Article

Antibodies to Squalene in Gulf War Syndrome

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Abstract

Gulf War Syndrome (GWS) is a multisystemic illness afflicting many Gulf War-era veterans. The molecular pathological basis for GWS has not been established. We sought to determine whether the presence of antibodies to squalene correlates with the presence of signs and symptoms of GWS. Participants in this blinded cohort study were individuals immunized for service in Desert Shield/Desert Storm during 1990-1991. They included 144 Gulf War-era veterans or military employees (58 in the blinded study), 48 blood donors, 40 systemic lupus erythematosus patients, 34 silicone breast implant recipients, and 30 chronic fatigue syndrome patients. Serum antibodies to squalene were measured. In our small cohort, the substantial majority (95%) of overtly ill deployed GWS patients had antibodies to squalene. All (100%) GWS patients immunized for service in Desert Shield/Desert Storm who did not deploy, but had the same signs and symptoms as those who did deploy, had antibodies to squalene. In contrast, none (0%) of the deployed Persian Gulf veterans not showing signs and symptoms of GWS have antibodies to squalene. Neither patients with idiopathic autoimmune disease nor healthy controls had detectable serum antibodies to squalene. The majority of symptomatic GWS patients had serum antibodies to squalene.

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... The putative role of ASAs, found in high percentage in the Gulf War Syndrome (GWS) veterans and civilian personnel as an experimental immunological adjuvant, was analyzed (107). The GWS, unknown its origins, affected approximately 100,000 American and British individuals of the 700,000 veterans deployed in the Persian Gulf War (1990)(1991). ...
... Statistically, there was no significant association (p=0.465) between SQ status and chronic multisymptom illness status (123). According to the study of Asa and coworkers (107), SQ in pre-military vaccines probably induced an autoimmune disease that could explain many of the symptoms exhibited by GWS veterans. ...
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The capability of sharks to resist infection and the low incidence of tumors found in different species of sharks (e.g. spiny dogfsh shark, tiger shark) suggested the presence into their tissues of active compounds, provided of anticancer activities, such as Alkylglycerols (from the shark liver), Squalene (from the shark mesenchyme and skin), and Cartilage (from the shark skeleton). The Alkylglycerols, highly concentrated in the shark liver oil, have several biological activities: stimulation of hematopoiesis, immune-modulation, anti-tumors. The Squalene is an anticancer, antioxidant, detoxifer, skin hydrating, drug carrier and emollient agent. The Cartilage has anti-inflammatory properties commonly used in the folk medicine for the treatment of arthritis, osteoarthritis, diabetic retinopathy, psoriasis, and supposedly also anticancer
... However, these observations have been criticized for the small cohorts and lack of a control group. In another study suggesting the occurrence of GWS, there were antibodies to squalene reported to occur in more than 95% of 38 sick veterans, whereas such antibodies were missing in 12 healthy controls (Asa et al., 2000). However again, due to methodological defects, this study was not widely accepted (Enserink, 2001). ...
... Interpretation of this association is unclear. Asa et al. (2000Asa et al. ( , 2002 suggested that the GWS may be caused by the then experimental vaccine adjuvant squalene. Squalene is a triterpenoid hydrocarbon oil produced by almost all plants and animals including humans. ...
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After the Gulf war, new diagnostic entity was claimed: the Gulf War Syndrome (GWS). A wide spectrum of exposures is widely discussed in order to explain the reported symptoms. Investigating tentative culprits we did not find clearly conclusive data about the existence of the GWS. The origin of described symptoms can be associated to the use of pesticides and the PB pill. However, the data about the use of both are influenced by a lack of precise records. Although other agents such as nerve agent exposure could not be definitively ruled out, its link to symptoms seems to be improbable.
... And second, their persistence may trigger the production of autoantibodies, if the pathogens happen to share common antigenic structure with body proteins, and this may lead to autoimmunity. The most obvious potential pathogens for Gulf War veterans include the vaccines administered (multiply in some veterans, see Institute of Medicine, 2000) and their adjuvants (Asa et al., 2000). The potential adverse role of the various vaccinations is described in detail in the report by the Institute of Medicine (2000), and specific mention is made of HLA in that context. ...
... Now, there is a link between chronic infections and the development of autoimmune disorders (Sherbet, 2009). In addition, a possible, direct connection of GWI to autoimmunity has been suggested (Asa et al., 2000;Israeli, 2012 and supported by the emergence of methotrexate, an immunosuppressive drug, as a possible treatment for GWI (Craddock et al., 2015). This connection of GWI to autoimmunity is probably the best explanation of the HLA-related neural effects found in this study. ...
Article
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Background: We recently reported that six alleles from class II genes of the Human Leukocyte Antigen (HLA) confer protection from Gulf War Illness (GWI) (Georgopoulos et al., 2015). The most significant effect is exerted on Neurological-Cognitive-Mood (NCM), Pain, and Fatigue symptoms, such that higher number of copies of the protective alleles are associated with lower symptom severity. Here we tested the hypothesis that this effect is exerted by modulating the strength of neural synchronicity. Methods: Eighty-one Gulf War veterans (65 with GWI and 16 healthy controls) underwent a magnetoencephalography (MEG) scan to assess the strength of brain synchronicity by computing zero-lag crosscorrelations (and their Fisher z transforms) between prewhitened MEG time series. A high-resolution HLA genotyping determined the number of copies, k, of the 6 protective alleles above in each participant. We tested the hypothesis above by regressing NCM, Pain and Fatigue symptom severity against the interaction term, k × z (HLA-related effect), while including z (non-HLA-related effect), gender and age as covariates. The k × z and z terms assessed HLA- and non-HLA-related effects, respectively, of neural synchronicity on symptom severity. The distributions of these effects in sensor space were visualized using statistical heatmaps. Findings: We found significant, graded HLA- and non-HLA-related effects: (a) NCM > Pain > Fatigue for HLA-related effects, (b) NCM > Fatigue > Pain for non-HLA-related effects, and (c) HLA-related > non-HLA-related effects for all symptoms. These effects had widespread but distinct distributions in sensor space that allowed the orderly separation of the 6 terms (3 symptom domains × 2 HLA factors) in a multidimensional plot, where one dimension separated the symptoms and the other the HLA relation. Interpretation: These findings demonstrate the presence of substantial, widespread, distinct and orderly HLA- and non-HLA-related neural influences on NCM, Pain and Fatigue symptom severity in GWI. Funding: U.S. Department of Veterans Affairs and University of Minnesota.
... Gulf War Syndrome comprises an ill-defined and varying group of systemic symptoms that occurred in veterans of the 1991 Persian Gulf War. The cause is unknown but links have been suggested with post-traumatic stress or exposure to chemicals and/or biological weapons or vaccination against anthrax [82]. An association was claimed between the presence of antibodies against squalene, an adjuvant used in the anthrax vaccine administered to soldiers, and the Gulf War Syndrome, based on the observation that antibodies to squalene were detected in the sera of most patients affected [82]. ...
... The cause is unknown but links have been suggested with post-traumatic stress or exposure to chemicals and/or biological weapons or vaccination against anthrax [82]. An association was claimed between the presence of antibodies against squalene, an adjuvant used in the anthrax vaccine administered to soldiers, and the Gulf War Syndrome, based on the observation that antibodies to squalene were detected in the sera of most patients affected [82]. Further studies have subsequently shown that squalene was not present in vaccines administered to these soldiers. ...
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The concept of stimulating the body's immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines.
