the qualities of food. However, all of the aforementioned additives increase intestinal permeability by breaching the integrity of tight junction paracellular transfer. In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part played by the tight junction in autoimmune diseases pathogenesis is extensively described. It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus, increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade. Future research on food additives exposure-intestinal permeability-autoimmunity interplay will enhance our knowledge of the common mechanisms associated with autoimmune progression.
Copyright © 2015. Published by Elsevier B.V.
A subgroup of coeliac disease patients continues to experience symptoms even on a gluten-free diet (GFD). We attempted to determine whether these symptoms could be due to either cross-contamination with gluten-containing foods or cross-reactivity between α-gliadin and non-gluten foods consumed on a GFD. We measured the reactivity of affinity-purified polyclonal and monoclonal α-gliadin 33-mer peptide antibodies against gliadin and additional food antigens commonly consumed by patients on a GFD using ELISA and dot-blot. We also examined the immune reactivity of these antibodies with various tissue antigens. We observed significant immune reactivity when these antibodies were applied to cow’s milk, milk chocolate, milk butyrophilin, whey protein, casein, yeast, oats, corn, millet, instant coffee and rice. To investigate whether there was cross-reactivity between α-gliadin antibody and different tissue antigens, we measured the degree to which this antibody bound to these antigens. The most significant binding occurred with asialoganglioside, hepatocyte, glutamic acid decarboxylase 65, adrenal 21-hydroxylase, and various neural antigens. The specificity of anti-α-gliadin binding to different food and tissue antigens was demonstrated by absorption and inhibition studies. We also observed significant cross-reactivity between α-gliadin 33-mer and various food antigens, but some of these reactions were associated with the contamination of non-gluten foods with traces of gluten. The consumption of cross-reactive foods as well as gluten-contaminated foods may be responsible for the continuing symptoms presented by a subgroup of patients with coeliac disease. The lack of response of some CD patients may also be due to antibody cross-reactivity with non-gliadin foods. These should then be treated as gluten-like peptides and should also be excluded from the diet when the GFD seems to fail.
The concept of molecular mimicry was established to explain commonalities of structure which developed in response to evolutionary pressures. Most examples of molecular mimicry in medicine have involved homologies of primary protein structure which cause disease. Molecular mimicry can be expanded beyond amino acid sequence to include microRNA and proteomic effects which are either pathogenic or salutogenic (beneficial) in regard to Parkinson's disease, Alzheimer's disease, and related disorders. Viruses of animal or plant origin may mimic nucleotide sequences of microRNAs and influence protein expression. Both Parkinson's and Alzheimer's diseases involve the formation of transmissible self-propagating prion-like proteins. However, the initiating factors responsible for creation of these misfolded nucleating factors are unknown. Amyloid patterns of protein folding are highly conserved through evolution and are widely distributed in the world. Similarities of tertiary protein structure may be involved in the creation of these prion-like agents through molecular mimicry. Cross-seeding of amyloid misfolding, altered proteostasis, and oxidative stress may be induced by amyloid proteins residing in bacteria in our microbiota in the gut and in the diet. Pathways of molecular mimicry induced processes induced by bacterial amyloid in neurodegeneration may involve TLR 2/1, CD14, and NFκB, among others. Furthermore, priming of the innate immune system by the microbiota may enhance the inflammatory response to cerebral amyloids (such as amyloid-β and α-synuclein). This paper describes the specific molecular pathways of these cross-seeding and neuroinflammatory processes. Evolutionary conservation of proteins provides the opportunity for conserved sequences and structures to influence neurological disease through molecular mimicry.
Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms `intestinal barrier¿ and `intestinal permeability¿ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by `intestinal permeability¿. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and ¿ more recently recognized ¿ obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
In spite of numerous research efforts, the exact etiology of autoimmune diseases remains largely unknown. Genetics and environmental factors, including xenobiotics, are believed to be involved in the induction of autoimmune disease. Some environmental chemicals, acting as haptens, can bind to a high-molecular-weight carrier protein such as human serum albumin (HSA), causing the immune system to misidentify self-tissue as an invader and launch an immune response against it, leading to autoimmunity. This study aimed to examine the percentage of blood samples from healthy donors in which chemical agents mounted immune challenges and produced antibodies against HSA-bound chemicals. The levels of specific antibodies against 12 different chemicals bound to HSA were measured by ELISA in serum from 400 blood donors. We found that 10% (IgG) and 17% (IgM) of tested individuals showed significant antibody elevation against aflatoxin-HSA adduct. The percentage of elevation against the other 11 chemicals ranged from 8% to 22% (IgG) and 13% to 18% (IgM). Performance of serial dilution and inhibition of the chemical–antibody reaction by specific antigens but not by non-specific antigens were indicative of the specificity of these antibodies. Although we lack information about chemical exposure in the tested individuals, detection of antibodies against various protein adducts may indicate chronic exposure to these chemical haptens in about 20% of the tested individuals. Currently the pathological significance of these antibodies in human blood is still unclear, and this protein adduct formation could be one of the mechanisms by which environmental chemicals induce autoimmune reactivity in a significant percentage of the population. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
Given the vast antigenic source of the gut microbiota, we hypothesized that human gut commensal bacteria induce and sustain autoreactivity via cross-reactivity. As a paradigm, we studied the antiphospholipid syndrome (APS), which is a serious autoimmune clotting disorder of unknown etiology but with a well-defined major autoantigen, b2-glycoprotein I (b2GPI). Infectious triggers are implicated in transient autoantibody production, but the persistent stimuli for anti-b2GPI antibodies remain unknown. To this end, we characterized b2GPI-specific monoclonal autoantibody reactivity to an in silico identified candidate commensal, Roseburia intestinalis (R.int), that is abundant in human stool from APS patients as detected by a species-specific PCR. Using an APS-derived monoclonal antibody, P1-117, that binds to the major B cell epitope in domain I of b2GPI (RGGMR), we tested for cross-reactivity to anaerobically cultured R.int and its candidate cross-reactive R.int protein (WP_006857340.1). P1-117 bound significantly to R.int lysates whereas a control antibody specific for another epitope within b2GPI did not. Further, P1-117 displayed significant binding to the recombinantly expressed R.int cross-reactive candidate protein. BALB/cJ mice immunized with whole heat-killed R.int displayed significant cross-reactive splenocytes and low titers of cross-reactive IgG autoantibodies. In conclusion, we present here in vitro and in vivo studies supporting cross-reactivity of pathogenic b2GPI-specific autoantibody with a common gut commensal. This study provides a concept for persistently colonizing gut commensals as chronic cross-reactive triggers in genetically susceptible autoimmune hosts such as APS patients.
Consumption of over-the-counter probiotics for promotion of health and well-being has increased worldwide in recent years. However, although probiotic use has been greatly popularized among the general public, there are conflicting clinical results for many probiotic strains and formulations. Emerging insights from microbiome research enable an assessment of gut colonization by probiotics, strain-level activity, interactions with the indigenous microbiome, safety and impacts on the host, and allow the association of probiotics with physiological effects and potentially useful medical indications. In this Perspective, we highlight key advances, challenges and limitations in striving toward an unbiased interpretation of the large amount of data regarding over-the-counter probiotics, and propose avenues to improve the quality of evidence, transparency, public awareness and regulation of their use. The use and promotion of probiotics is widespread, but debatable in many cases. Prospective large-scale randomized studies that assess their effectiveness in promoting health and curing disease and take into account personalized responses of discrete human subpopulations will help clarify specific indications in which probiotics may be safe and beneficial.
Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by a heterogeneous clinical response to the different treatments. Some patients are difficult to treat and do not reach the treatment targets as clinical remission or low disease activity. Known negative prognostic factors, such as the presence of auto-antiantibodies and joint erosion, the presence of a genetic profile, comorbidities and extra-articular manifestations, pregnancy or a pregnancy wish may concur to the treatment failure. In this review we aimed at identify difficult to treat RA patients and define the optimal therapeutic and environmental targets. Genetic markers of severity such as HLA-DRB1, TRAF1, PSORS1C1 and microRNA 146a are differently associated with joint damage; other gene polymorphisms seem to be associated with response to biologic disease modifying anti-rheumatic drugs (bDMARDs). The presence of comorbidities and/or extra-articular manifestations may influence the therapeutic choice; overweight and obese patients are less responsive to TNF inhibitors. In this context the patient profiling can improve the clinical outcome. Targeting different pathways, molecules, and cells involved in the pathogenesis of RA may in part justify the lack response of some patients. An overview of the future therapeutic targets, including bDMARDs (inhibitors of IL-6, GM-CSF, matrix metalloproteinases, chemokines) and targeted synthetic DMARDs (filgotinib, ABT-494, pefacitinib, decernotinib), and environmental targets is addressed. Environmental factors, such as diet and cigarette smoke, may influence susceptibility to autoimmune diseases and interfere with inflammatory pathways. Mediterranean diet, low salt intake, cocoa, curcumin, and physical activity seem to show beneficial effects, however studies of dose finding, safety and efficacy in RA need to be performed.
In addition to protecting body from infections and diseases, the immune system produces auto-antibodies that can cause complex autoimmune disorders, such as Type I diabetes, primary biliary cirrhosis, rheumatoid arthritis, and multiple sclerosis, to name a few. In such cases, the immune system fails to recognize between foreign agents and its own body cells. Different factors, such as genetic factors (CD25, STAT4), epigenetic factors (DNA methylation, histone modifications)and environmental factors (xenobiotics, drugs, hormones)trigger autoimmunity. Glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressive and biological agents are currently used to manage autoimmune diseases of different origins. However, complete cure remains elusive. Many dietary and natural products including polyphenols have been widely studied as possible alternative treatment strategies for the management of autoimmune disorders. Polyphenols possess a wide-range of pharmacological and therapeutic properties, including antioxidant and anti-inflammatory activities. As immunomodulatory agents, polyphenols are emerging pharmaceutical tools for management of various autoimmune disorders including vitiligo, ulcerative colitis and multiple sclerosis (MS). Polyphenols activate intracellular pathways such as arachidonic acid dependent pathway, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)signaling pathway, mitogen-activated protein kinases (MAPKs)pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)signaling pathway and epigenetic modulation, which regulate the host's immune response. This timely review discusses putative points of action of polyphenols in autoimmune diseases, characterizing their efficacy and safety as therapeutic agents in managing autoimmune disorders.
Current therapies for gut inflammation have not reached the desired specificity and are attended by unintended immune suppression. This study aimed to provide evidence for supporting a hypothesis that direct in vivo augmentation of the induction of gut-homing regulatory T (Treg) cells is a strategy of expected specificity for the treatment of chronic intestinal inflammation (e.g., inflammatory bowel disease). We showed that dendritic cells (DCs), engineered to de novo produce high concentrations of both 1,25-dihydroxyvitamin D, the active vitamin D metabolite, and retinoic acid, an active vitamin A metabolite, augmented the induction of T cells that express both the regulatory molecule Foxp3 and the gut-homing receptor CCR9 in vitro and in vivo. In vivo, the newly generated Ag-specific Foxp3+ T cells homed to intestines. Additionally, transfer of such engineered DCs robustly suppressed ongoing experimental colitis. Moreover, CD4+ T cells from spleens of the mice transferred with the engineered DCs suppressed experimental colitis in syngeneic hosts. The data suggest that the engineered DCs enhance regulatory function in CD4+ T cell population in peripheral lymphoid tissues. Finally, we showed that colitis suppression following in vivo transfer of the engineered DCs was significantly reduced when Foxp3+ Treg cells were depleted. The data indicate that maximal colitis suppression mediated by the engineered DCs requires Treg cells. Collectively, our data support that DCs de novo overproducing both 1,25-dihydroxyvitamin D and retinoic acid are a promising novel therapy for chronic intestinal inflammation.
OBJECTIVE:
Although the etiology of rheumatoid arthritis (RA) is unknown, recent studies have led to the concept that gut dysbiosis may be involved in onset. In this study, we aimed to determine if human gut commensals modulate the immune response and gut epithelial integrity in DQ8 mice.