... Skualen antijenik epitoplara sahip bir bileşik olduğundan immünostimülan özellikler barındırabilir. 2000 yılında yayınlanan bir çalışmaya göre Körfez savaşı sendromu semptomları gösteren eski askerlerde skualene karşı antikorlar saptanmış, oysa sağlıklı eski askerlerde bu antikorlara rastlanmamıştır (4) . Körfez savaşı sendromu; 1990-1991 yıllarında Basra Körfezindeki askeri müdaheleye katılan erkek ve bayan askerlerde görülen yorgunluk, döküntü, baş ağrısı, artralji, miyalji, lenfadenopati, ishal, hafıza kaybı, otoimmün tiroid hastalığı, çevresel elemanlara duyarlılık ve alerjide artış ile nörolojik anormallikler gibi semptomlara topluca verilen isimdir (8,12,14) . ...
... Bu iki grup dışında kalan idiopatik otoimmün hastalığa sahip olanlar ve kontrol grubunda da skualene karşı serum antikorlarına rastlanmamıştır. Bütün bu bulgular yanında çalışmada askeri personele yapılan bu aşıların herhangi birinin skualen içerip içermediğinin bilinmediği belirtilmiştir (4) . Bu çalışma, uygun pozitif ve negatif kontrollerin bulunmaması ve onaylanmış analitik yöntemlerin kullanılmaması gerekçeleriyle eleştirilse de (2) aynı grup tarafından 2001 yılında bağışıklama programı dâhilinde kullanılan şarbon aşısının bazı lotlarının skualen içerdiği ve körfez savaşı sendromunun anti-skualen antikorlarla bağlantılı olduğu bildirilmiştir (5) . ...
... Similarly, no associations between GWI and vaccines received in theater were reported in a 2012 study of Kansas City-area veterans (Steele et al., 2012). Some investigators have suggested that certain vaccines used during the GW contained squalene, which potentially gave rise to antibodies that might be associated with GWI (Asa, Cao, & Garry, 2000). However, a 2009 study found no association between diagnosis of CMI and the presence of squalene antibodies in Navy Seabees who served in the GW (Phillips et al., 2009). ...
Article
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Veterans of Operation Desert Storm/Desert Shield – the 1991 Gulf War (GW) – are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25–32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called “toxic wounds” by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.
... In contrast, none of the veterans without symptoms had these antibodies. 41 At first the anthrax vaccine was suspected, but the manufacturers claim that squalene was not used as the adjuvant during that period. It has never been determined why squalene antibodies were formed in the veterans with Gulf War Syndrome. ...
Research
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An overview of how autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) may impact epidemiology and perception of disease
... The ingredient is an emulsion of a squalene, polyoxyethylene sorbitan monooleate (Tween 80) and sorbitan trioleate [55]. [56,57]. Squalene was also reported as being illegally added to the anthrax vaccine adsorbed (AVA) formulation, which is why Asa's publications were the trigger for nationwide concerns in the US about the safety of squalene-based adjuvants. ...
Article
Vaccination is defined as the administration of an antigenic material in order to stimulate the immune system, leading to the development of adaptive immunity to a pathogen. Vaccines can prevent or reduce morbidity from a vast number of infections. This manuscript presents an analysis of vaccine types and vaccine substances, concentrating on individual components including the active ingredient, adjuvants, preservatives, stabilizers, inactivators, antibiotics, diluents and other substances. While many papers have been published on individual vaccine components, this review provides detail on a wide range of the most commonly-used vaccine ingredients and components that have been tested in clinical trials.
... Some studies have suggested that squalene in the anthrax vaccine may have also contributed to GWI, as antibodies against squalene were more prevalent among veterans with GWI compared to healthy GW veterans. 11,12 Another study showed no association between the presence of squalene antibodies and the diagnosis of GWI. 13 A recent case-control study of GWI showed that even though cases appeared to have a higher rate of vaccination compared to 2 Neuroscience Insights controls, adverse effects reported by GWI patients were more strongly associated with pesticide exposure. 14 Both 2008 and 2016 reports by the Research Advisory Committee on GW Veterans' Illnesses concluded that potential contributions of vaccines to GWI remain unconfirmed. ...
Article
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Gulf War Illness is a multisymptomatic condition which affects 30% of veterans from the 1991 Gulf War. While there is evidence for a role of peripheral cellular and humoral adaptive immune responses in Gulf War Illness, a potential role of the adaptive immune system in the central nervous system pathology of this condition remains unknown. Furthermore, many of the clinical features of Gulf War Illness resembles those of autoimmune diseases, but the biological processes are likely different as the etiology of Gulf War Illness is linked to hazardous chemical exposures specific to the Gulf War theatre. This review discusses Gulf War chemical–induced maladaptive immune responses and a potential role of cellular and humoral immune responses that may be relevant to the central nervous system symptoms and pathology of Gulf War Illness. The discussion may stimulate investigations into adaptive immunity for developing novel therapies for Gulf War Illness.
... Recently, potential issues in relation to the efficacy and safety of vaccine adjuvant have been raised (41)(42)(43)(44). Thus, demand has increased for new adjuvants with minimal adverse effects and enhanced capacity to stimulate antigen-specific adaptive immune responses. ...
Article
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2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is a chemically modified cyclic oligosaccharide produced from starch that is commonly used as an excipient. Although HP-β-CD has been suggested as a potential adjuvant for vaccines, its immunological properties and mechanism of action have yet to be characterized. In the present study, we investigated the maturation and activation of human dendritic cells (DCs) treated with HP-β-CD. We found that DCs stimulated with HP-β-CD exhibited a remarkable upregulation of costimulatory molecules, MHC proteins, and PD-L1/L2. In addition, the production of cytokines, such as TNF-α, IL-6, and IL-10, was modestly increased in DCs when treated with HP-β-CD. Furthermore, HP-β-CD-sensitized DCs markedly induced the proliferation and activation of autologous T lymphocytes. HP-β-CD also induced a lipid raft formation in DCs. In contrast, filipin, a lipid raft inhibitor, attenuated HP-β-CD-induced DC maturation, the cytokine expression, and the T lymphocyte-stimulating activities. To determine the in vivo relevance of the results, we investigated the adjuvanticity of HP-β-CD and the modulation of DCs in a mouse footpad immunization model. When mice were immunized with ovalbumin in the presence of HP-β-CD through a hind footpad, serum ovalbumin-specific antibodies were markedly elevated. Concomitantly, DC populations expressing CD11c and MHC class II were increased in the draining lymph nodes, and the expression of costimulatory molecules was upregulated. Collectively, our data suggest that HP-β-CD induces phenotypic and functional maturation of DCs mainly mediated through lipid raft formation, which might mediate the adjuvanticity of HP-β-CD.
... [223] The Gulf War syndrome was thought for some years to be caused by these anti-squalene antibodies in the serum. [224,225] As squalene is used as adjuvant in a lot of vaccines (including the seasonal influenza vaccine), pharmaceutical companies suggested lately that anti-squalene antibodies are present at low levels in the serum of individuals who were never immunized with squalene-containing formulations. [226][227][228] Additionally, the study from Novartis seems to show that administering squalenecontaining vaccines neither induced anti-squalene antibodies nor enhanced preexisting antisqualene antibody titers. ...
Thesis
Koffein (1,3,7-Trimethylxanthin) und Coprostanol (5beta-cholestan-3beta-ol) wurden im Berliner Oberflächenwasser nachgewiesen. Ihre Konzentrationen korrelierten mit dem Verunreinigungsgrad der Proben, was nahelegt, dass sie sich als Marker für menschliche Aktivität eignen. Bemerkenswerterweise wurde Koffein in jeder einzelnen Oberflächenwasserprobe oberhalb der Bestimmungsgrenze von 0,025 µg/L gefunden. Um Oberflächenwasserproben in größeren Serien zu untersuchen, war die Entwicklung zweier neuer Methoden erforderlich: ein Immunoassay, basierend auf einem monoklonalen Antikörper für Koffein und eine dispersive flüssig-flüssig Mikroextraktionsmethode (DLLME), gefolgt von Flüssigkeitschromatographie gekoppelt mit Tandem-Massenspektrometrie (LC-MS/MS) für Coprostanol. Der entwickelte Koffein-Immunoassay zeigt die beste je erhaltene Nachweisgrenze für Koffein (0,001 µg/L), erlaubt Hochdurchsatz-Analysen und erfordert keine Probenvorbereitung. Der Assay wurde auch erfolgreich für die Messung von Koffein in Getränken, Haarwaschmitteln, Koffeintabletten und menschlichem Speichel angewendet. Antikörper gegen Coprostanol sind nicht kommerziell erhältlich. Eine neue Strategie Anti-Coprostanol-Antikörper zu generieren wurde erarbeitet, die eine analoge Verbindung – Isolithocholsäure (ILA) – als Hapten verwendet, mit der eine Gruppe von Mäusen immunisiert wurde. Ein polyklonales Anti-ILA-Serum wurde produziert, welches Coprostanol bindet, aber die niedrige Affinität erlaubte nicht den Aufbau eines Immunoassays, der die Messung von Umweltkonzentrationen des Anayten (im Bereich ng/L) zulässt. Spezifische Anti-ILA-Immunglobuline G wurden auch in den Faeces der Mäuse gefunden. Coprostanol wurde in den Wasserproben durch die Verwendung einer neuentwickelten LC-MS/MS-Methode unter APCI-Ionisation (atmospheric pressure chemical ionisation) gemessen. Konzentrationen oberhalb von 0,1 µg/L wurden nach Voranreicherung der Probe mittels DLLME bestimmt.
... Since the soldiers had been exposed to unique hazardous environmental conditions, many causal factors have been proposed, including vaccinations (52). One study showed a connection between the anti-squalene antibodies and GWS (53). Squalene-based adjuvant was allegedly used in antrax vaccine that was administered to the soldiers, and antibodies to squalene were detected in the sera of most patients affected. ...
Article
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The purpose of this review is to provide a general overview of adjuvants as immune potentiators, and to offer new insights into the immunological basis and molecular mechanisms of their action. Adjuvants are a key component of many vaccines and their use and development enables many avenues of vaccine design that would otherwise be impossible. Nevertheless, adjuvants are often associated with many safety concerns. Search of available medical literature on adjuvants, vaccines, and their mechanisms of action was performed. Additional articles were identified based on citations in retrieved articles. The main role of adjuvants is to trick the immune system in perceiving vaccine antigen as a serious threat, and thus initiate innate and consecutively adaptive response mechanisms, including long-term immune memory to that antigen. Adjuvants do that by triggering the same evolutionary conserved mechanisms that innate immunity utilizes to detect danger. By inducing innate immune reaction, adjuvants can concurrently provoke some undesirable immune response. However, serious adverse reactions to adjuvanted (as well as nonadjuvanted) vaccines are extremely rare, and there are carefully elaborated regulatory mechanisms to ensure that risks of such adverse reactions are kept at minimum. Conclusion. The use of adjuvants allows a great variety of vaccine designs, enabling the development of safer, more effective, more optimized, and more accessible vaccines than it would be possible without adjuvants. Despite frequent calls to debate, all currently used adjuvanted vaccines have repeatedly demonstrated an excellent safety profile and remain one of the principal tools of science-based medicine in preventing infectious diseases.
... El esquema de inmunización incluyó la vacuna contra el ántrax adyuvada con hidróxido de aluminio y escualeno, y se postularon como posibles mecanismos el desarrollo de anticuerpos contra escualeno, la exposición concomitante a sustancias tóxicas y el estrés. 20 También se ha planteado la posibilidad de un efecto adyuvante con una estimulación tipo Th2 prolongada. 21 Hasta el momento, ningún mecanismo ha sido confirmado, por lo que la patogénesis del GWS continúa bajo escrutinio. ...
Article
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Recently Shoenfeld and Agmon-Levin proposed a new clinical entity called autoimmune/inflammatory syndrome induced by adjuvants (ASIA), which includes four clinical entities called: 1) siliconosis, 2) Gulf War syndrome, 3) macrophage myofasciitis) and 4) post-vaccination phenomenon associated with adjuvants. They all have a common denominator: a prior exposure to immunoadjuvants, and, in addition, they also share several clinical criteria associated to chronic inflammation and autoimmune reactions. This proposal still needs to be validated by the scientific community, but nowadays is a topic of hot discussion in the literature and in various international conferences. In this revision article, we analyze the characteristics of this syndrome, the current mechanisms possibly involved in the pathogenesis, and the more recent reports regarding ASIA associated to vaccine and some foreign substances
... Since vaccines are the milestone of public health, several strategies are used to promote their immunogenicity (23). Vaccines often contain adjuvants (e.g., squalene) to enhance antigen specific immune responses, together with preservatives (e.g., Thimerosal) to prevent bacterial or fungal contamination (24)(25)(26), which are important for vaccine delivery (27). It was reported that squalene causes pathologic reactions at the injection site, together with mild erythema, muscle aches and swelling (25,28), followed by tissue necrosis, intense inflammation and granulomatous lesions (25,29), as well as Guillain Barre Syndrome (25,30). ...
Article
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Background Drug-Induced Liver Injury (DILI) changes, occur post exposure to natural or chemical compounds including apoptosis. Aim To assess the H1N1 vaccine-caused DILI by histochemical and immunohistochemical methods. Methods This 2014’s experimental study was conducted on 70 albino rats. They were given ArepanrixTM H1N1 vaccine and were divided into 7 groups; 10 mice each, as control (non-vaccinated), vac2 and vac4 injected with 1st and 2nd doses of vaccine (suspension only) and euthanized after 3 weeks each, vac5 euthanized 6 weeks after 2nd dose, mix2 and mix4 injected with 1st and 2nd doses of vaccine (mixture of suspension and adjuvant) and euthanized after 3 weeks each, mix5 and euthanized 6 weeks after 2nd dose. Histopathological evaluation and histochemical assessment of metabolic protein, glycogen and collagen changes using PAS, bromophenol blue, Mallory’s trichrome and immunohistochemistry for caspase 3 on liver tissue paraffin sections were done. Image analysis system Leica QIIN 500 was used. Data were analyzed by SPSS software, using descriptive statistics and ANOVA. Results Histopathological changes ranging from subtle up to necrosis were noticed, mainly in mix groups. Metabolic protein and glycogen changes were the maximum in mix5 group (p<0.01). Collagen deposition in sinusoids was higher in mix groups, and maximally in vac5 and mix5. Apoptotic hepatocytes expressing diffuse strong nuclear and cytoplasmic caspase 3 were the highest in mix5. Conclusion H1N1 vaccine can cause DILI by either direct toxic or idiosyncratic metabolic type reactions rather than immunologic hypersensitivity type. It ranges from subtle changes up to necrosis. Caspase 3 is pivotal in liver damage etiology, apoptosis induction and processing. Follow up for at least 2 months after the 2nd dose of H1N1 vaccine is recommended to rule out H1N1-induced DILI.