METHODS:
DQ8 mice were orally gavaged with RA-associated (Eggerthella lenta or Collinsella aerofaciens) and non-associated (Prevotella histicola or Bifidobacterium sp.) on alternate days for 1 week in naïve mice. Some mice were immunized with type II collagen and oral gavage continued for 6 weeks and followed for arthritis. Epithelial integrity was done by FITC-Dextran assay. In addition, cytokines were measured in sera by ELISA and various immune cells were quantified using flow cytometry.
RESULTS:
Gut permeability was increased by the RA-associated bacteria and was sex and age-dependent. In vivo and in vitro observations showed that the RA-non-associated bacteria outgrow the RA-associated bacteria when gavaged or cultured together. Mice gavaged with the RA-non-associated bacteria produced lower levels of pro-inflammatory MCP-1 and MCP-3 and had lower numbers of Inflammatory monocytes CD11c+Ly6c+, when compared to controls. E. lenta treated naïve mice produce Th17 cytokines.
CONCLUSIONS:
Our studies suggest that gut commensals influence immune response in and away from the gut by changing the gut permeability and immunity. Dysbiosis helps the growth of RA-associated bacteria and reduces the beneficial bacteria.
Vitamin D deficiency is an established risk factor for many autoimmune diseases and the anti-inflammatory properties of vitamin D underscore its potential therapeutic value for these diseases. However, results of vitamin D3 supplementation clinical trials have been varied. To understand the clinical heterogeneity, we reviewed the pre-clinical data on vitamin D activity in four common autoimmune diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), in which patients are commonly maintained on oral vitamin D3 supplementation. In contrast, many pre-clinical studies utilize other methods of manipulation (i.e. genetic, injection). Given the many actions of vitamin D3 and data supporting a vitamin D-independent role of the Vitamin D receptor (VDR), a more detailed mechanistic understanding of vitamin D3 activity is needed to properly translate pre-clinical findings into the clinic. Therefore, we assessed studies based on route of vitamin D3 administration, and identified where discrepancies in results exist and where more research is needed to establish the benefit of vitamin D supplementation.
As a mirror image of the Roman god Janus Bifrons, the environment has a hidden face. To highlight this hidden face of the environment in the field of systemic sclerosis (SSc) will allow to identify responsible agents emerging in the future. To date, there is, in fact, a growing scientific evidence that environmental factors have a crucial impact on both alterations and modulation of epigenetic determinants, resulting in SSc onset and progression. It has been well established that there is a marked correlation between SSc onset and occupational exposure to crystalline silica and organic solvents. More recently, an association between SSc and exposure to heavy metals has further been found, including: antimony, cadmium, lead, mercury. These latter findings interestingly underscore that occupational exposure to heavy metals should be systematically checked in all SSc patients at diagnosis, as the identification of the occupational toxic agent will allow its interruption, which may result in potential improvement of SSc outcome.
In the professional medical and scientific world, there is not many interest in the correlation of food intolerance and autoimmune diseases. However there is a lot of evidence that e.g. gluten or gliadine can induce autoimmmune diseases: example the interest in coeliac disease and autoimmunity. There is however a lot of informationavailable about leaky gut and autoimmunity.
We performed an observational study in our data base;, where we selected 100 patients with manifest autoimmune disease with clear symptoms and autoimmune antibodies in the form of positive anf more tehn 160 titer. These patients were compared with 25 control patients without any autoimmunity.
We could clearly find a difference in food intolerance profiles when we compared AI patients with people without any AI. Overall there is a much greater reaction to several food epitopes, which can be observed on the level of specific antibodies tot he food epitopes. These igG levels for specific food antibodies are significantly higher in the patient group then in the control group. We can also see that some food epitopes provocate a very pronounced reaction, while other show no increased level of igG. Among the most reactive food epitopes are caseine, cow milk, wheat, gliadine, white of egg and rice. A variable reaction can bes een on nuts e.g.; walnuts and almonds. Almost no antibody reaction is noticed on vegetables, fish and meat products, who seem tob e immunologially very neutral.
We conclude that food intolerance test is very important tool in patients with AI disease, and should be performed in each patient to tailor an individual diet program, which if properly followed, could relieve symptoms and probably stop or slow the the progression of the autoimmune disease.