... At that moment, the immunization schedule included a vaccine with an aluminum hydroxide adjuvant and squalene. The identification of antibodies to squalene adjuvant was associated with the presence of signs and symptoms of this syndrome [8]. ...
Article
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The term autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) or Shoenfeld’s syndrome refers to a wide group of immune-mediated diseases triggered by external agents. Several substances, such as vaccine adjuvants, squalene and silicone implants, are implied in the pathogenesis of ASIA syndrome. Treatment and prognosis of this complex condition are not completely known due to lack of good quality evidence. After a brief introductory literature review on ASIA, we report here two cases of patients that developed rapidly progressive systemic sclerosis clinical features after multiple intramuscular local injections of a substance recommended by a non-medical professional called ADE. ADE is an oily vitamin complex for veterinary use, and it was used in these cases for cosmetic muscular definition and enhancement purpose. To our knowledge, this is the first paper to describe the relation between injections of ADE and the development of ASIA with severe systemic sclerosis phenotype. Further investigation is needed to better understand the pathophysiology and to provide the basis for the treatment of this condition.
... Discussion of the ASIA is very useful since it may alert physicians, when they encounter the above-mentioned symptoms, to check for prior vaccinations, and may help them to put a name on such conditions. Symptoms associated with MMF are strikingly similar to those described as the Gulf war syndrome (GWS), a condition strongly associated with the administration of multiple vaccinations to soldiers (80,81), especially the anthrax vaccine that contains alum, capable of inducing MMF (82), and possibly squalene (83). On these grounds, we proposed to delineate a vaccine adjuvant syndrome (84). ...
Article
Aluminum oxyhydroxide (alum) is a crystaline compound widely used as an immunologic adjuvant of vaccines. Concerns linked to the use of alum particles emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion detected in patients with myalgic encephalomyelitis/chronic fatigue/syndrome. MMF revealed an unexpectedly long-lasting biopersistence of alum within immune cells in presumably susceptible individuals, stressing the previous fundamental misconception of its biodisposition. We previously showed that poorly biodegradable aluminum-coated particles injected into muscle are promptly phagocytozed in muscle and the draining lymph nodes, and can disseminate within phagocytic cells throughout the body and slowly accumulate in brain. This strongly suggests that long-term adjuvant biopersistence within phagocytic cells is a prerequisite for slow brain translocation and delayed neurotoxicity. The understanding of basic mechanisms of particle biopersistence and brain translocation represents a major health challenge, since it could help to define susceptibility factors to develop chronic neurotoxic damage. Biopersistence of alum may be linked to its lysosome-destabilizing effect, which is likely due to direct crystal-induced rupture of phagolysosomal membranes. Macrophages that continuously perceive foreign particles in their cytosol will likely reiterate, with variable interindividual efficiency, a dedicated form of autophagy (xenophagy) until they dispose of alien materials. Successful compartmentalization of particles within double membrane autophagosomes and subsequent fusion with repaired and re-acidified lysosomes will expose alum to lysosomal acidic pH, the sole factor that can solubilize alum particles. Brain translocation of alum particles is linked to a Trojan horse mechanism previously described for infectious particles (HIV, HCV), that obeys to CCL2 signaling the major inflammatory monocyte chemoattractant.
... It acts as a precursor for cholesterol, steroid hormones, and vitamin D. Squalene for commercial purposes is usually extracted from shark liver oil, but it can also be obtained from vegetable oils, such as olive oil and palm oil [19,20]. There were reports by Asa et al. [21] that squalene-based vaccines could lead to the production of anti-squalene antibodies [22,23], although these claims were later criticized and have been a controversial subject [22,24,25]. Nevertheless, more than 20 million doses of squalene-based vaccines have been administered 2 ...
... Anti-squalene antibodies have been reported in individuals who have received anthrax vaccine (Asa et al., 2002;Matyas et al., 2004) and in Gulf War veterans, some of whom developed Gulf War Syndrome characterized by a presence of pseudo-rheumatic symptoms, e.g. muscle and joint pain, fatigue (Asa et al., 2000). But these results are controversial. ...
... It acts as a precursor for cholesterol, steroid hormones, and vitamin D. Squalene for commercial purposes is usually extracted from shark liver oil, but it can also be obtained from vegetable oils, such as olive oil and palm oil [19,20]. There were reports by Asa et al. [21] that squalene-based vaccines could lead to the production of anti-squalene antibodies [22,23], although these claims were later criticized and have been a controversial subject [22,24,25]. Nevertheless, more than 20 million doses of squalene-based vaccines have been administered 2 ...
Article
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Adjuvants are a diverse family of substances whose main objective is to increase the strength, quality, and duration of the immune response caused by vaccines. The most commonly used adjuvants are aluminum-based, oil-water emulsion, and bacterial-origin adjuvants. In this paper, we will discuss how the election of adjuvants is important for the adjuvant-mediated induction of immunity for different types of vaccines. Aluminum-based adjuvants are the most commonly used, the safest, and have the best efficacy, due to the triggering of a strong humoral response, albeit generating a weak induction of cell-mediated immune response. Freund’s adjuvant is the most widely used oil-water emulsion adjuvant in animal trials; it stimulates inflammation and causes aggregation and precipitation of soluble protein antigens that facilitate the uptake by antigen-presenting cells (APCs). Adjuvants of bacterial origin, such as flagellin, E. coli membranes, and monophosphoryl lipid A (MLA), are known to potentiate immune responses, but their safety and risks are the main concern of their clinical use. This minireview summarizes the mechanisms that classic and novel adjuvants produce to stimulate immune responses.
... Low vitD and altered receptor function are linked to risk of autoimmune disease [115][116][117][118][119] . Autoimmune markers are elevated in GWI 120,121 , as well as in other CMI 74, 75, 122 ). Vaccines have been linked to illness in GWV 6, 68-71 and in some cases chronic fatigue. ...
Article
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Background Overlapping chronic multisymptom illnesses (CMI) include Chronic Fatigue Syndrome (CFS), fibromyalgia, irritable bowel syndrome, multiple chemical sensitivity, and Gulf War illness (GWI), and subsets of autism spectrum disorder (ASD). GWI entails a more circumscribed set of experiences that may provide insights of relevance to overlapping conditions. Objectives To consolidate evidence regarding a role for oxidative stress and mitochondrial dysfunction (OSMD), as primary mediators in CMI, using GWI as a departure point. Methods Exposure relations, character, timecourse and multiplicity of symptoms, and objective correlates of GWI are compared to expectation for OSMD. Objective correlates of OSMD in GWI and overlapping conditions are examined. Discussion OSMD is an expected consequence of known GWI exposures; is compatible with symptom characteristics observed; and accords with objective markers and health conditions linked to GWI, extending to autoimmune disease and infection. Emergent triangulating evidence directly supports OSMD in multisymptom “overlap” CMI conditions, with similarities to, and diagnosed at elevated rates in, GWI, suggesting a common role in each. Conclusions GWI is compatible with a paradigm by which uncompensated exposure to oxidative/nitrative stressors accompanies and triggers mitochondrial dysfunction, cell energy compromise, and multiple downstream effects such as vulnerability to autoantibodies. This promotes a profile of protean symptoms with variable latency emphasizing but not confined to energy-demanding post-mitotic tissues, according with (and accounting for) known properties of multisystem overlap conditions. This advances understanding of GWI; health conditions attending GWI at elevated rates; and overlap conditions like CFS and ASD, providing prospects for vulnerability assessment, mitigation of progression, treatment, and future prevention – with implications germane to additive and excessive environmental oxidative stressor exposures in the civilian setting.
... Several controversies have revolved around the use of squalene as an adjuvant for the anthrax vaccine (Asa et al., 2000). A downside of using squalene was debated following its relation to treatments of Gulf War Syndrome (GWS) that included a pool of symptoms such as fatigue, headache, diarrhea, rashes and allergies, memory loss and neurological abnormalities, arthralgias, myalgias, and lymphadenopathy (Gronseth, 2005;Lippi et al., 2010). ...
Article
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The triterpene squalene is a natural compound that has demonstrated an extraordinary diversity of uses in pharmaceutical, nutraceutical, and personal care industries. Emboldened by this range of uses, novel applications that can gain profit from the benefits of squalene as an additive or supplement are expanding, resulting in its increasing demand. Ever since its discovery, the primary source has been the deep-sea shark liver, although recent declines in their populations and justified animal conservation and protection regulations have encouraged researchers to identify a novel route for squalene biosynthesis. This renewed scientific interest has profited from immense developments in synthetic biology, which now allows fine-tuning of a wider range of plants, fungi, and microorganisms for improved squalene production. There are numerous naturally squalene producing species and strains; although they generally do not make commercially viable yields as primary shark liver sources can deliver. The recent advances made toward improving squalene output from natural and engineered species have inspired this review. Accordingly, it will cover in-depth knowledge offered by the studies of the natural sources, and various engineering-based strategies that have been used to drive the improvements in the pathways toward large-scale production. The wide uses of squalene are also discussed, including the notable developments in anti-cancer applications and in augmenting influenza vaccines for greater efficacy.
... on the other hand, healthy adults, or patients with other autoimmune syndromes, and vaccinated veterans without clinical signs of GwS did not form squalene antibodies. 38 while an exact causal relationship still requires elucidation, the evidence of an association between adjuvant administration and GWS is present, a finding that necessitates caution regarding the induced side effects after vaccination administration. ...
Article
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The autoimmune/inflammatory syndrome induced by adjuvants (ASIA), also known as Shoenfeld’s syndrome, encompasses several autoimmune conditions/phenomena that are induced following the exposure to substances with adjuvant activity. The disease spectrum is heterogeneous in respect to clinical presentation as well as severity of the clinical manifestations. Adjuvants are included in vaccination formulations for their immunogenic properties. Despite being generally well tolerated, safe and effective, some genetically predisposed individuals can develop generalized non-specific constitutional symptoms, autoantibody production, new onset, or worsening of disease presentation. In this review, we focus on the current knowledge presented in the literature on ASIA syndrome, increasing physician awareness about the basic concepts of ASIA syndrome and highlight the devastating amount of data accumulated in the last few years concerning the relationship between various adjuvants and autoimmunity.
... El esquema de inmunización incluyó la vacuna contra el ántrax adyuvada con hidróxido de aluminio y escualeno, y se postularon como posibles mecanismos el desarrollo de anticuerpos contra escualeno, la exposición concomitante a sustancias tóxicas y el estrés. 20 También se ha planteado la posibilidad de un efecto adyuvante con una estimulación tipo Th2 prolongada. 21 Hasta el momento, ningún mecanismo ha sido confirmado, por lo que la patogénesis del GWS continúa bajo escrutinio. ...
Article
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Recently Shoenfeld and Agmon-Levin proposed a new clinical entity called autoimmune/inflammatory syndrome induced by adjuvants (ASIA), which includes four clinical entities called: 1) siliconosis, 2) Gulf War syndrome, 3) macrophage myofasciitis) and 4) post-vaccination phenomenon associated with adjuvants. They all have a common denominator: a prior exposure to immunoadjuvants, and, in addition, they also share several clinical criteria associated to chronic inflammation and autoimmune reactions. This proposal still needs to be validated by the scientific community, but nowadays is a topic of hot discussion in the literature and in various international conferences. In this revision article, we analyze the characteristics of this syndrome, the current mechanisms possibly involved in the pathogenesis, and the more recent reports regarding ASIA associated to vaccine and some foreign substances.
... Six common myths were identified. Such flawed statements together with evidence-based information belying these myths are reported in Table 5. 10,11,[54][55][56][57][58][59][60][61] Moreover, some conspiracy theories, which are common among anti-vaccination activists, 15 around squalene and/or squalene-based adjuvants were also present. In particular, in the pilot study we identified two such statements: (i) "politicians are personally immunized with nonadjuvanted vaccines, while laypeople are immunized with vaccines containing squalene" and (ii) "the only reason to include squalene in vaccines is for profit, by sparing the amount of antigen and selling adjuvanted vaccines for a higher price." ...
Article
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Squalene-based adjuvants have been included in influenza vaccines since 1997. Despite several advantages of adjuvanted seasonal and pandemic influenza vaccines, laypeople's perception of such formulations may be hesitant or even negative under certain circumstances. Moreover, in Italian, the term “squalene” has the same root as such common words as “shark” (squalo), “squalid” and “squalidness” that tend to have negative connotations. This study aimed to quantitatively and qualitatively analyze a representative sample of Italian web pages mentioning squalene-based adjuvants used in influenza vaccines. Every effort was made to limit the subjectivity of judgments. Eighty-four unique web pages were assessed. A high prevalence (47.6%) of pages with negative or ambiguous attitudes toward squalene-based adjuvants was established. Compared with web pages reporting balanced information on squalene-based adjuvants, those categorized as negative/ambiguous had significantly lower odds of belonging to a professional institution [adjusted odds ratio (aOR) = 0.12, p = .004], and significantly higher odds of containing pictures (aOR = 1.91, p = .034) and being more readable (aOR = 1.34, p = .006). Some differences in wording between positive/neutral and negative/ambiguous web pages were also observed. The most common scientifically unsound claims concerned safety issues and, in particular, claims linking squalene-based adjuvants to the Gulf War Syndrome and autoimmune disorders. Italian users searching the web for information on vaccine adjuvants have a high likelihood of finding unbalanced and misleading material. Information provided by institutional websites should be not only evidence-based but also carefully targeted towards laypeople. Conversely, authors writing for non-institutional websites should avoid sensationalism and provide their readers with more balanced information.
Conference Paper
Several articles have suggested that immune dysregulation related to Gulf War deployment may be involved in chronic illnesses with an unclear etiology among Gulf War veterans. To determine whether genetic susceptibility related to the human leukocyte antigen (HLA) system might play a role in development of the veterans' illnesses, we examined the frequency distribution of HLA A, B, DR, and DQ antigens from symptomatic veterans residing in south-central Pennsylvania compared with a local healthy population database. Only HLA-A28 demonstrated statistical significance. A28 was present in 7 (21.9%) of 32 of the veterans and 15 (6.9%) of 217 of the healthy population (p = 0.01, Fisher's exact test). This accounts for a minority of the ill veterans tested and is not statistically significant when corrected for the number of antigens determined. We conclude that specific HLA antigens are not strongly associated with the illnesses of Gulf War veterans.