Also interesting for global research in AI disease is the fact that food is probably an important trigger for autoimmunity in vulnerable patients. More research on great scale and multicenter around this topic is mandatory and urgent.
Osteoarthritis (OA) is the most prevalent chronic rheumatic diseases worldwide, with a strong impact on individual and population health. OA is a clinically heterogeneous disease presenting with different clinical phenotypes recognising systemic and local risk factors. The pathogenesis is multifactorial including constitutive features of the joint, non-modifiable and modifiable risk factors. Epidemiological studies highlight the link between metabolic syndrome and OA and the effect of interplay between immunological and metabolic processes is getting increasing emphasis because of to the discovery that metabolic syndrome is implicated in OA pathogenesis and progression. In addition, recent findings suggest a potential role of dietary factors in susceptibility and progression of OA. In this review, we summarise the most robust evidence on epidemiology and classical risk factors OA, also exploring the most recent evidence on metabolic changes and Mediterranean diet for OA as a possible target to impact on the natural history of the disease.
Autoimmune diseases are a group of heterogeneous condition that occur secondary to the intrinsic loss of tolerance to self- antigens. In genetically susceptible individuals, the complex interplay of environmental factors and epigenetic deregulations have been proposed to drive disease etiopathogenesis. Various environmental variables have been identified including viral infections, exposure to pollutants, stress and dietary factors. Sodium, a major constituent of salt is essential for mammalian physiology. However, high salt intake may play a role in the development of autoimmune diseases. Several lines of evidence point toward the role of high sodium intake in reversing the suppressive effects of Regulatory T cells (Tregs) and instead promoting cellular shift toward T-helper (Th)-1 and Th17 pro-inflammatory phenotypes. These effects have been attributed to cascade of events that ultimately results in downstream activation of serum glucocorticoid kinase 1 (Sgk1). In vivo, various autoimmune animal models have confirmed the role of high sodium diet in the emergence and the exacerbation of autoimmune conditions including for instance Experimental Autoimmune Encephalomyelitis model for multiple sclerosis, MRL/lpr mouse model for lupus nephritis, collagen induced arthritis model for rheumatoid arthritis, and dextran sulfate sodium induced colitis, and TNBS-induced colitis models for Crohn's disease. Clinical epidemiological studies are scarce. High sodium intake was associated with increased risk of rheumatoid arthritis disease emergence. In multiple sclerosis, some studies suggest a relation to clinical exacerbation rates however other studies did not corroborate these results.
Taken together, high dietary salt intake plays a role in the spectrum of autoimmune disease etiology. Further research is warranted to better characterize such relationship and assist in identifying individuals that would benefit from dietary salt restriction.
Accumulating research evidence suggests that individual dietary factors and dietary patterns might be implicated in the risk of development of rheumatoid arthritis (RA). This narrative review aims to present this evidence and provide nutritional recommendations for reducing RA risk in susceptible individuals. Overall, a 'Western' type diet rich in energy intake, total and saturated fat, an unbalanced ratio of n-3 to n-6 fatty acids, high in refined carbohydrates and sugar and low in fiber and antioxidants might increase the risk of RA both directly through increasing inflammation and indirectly through increasing insulin resistance and obesity, with the latter being a known risk factor for RA. On the contrary, consumption of long-chain omega-3 polyunsaturated fatty acids, derived from fish and fish oil, is associated with a reduced risk of RA probably due to their anti-inflammatory properties. The Mediterranean diet (MD), rich in plant-based foods such as wholegrains, legumes, fruit, vegetables, extra-virgin olive oil and low in red meat consumption, might have the potential to reduce the risk of RA. Based on current research evidence, it is suggested that adherence to the MD enhanced with an increased consumption of fatty fish, reduced consumption of sugar-sweetened drinks and maintenance of a normal body weight, contributes to reducing the risk of RA. Further research on RA susceptibility will allow for more specific dietary recommendations to be made.