Article
The development and increasing diffusion of new vaccinations and global immunization protocols have aroused burning debates about safety of adjuvants and their immunogenicity-enhancing effect in vaccines. Shoenfeld and Agmon-Levin have grouped under the term "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) a complex of variable signs and symptoms that may occur after a previous exposure to different adjuvants and also external environmental triggers, even eliciting specific overt immune-mediated disorders. This entity subsumes five medical conditions: post-vaccination phenomena, gulf war syndrome, macrophagic myofasciitis syndrome, siliconosis, and sick building syndrome, but the relevance and magnitude of the syndrome in the pediatric age is fundamentally limited to post-vaccination autoimmune or inflammatory disorders. The occurrence of vaccine-triggered phenomena represents a diagnostic challenge for clinicians and a research conundrum for many investigators. In this paper, we will analyze the general features of ASIA and focus on specific post-vaccination events in relation with the pediatric background. In the presence of a favorable genetic background, many autoimmune/inflammatory responses can be triggered by adjuvants and external factors, showing how the man himself might breach immune tolerance and drive many pathogenetic aspects of human diseases. Nonetheless, the elective application of ASIA diagnostic criteria to the pediatric population requires further assessment and evaluations. Additional studies are needed to help clarify connections between innate or adaptive immunity and pathological and/or protective autoantibodies mostly in the pediatric age, as children and adolescents are mainly involved in the immunization agendas related to vaccine-preventable diseases.
Book
Since 1990, the number of mandated vaccines has increased dramatically. Today, a fully vaccinated child will have received nearly three dozen vaccinations between birth and age six. Along with the increase in number has come a growing wave of concern among parents about the unintended side effects of vaccines. In Vaccine, Mark A. Largent explains the history of the debate and identifies issues that parents, pediatricians, politicians, and public health officials must address. Nearly 40% of American parents report that they delay or refuse a recommended vaccine for their children. Despite assurances from every mainstream scientific and medical institution, parents continue to be haunted by the question of whether vaccines cause autism. In response, health officials herald vaccines as both safe and vital to the public's health and put programs and regulations in place to encourage parents to follow the recommended vaccine schedule. For Largent, the vaccine-autism debate obscures a constellation of concerns held by many parents, including anxiety about the number of vaccines required (including some for diseases that children are unlikely ever to encounter), unhappiness about the rigorous schedule of vaccines during well-baby visits, and fear of potential side effects, some of them serious and even life-threatening. This book disentangles competing claims, opens the controversy for critical reflection, and provides recommendations for moving forward. © 2012 The Johns Hopkins University Press. All rights reserved.
Article
Epidemiology is the study of the distribution of illnesses and diseases and the factors affecting their incidence and clinical course in the population. Systemic lupus erythematosus (SLE), an autoimmune disease with a broad spectrum of clinical and immunological manifestations, is a major challenge to study epidemiologically, but research on SLE has been carried out in many parts of the world. These include descriptive studies of incidence and prevalence, observational studies of SLE prognosis, and the identification of potentially preventable causes of morbidity and mortality. Analytic and genetic epidemiologic studies suggest a multifactorial etiology of SLE. A better understanding of the epidemiology of SLE should help us understand its etiology, identify predictors of morbidity and mortality, and improve SLE care and outcomes. Epidemiologic clues for potential cause(s) remain elusive, not so much from lack of effort, but lack of strong signals. Even the most established risk factors, except for gender, explain the minority of cases. Overall, epidemiologic studies demonstrate a good and possibly improved prognosis since its first description, making SLE a chronic but potentially dangerous illness. Studies also indicate considerable variations in outcome and differences between ethnic groups and between industrial and preindustrial countries that are probably increasing, comprising a major research challenge and a possible public health opportunity to correct these inequalities. Long-term morbidity is appreciated but its study is only just beginning. Future studies will need to look at what is really modifiable and to test interventions rigorously.
Article
In this study, nine crude extracts from Thai plants in the Moraceae and Leguminosae families were screened for their immunoadjuvant activities on the proliferation of swine lymphocytes and the maturation of monocyte-derived dendritic cells (MoDCs). The study demonstrated that the total phenolic content was significantly higher in the extract from Artocarpus gomezianus (264.17±6.5 mg of gallic acid equivalents/gm of extract) than in the extracts from the other plants. The crude extract from the root bark of A. gomezianus significantly increased the proliferative response of peripheral blood mononuclear cells measured using both MTT and CFSE assays (p < 0.05). In addition, the A. gomezianus extract induced the maturation of MoDCs through major histocompatibility (MHC) Class II and CD80 expression. Constituents of phenolic compounds, in particular tannins and flavonoids in the γ-benzopyrone nucleus group, may be important for the immunoadjuvant effect. The results of this study suggest that the extract from A. gomezianus have immunoadjuvant activities that may be developed as vaccine adjuvants.
Article
After started at March 2009 in Mexico, the pandemic influenza started to spread with rapidly in the world. World Health Organization (WHO) said that over 16000 people died from this infection. The Ministry of Health of Turkey announced 627 people died from pandemic influenza at 20 January 2010. H1N1 started to spread rapidly nearly pandemic, the vaccine research has been started and the vaccines developed. The pandemic influenza vaccines are non-adjuvanded, adjuvanded, and live attenuated vaccines. Since the application of pandemic influenza vaccine started swiftly, the community could not be informed sufficiently. Therefore, problems about application confronted. Squalene and thiomersal in adjuvanded vaccines and Guillain Barré syndrome (GBS) are the most discussed topics. Start of vaccination adverse effects and their activity is been observing and the studies are continuing, the vaccine several adverse effects have no difference of security profiles. Perspiration, erythema and pain on enjected area are the most seen side effects as predicted. Also these side effects healed without any treatment at short time. Fever, headache, fatigue, myalgia are reported as rarely side effects. These side effects healed without any treatment in 48 hours too. At this article, we purpose to give information about H1N1 vaccines which are using in Europe and USA.
Chapter
Adjuvants are key components of many vaccines, used to enhance the level and breadth of the immune response to a target antigen, thereby enhancing protection from the associated disease. In recent years, advances in our understanding of the innate and adaptive immune systems have allowed for the development of a number of novel adjuvants with differing mechanisms of action. Herein, we review adjuvants currently approved for human and veterinary use, describing their use and proposed mechanisms of action. In addition, we will discuss additional promising adjuvants currently undergoing preclinical and/or clinical testing.
Chapter
Fibromyalgia syndrome (FMS) represents a unique entity within the field of rheumatology, differing from the more “classical” rheumatological disorders both in pathogenesis and in its modes of management. Gulf War syndrome (GWS) is an unusual case of a functional disorder strictly situated in a specific historical and geographical circumstance. Characterized by chronic fatigue, musculoskeletal symptoms, malaise, and cognitive impairment, GWS clinically overlaps with both post-traumatic stress disorders (PTSD) and FMS/chronic fatigue syndrome (CFS), as well as with other functional disorders. FMS and CFS are conditions with considerable clinical overlap. Fatigue is an inherent symptom of FMS, along with disturbed nonrefreshing sleep, while muscular pain is a common symptom among those diagnosed as suffering from CFS. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a recently described entity that encompasses symptoms from a number of clinical syndromes, including siliconosis, GWS, macrophagic myofasciitis (MMF), and post-vaccination phenomena linked with exposure to an adjuvant.