The impact of dietary interventions such as specific types of diet or nutritional supplements in rheumatoid arthritis (RA) has been subject to increased attention in recent years. The recognition of the unmet need to better understand the effects of specific dietary interventions on disease outcomes in RA, along with the growing patient interest on lifestyle interventions beyond pharmacotherapy, have informed the undertaking of this narrative literature review. The benefits of the Mediterranean Diet (MD) have been shown in various studies, although only a limited number of trials focus specifically on RA. Based on the studies reviewed, the MD may provide benefits in reducing pain and swollen and tender joints in RA patients. There is more and better evidence that n-3 polyunsaturated fat (PUFA) supplementation has the potential to reduce inflammation and provide clinical benefit, possibly slowing progression to pharmacotherapy. Yet, many of these studies to date are limited in their methodology; this being partly a reflection of the complexity of the research questions being addressed. Consequently, the conclusions that can be robustly drawn from their results are restricted. With a focus on clinical trials on the MD and fish oil supplementation, this review critically appraises the evidence, discussing the findings of studies in the wider context of impact on RA outcomes, methodological challenges and practical points to consider as part of the routine care of RA patients.
Objective: The aim of our study was to examine immunoreactivity between AβP-42, toxic chemicals, and food proteins that could be involved in AD. Methods: We applied monoclonal anti-AβP-42 to a variety of chemicals bound to human serum albumin (HSA) and 208 different food extracts. Results: We found that anti-AβP-42 reacts from moderately to strongly with mercury-HSA, dinitrophenyl-HSA (DNP-HSA), phthalate-HSA, and aluminum-HSA, but not to many other tested chemicals bound to HSA nor to HSA alone. This antibody also reacted with 19 out of the 208 food antigens used in the assay. One example of a food that reacted strongly with anti-AβP-42 in our study was canned tuna, although raw tuna reacted only moderately. Conclusion: Based on these results, we hypothesized that reaction between AβP-42 antibody with chemicals bound to HSA and numerous food antigens might play a role in Alzheimer’s disease (AD). These anti-AβP antibodies could be derived from protein misfolding similar to β-amyloid, or from antibodies to various food antigens that cross-react with AβP-42. Removal of toxic chemicals and food items that share a homology with β-amyloid may be recommended at least for patients in the early stages of AD. Therefore, the role of AβP-42 cross-reactive foods and chemicals bound to HSA in neurodegeneration should be investigated further.
Importance:
Workers exposed to aerosolized brain in a swine-processing plant developed immune-mediated polyradiculoneuropathy (IP) possibly triggered by an immune response.
Objective:
Immunohistochemistry results were correlated with electrophysiological variables to examine the immunopathogenesis of this disorder.
Design/setting:
Laboratory studies used normal nerve tissue that was exposed to sera from 12 IP patients; 10 exposed controls; and 10 unexposed controls. Clinical and electrophysiological data from IP patients were obtained from medical record reviews.
Main outcome measures:
Analysis included electromyography results of IP patients and nerve conduction studies examining CMAP amplitude, distal motor latency, motor conduction velocity, F-wave latency, sensory nerve action potential amplitude, and sensory nerve conduction velocity. Case and control results were compared relative to distance from exposure.
Results:
Electrodiagnostic findings revealed prolongation of the distal and f-wave latencies suggestive of demyelination at the level of the nerve root and distal nerve terminals. Immunohistochemical results identified an antibody to the peripheral nerve, with staining at the level of the axolemma. Thus, IP may be a primary axonopathy with secondary paranodal demyelination causing the conduction changes. Staining of the distal and proximal portions of the nerve appears consistent with easier access through the blood-nerve barrier.
Conclusions and relevance:
IP is an immune-mediated neuropathy related to antibodies to an axon-based antigen on peripheral nerves. Secondary paranodal demyelination is likely. Further studies to identify the primary axonal antigenic target would be useful.
Carbamylation is a non-enzymatic post-translational modification that physiologically occurs during aging and is a risk factor for various diseases. The most common product of carbamylation is homocitrulline (HCit), where a lysine (Lys) amino group has reacted with urea-derived cyanate. HCit has recently been detected in collagen; however, given that 15%-90% of total Lys in collagen is hydroxylated, it is unclear how hydroxylation affects collagen carbamylation. Here, we identified a collagen-specific carbamylation product, hydroxyhomocitrulline (HHCit), and showed that high levels of HHCit are correlated with age in rat tissue collagen and in vivo carbamylation in mice, as well as with the decline of kidney function in the serum of dialysis patients. Proteomic analysis of the carbamylated collagens identified α2(I) Lys(933), a major cross-linking site, as a preferential HHCit site. Furthermore, our results suggest that hydroxylysine carbamylation affects the mechanical properties of connective tissue by competitively inhibiting collagen cross-link formation.
In rheumatoid arthritis (RA), immunological triggers at mucosal sites, such as the gut microbiota, may promote autoimmunity that affects joints. Here, we used discovery-based proteomics to detect HLA-DR-presented peptides in synovia or peripheral blood mononuclear cells and identified 2 autoantigens, N-acetylglucosamine-6-sulfatase (GNS) and filamin A (FLNA), as targets of T and B cell responses in 52% and 56% of RA patients, respectively. Both GNS and FLNA were highly expressed in synovia. GNS appeared to be citrullinated, and GNS antibody values correlated with anti-citrullinated protein antibody (ACPA) levels. FLNA did not show the same results. The HLA-DR-presented GNS peptide has marked sequence homology with epitopes from sulfatase proteins of the Prevotella sp. and Parabacteroides sp., whereas the HLA-DR-presented FLNA peptide has homology with epitopes from proteins of the Prevotella sp. and Butyricimonas sp., another gut commensal. Patients with T cell reactivity with each self-peptide also had responses to the corresponding microbial peptides, and the levels were directly correlated. Furthermore, HLA-DR molecules encoded by shared-epitope (SE) alleles were predicted to bind these self- and microbial peptides strongly, and these responses were more common in RA patients with SE alleles. Thus, sequence homology between T cell epitopes of 2 self-proteins and a related order of gut microbes may provide a link between mucosal and joint immunity in patients with RA.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease where a loss of tolerance to nuclear antigens leads to inflammation in multiple organ systems. The cause of SLE remains ill defined, although it is known that a complex interplay between genes and environment is necessary for disease development. In recent years, case studies have reported that the incidence of SLE in the USA, for example, has increased by approximately 3 fold. Although the reason for this is likely to be multifactorial, it has been hypothesized that the increasing incidence of autoimmune disease is due to considerable shifts in the bacterial communities resident the gut, collectively known as the gut microbiota, following a change in diet and the widespread introduction of antibiotics. Furthermore, a growing body of evidence suggests that the gut microbiota plays a role in the development of a range of autoimmune diseases including inflammatory bowel disease, multiple sclerosis, type one diabetes and rheumatoid arthritis. In this review, we summarize how advances in DNA-based sequencing technologies have been critical in providing baseline information concerning the gut microbiota in health and how variation amongst individuals in controlled by multiples factors including age, genetics, environment and the diet. We also discuss the importance of the gut microbiota in the development of a healthy immune system and how changes in particular bacterial phyla have been associated with immune abnormalities in animal models of autoimmune disease. Finally, in order to place the data in a clinical context, we highlight recent findings showing that abnormalities in the gut microbiota can be detected in patients with SLE, which provides the rationale for greater investigation into whether microbiota-targeted therapies could be used for the treatment/prevention of disease.
Autoimmune diseases have a multifactorial etiology including genetic and environmental factors. Recently, there has been increased appreciation of the critical involvement of the microbiota in the pathogenesis of autoimmunity, although in many cases, the cause and the consequence are not easy to distinguish. Here, we suggest that many of the known cues affecting the function of the immune system, such as genetics, gender, pregnancy and diet, which are consequently involved in autoimmunity, exert their effects by influencing, at least in part, the microbiota composition and activity. This, in turn, modulates the immune response in a way that increases the risk for autoimmunity in predisposed individuals. We further discuss current microbiota-based therapies.
Oral tolerance prevents pathological inflammatory responses to innocuous foreign antigens by peripheral regulatory T cells (pTreg cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure for the 'instruction' of naive CD4(+) T cells to differentiate into pTreg cells has not been defined. Using myeloid lineage-specific APC depletion in mice, we found that monocyte-derived APCs were dispensable, while classical dendritic cells (cDCs) were critical, for pTreg cell induction and oral tolerance. CD11b(-) cDCs from the gut-draining lymph nodes efficiently induced pTreg cells and, conversely, loss of transcription factor IRF8-dependent CD11b(-) cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in the induction of pTreg cells and their redundancy during the development of oral tolerance.