Article
Aims Gulf War Illness (GWI) is a chronic multisymptom illness with debated etiology and pathophysiology. This systematic review catalogues studies of validated biological tests for diagnosing GWI and of associations between biological measures and GWI for their promise as biomarkers. Main methods We searched multiple sources through February 2020 for studies of diagnostic tests of GWI and of associations between biological measures and GWI. We abstracted data on study design, demographics, and outcomes. We assessed the risk of bias of included studies. Key findings We did not identify any studies validating tests of biomarkers that distinguish cases of GWI from non-cases. We included the best-fitting studies, 32 completed and 24 ongoing or unpublished studies, of associations between GWI and biological measures. The less well-fitting studies (n = 77) were included in a Supplementary Table. Most studies were of the central nervous and immune systems and indicated a significant association of the biological measure with GWI case status. Biological measures were heterogeneous across studies. Significance Our review indicates that there are no existing validated biological tests to determine GWI case status. Many studies have assessed the potential association between a variety of biological measures and GWI, the majority of which pertain to the immune and central nervous systems. More importantly, while most studies indicated a significant association between biological measures and GWI case status, the biological measures across studies were extremely heterogeneous. Due to the heterogeneity, the focus of the review is to map out what has been examined, rather than synthesize information.
Research
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The Study of the impact of the H1N1 vaccine and its components on immune system, done by studying the changes of the immunological, histological and histochemical studies on some immune tissues of rats. Where the study showed a higher immune potential changes to the squalene adjuvanted H1N1 vaccine developed against influenza virus spread during 2009 l than those of non adjuvanted vaccine. Despite the promising immune potential of developed vaccine. H1N1 vaccine and its components showed a drastic hematological and immunological changes in addition to the sever histopathological changes.
Research
The Study of the impact of squalene as ajuvant on immune system, done by studying the changes of the immunological and immunohistochemical studies on some immune tissues of rats. Where the study showed severe changes to the squalene immunization, despite the adverse events induced post administration of squalene at different intervals. Squalene as adjuvant showed drastic hematological and immunological changes in addition to sever histopathological changes.
Article
The pandemic flu (2009) is a global outbreak of anewstrain ofH1N1 influenza virusthat referred as "swine flu".The 2009 flu pandemic vaccines (H1N1 vaccines) are thebiological preparation ofinfluenza vaccinesthat have beendeveloped to protect and improve immunity against thepandemic H1N1/09 virus. Squalene has been added tovaccineasimmunologic adjuvantto stimulate theimmunesystem, increase the response to the vaccine and reduceamount of usage vaccine. Thimerosal has been added tosome vaccines as a preservative because itis effective inpreventing bacterial contamination, particularly inmultidose containers. To investigate the possibleimmunological effects of swine flu vaccine, Albino ratswere injected with H1N1 antigen contained thimerosal,adjuvant and H1N1 vaccine.Results obtained in the presentstudy showed thatsqualeneandthimerosalcontributed tothe regiment of adverse reactions and symptoms, which actas detergents instead of its helper role of vaccine thatundergone toxicity effectors in the biological pathwaysincluding; immunopathological and histopathologicaleffects; the damage was done by vaccine, particularly whenpotentiated by powerful "immunoenhancers" caused astrong immunostimulation that emphasized by results ofthis research as well as its biological hazards which aremore pronounced when act together as whole vaccine thanthey act individually so the adverse events that resultedfrom treatment with squalene-adjuvanted vaccine are morepotent than those of either antigen or squalene-treatedgroups.
Article
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La capacità degli squali di resistere alle infezioni e la bassa incidenza dei tumori riscontrata in queste specie marine suggerisce la presenza di specifici composti anti-tumorali estratti dai loro tessuti, quali alchilgliceroli, estratti dal fegato, squalene, estratto dal mesenchima e dalla cute, e cartilagine, estratta dallo scheletro. Gli alchilgliceroli, altamente concentrati nell'olio di fegato di squalo, hanno un'azione anti-tumorale, stimolano l'ematopoiesi e l'immuno-modulazione. Lo squalene è anch'esso un agen-te antitumorale, nonché antiossidante, detossificante, con azione emolliente, lenitiva, seborestitutiva e protettiva della cute. La cartilagine, con azione anti-infiammatoria, è comunemente utilizzata nella medicina tradizionale per il trattamento di artrite, osteoartrite, retinopatia diabetica e psoriasi.
Article
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Dotychczas opisano wiele przypadków pojawienia się autoprzeciwciał i objawów chorobowych po ekspozycji na adiuwanty, nie tylko w kontekście wszczepienia silikonowych implantów piersi, ale również jako bardzo rzadko występujące odczyny poszczepienne, zespół wojny w Zatoce Perskiej (Gulf war syndrome) czy zespół makrofagowego zapalenia mięśniowo-powięziowego. Grupę chorób, których objawy wystąpiły po tego typu ekspozycji, nazwano autoimmunologicznym zespołem indukowanym przez adiuwanty (autoimmune/inflammatory syndrome induced by adjuvants – ASIA). Do adiuwantów, oprócz silikonowych implantów, zalicza się krzem, skwalen i glin, a także składniki pigmentów stosowanych do wykonywania tatuaży itp. Analizując piśmiennictwo odnoszące się do wpływu adiuwantów na rozwój chorób autoimmunologicznych, nasuwa się wniosek, że oprócz długotrwałej ekspozycji na silikon konieczne jest również współistnienie innych czynników, takich jak predyspozycja genetyczna czy wpływ czynników środowiskowych. Metaanalizy jednoznacznie nie potwierdzają zwiększenia ryzyka wystąpienia choroby autoimmunologicznej po wszczepieniu silikonowych implantów piersi lub wykonaniu tatuażu, ale możliwe jest zwiększenie predyspozycji do ich wystąpienia w pewnej grupie badanych pacjentów. W populacji ogólnej pozytywny wpływ stosowanych szczepień jest znaczący, a ryzyko wystąpienia poważnych odczynów poszczepiennych jest nieporównywalnie mniejsze niż ryzyko zachorowania na daną jednostkę chorobową i wystąpienia jej powikłań, również u chorych z rozpoznanymi chorobami reumatycznymi. Ze względu na niejednorodność wyników dotychczasowych badań oraz trudności w diagnostyce i rozpoznawaniu ASIA, konieczne będzie prowadzenie dalszych badań na temat wpływu adiuwantów na rozwój chorób autoimmunologicznych oraz dopracowanie kryteriów ASIA, które pozwalają obecnie na zbyt łatwe rozpoznawanie tego zespołu.
Chapter
Aluminum hydroxide (alum), a nanocrystalline compound that forms micron-sized agglomerates, is widely used as an adjuvant of vaccines. Alum strongly binds antigens, activates the NLRP3 inflammasome, and stimulates immune responses through poorly understood mechanisms likely implicating phagocytosis and lysosome destabilization. Although generally well tolerated, alum may occasionally cause chronic health problems in presumably susceptible individuals. Some patients present with delayed onset of diffuse myalgia, chronic exhaustion, and cognitive dysfunction, associated with long-term persistence (up to 12 years) of alum-loaded macrophages at the site of immunizations, forming the so-called macrophagic myofasciitis (MMF). Symptoms are consistent with the myalgic encephalitis/chronic fatigue syndrome (ME/CFS), which may or may not be associated with overt autoimmunity. The symptoms are similar to those of Gulf War Syndrome and have been considered as one paradigm of autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Cognitive dysfunction is reminiscent of that described after occupational exposure to aluminum. Biopersistent particles, such as fluorescent nanohybrids coated with precipitated alum, injected into mouse muscle are captured by monocyte-lineage cells and, in part, carried to the draining lymph nodes and then, probably via the thoracic duct, to the blood and to distant organs, with slow accumulation in the brain (microglial cells). Brain penetration occurs at extremely low level in normal conditions, which is consistent with good tolerance to alum despite its high neurotoxic potential. However, systemic diffusion of particles considerably increases under the potentiating effect of MCP-1, the main monocyte chemoattractant factor, the production of which is subjected to important variations linked to age, genetic, and environmental factors (circulating MCP-1 is selectively increased in MMF patients). Clinical and experimental data strongly suggest that alum may be insidiously unsafe, that alum safety should be evaluated in the long term, and that replacement of alum by other adjuvants should be envisaged.