A child is born with almost no protective immune system other than passive immunity and maternal transfer of immunoglobulin G (IgG) against various food antigens and infectious agents. This lack provides a window of opportunity for infectious attacks in the first 6 mo of life as the infant's body begins to develop its own immune system. As the maternal IgG is catabolized, the child's mucosal immune system evolves its own immunocytes and starts producing a significant amount of immunoglobulin A (IgA) and immunoglobulin M (IgM) against pathogens and food antigens. This antibody production helps modulate or inhibit colonization by bacteria or yeast and to prevent penetration of the mucosal tissue by a variety of dangerous lumenal antigens. Simultaneously, the body develops its own suppressive mechanism or oral tolerance to avoid local and peripheral immune reactivities to microbial and dietary antigens. In this article, the author describes the (1) importance of oral tolerance in maintaining homeostasis against bacterial toxins and food antigens; (2) way in which antigen-presenting cells (APCs), through their collaboration with effector T (TEFF) cells, T-helper (TH) cells, and regulatory T (TREG) cells, regulate the immune system to induce anergy or immune suppression; (3) the importance of various factors in the induction of oral tolerance and the consequences of its breakdown; and (4) the reasons why a disruption of oral tolerance to food antigens and bacterial toxins can result in autoimmunity.
Lectins are carbohydrate-binding proteins present throughout nature that act as agglutinins. Approximately 30% of our food contains lectins, some of which may be resistant enough to digestion to enter the circulation. Because of their binding properties, lectins can cause nutrient deficiencies, disrupt digestion, and cause severe intestinal damage when consumed in excess by an individual with dysfunctional enzymes. These effects are followed by disruption of intestinal barrier integrity, which is the gateway to various autoimmunities. Shared amino acid motifs between dietary lectins, exogenous peptides, and various body tissues may lead to cross-reactivity, resulting in the production of antibodies against lectin and bacterial antigens, followed by autoimmunity. The detection of immunoglobulin G (IgG) or immunoglobulin A (IgA) antibodies against specific lectins may serve as a guide for the elimination of these lectins from the diet. It is proposed that this process can reduce the peripheral antigenic stimulus and, thereby, result in a diminution of disease symptoms in some-but not all-patients with autoimmune disorders.
The mucosal immune system is constantly exposed to challenges from the antigenic substances found in food and released from the body's own microbial flora. The body's normal tolerance to friendly antigenic substances can be disrupted by a number of factors, such as disease, injury, shock, trauma, surgery, drugs, blood transfusion, environmental triggers, etc. When this disruption happens, the ingestion of foods containing antigenic substances that have compositions similar to those of the body's autoantigens can result in the production of antibodies that react not only against the food antigens but also the body's own tissues. This response is known as food autoimmune reactivity. Between 7% and 10% of the world's population suffers from some form of autoimmune disease. Each patient's antibodies, both immunoglobulin A (IgA) + immunoglobulin M (IgM) in the saliva and immunoglobulin G (IgG) and IgA in the blood must be examined to give a complete picture of food immune reactivity. A host of health problems and autoimmune disorders have increasingly become associated with some of the most commonly consumed foods in the world, such as wheat and milk. Many of these problems can be traced to molecular mimicry. The peptide sequences of foods such as milk and wheat are similar to those of human molecules, such as myelin oligodendrocyte glycoprotein, human islet cell tissue, and human aquaporin 4 (AQP4). This similarity can result in cross-reactivity that leads to food autoimmunity and even autoimmune disorders, such as multiple sclerosis (MS), celiac disease (CD), and neuromyelitis optica. Further research is needed to determine what other foods have dangerous sequence similarities to human tissues and what methods are available to test for the autoantibodies resulting from these molecular, mimicry-induced misfires of the immune system. The identification and removal of corresponding food triggers can then be used as the basis of therapy.