Article
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The Study of the impact of squalene as ajuvant on immune system, done by studying the changes of the immunological and immunohistochemical studies on some immune tissues of rats. Where the study showed severe changes to the squalene immunization, despite the adverse events induced post administration of squalene at different intervals. Squalene as adjuvant showed drastic hematological and immunological changes in addition to sever histopathological changes.
Chapter
Whether it was the spread of plague following Mongol invasions, or the near eradication of Native Americans due to disease brought in from the Old World, disease has played a significant role in strategy and geopolitics. Of the many lives lost due to the violence of war throughout history, many more have succumbed to disease during battle rather than actual combat. Typhus (spread by lice), plague (via fleas and infected rats), and dysentery have caused enormous numbers of deaths in major wars as far back as one can go. For every one British soldier killed by Russian rifle or artillery, for example, at least ten died from dysentery during the Crimean War (1854–56). Ten years later during the American Civil War, infectious disease also took a disproportionate toll.
Chapter
Small molecules are unable to stimulate the immune system by themselves, and so require conjugation to a larger structure, i.e., a carrier molecule (often a protein) to enable effective engagement of immune cell receptors that can initiate adaptive immune responses. However, in most circumstances, the molecular structure of the hapten and a protein carrier molecule alone are inadequate to elicit a strong immune response. Since blocking the pharmacological effects of substance abuse drugs requires binding of a large fraction of the drug molecules, robust antibody responses are essential for drugs that are active in the high nanomolar or low micromolar range. To achieve such high specific antibody levels, vaccine formulations must have additional costimulatory signals in order to ramp up the immune responses. The costimulatory signals are most often provided by added materials that are generally called adjuvants. While the field has become markedly better understood and more complex than when the early adjuvants were described by Charles Janeway as the “immunologists’ dirty little secret,” the fundamental issues involved remain the same – stimulating antigen-presenting cells, activating helper T cells, and activating B cells in order to promote differentiation, proliferation, and high-level specific immune responses. Each of these steps is now understood to involve multiple molecular signals and pathways both inside and outside each cell type, resulting in an elegant and flexible, though incredibly complex, regulated immune response.
Chapter
Some adjuvants may exert adverse effects upon injection, or on the other hand, may not trigger a full immunological reaction. The mechanisms underlying adjuvant adverse effects are under renewed scrutiny because of their enormous implications for vaccine development. In the search for new and safer adjuvants, several new ones have been developed by pharmaceutical companies utilizing new immunological and chemical innovations. The ability of the immune system to recognize molecules that are broadly shared by pathogens results, in part, from the presence of special immune receptors called toll-like receptors (TLRs) that are expressed on leukocyte membranes. The fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used in vaccinations today are developed to mimic TLR ligands. Alongside their supportive role in eliciting the immune response to vaccine antigens, however, adjuvants have themselves been found to inflict illnesses of autoimmune nature, defined as “the adjuvant diseases.” This chapter looks at the use of silicone as an adjuvant and at connective tissue diseases, as well as the Gulf War Syndrome and Macrophagic myofasciitis following multiple injections of aluminum-based vaccines. There is no question that safer adjuvants are needed for incorporation into future vaccines. In light of new vaccine technologies adjuvants suitable for use with mucosally delivered vaccines, DNA vaccines, and cancer and autoimmunity vaccines are also needed. In particular, there is demand for safe and non toxic adjuvants capable of stimulateing cellular (Th1) immunity. Besides alum, many other adjuvants have been approved for use in human vaccines including: MF59 in some viral vaccines; MPL, AS04, As01B, and AS02A against viral and parasitic infections; virosomes for HBV, HPV, and HAV; and cholera toxin for cholera. Perhaps future adjuvants occupying other putative receptors will be employed to bypass the TLR signaling pathway completely, in order to circumvent common side effects such as local inflammation and the general malaise caused by the costly whole- body immune response to antigen.
Chapter
Many studies have been carried out to investigate the immune pathways stimulated by adjuvants, the role of adjuvants in enhancing pathogen-specific immune responses, and the potential noxious effects of adjuvants for the recipient, both in animal models and in humans. In order to prevent several costly infectious diseases, farmed salmon are intraperitoneally injected with vaccines containing adjuvant oil and a number of different antigens. The rabbit model is often used for vaccines intended for intramuscular injection. The adjuvants were inoculated in swine neck, quadriceps, and semitendinosus muscles. Several kinds of animal models have been employed to investigate adjuvant effects and midterm reactions in vivo, in an attempt to better unravel adverse events in humans following vaccinations or prosthesis implantations. Higher organisms, such as primates, are rarely used; rather, different mouse models have provided the bulk of the evidence for vaccine and adjuvants effects in living beings.
Article
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Squalene, a key intermediate of cholesterol synthesis, is present especially in olive oil. Regulation of cholesterol metabolism by dietary squalene in man is unknown, even though olive oil users in Mediterranean areas have low serum cholesterol levels. We have investigated absorption and serum levels of squalene and cholesterol and cholesterol synthesis with the sterol balance technique and serum levels of cholesterol precursors in humans during squalene feeding (900 mg/d for 7-30 days). The results were compared with those during cholestyramine treatment. Fecal analysis suggested that about 60% of dietary squalene was absorbed. Serum squalene levels were increased 17 times, but serum triglyceride and cholesterol contents were unchanged. The squalene feeding significantly (P less than 0.05) increased serum levels of free (1.7-2.3 times) and esterified (1.9-2.4 times) methyl sterol contents, while elevations of free and esterified delta 8-cholesterol and lathosterol levels were inconsistent. Cholestyramine treatment modestly augmented free methyl sterol levels (1.3-1.7 times), less consistently than those of esterified ones, while, in contrast to the squalene feeding, serum contents of free and esterified delta 8-cholesterol and lathosterol were dramatically increased (3.3-8 times). Neither of the treatments significantly affected serum plant sterol and cholestanol levels. The squalene feeding had no consistent effect on absorption efficiency of cholesterol, but significantly increased (paired t-test, P less than 0.05) the fecal excretions of cholesterol and its nonpolar derivatives coprostanol, epicoprostanol, and coprostanone (655 +/- 83 SE to 856 +/- 146 mg/d) and bile acids (212 +/- 24 to 255 +/- 24 mg/d), indicating an increase of cholesterol synthesis by about 50%. We suggest that a substantial amount of dietary squalene is absorbed and converted to cholesterol in humans, but this squalene-induced increase in synthesis is not associated with consistent increases of serum cholesterol levels. The clearly increased serum contents of esterified methyl sterols may reflect stimulated tissue acyl CoA: cholesterol acyltransferase (ACAT, EC 2.3.1.26) activity during squalene feeding as these sterols are not esterified in serum.
Article
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Interleukin 1 (IL 1) is a polypeptide that is produced after infection, injury, or antigenic challenge. Although the macrophage is a primary source of IL 1, epidermal, epithelial, lymphoid, and vascular tissues synthesize IL 1. When IL 1 gains access to the circulation, it acts like a hormone and induces a broad spectrum of systemic changes in neurological, metabolic, hematologic, and endocrinologic systems. Some of the IL 1 that is synthesized remains associated with the plasma membrane and induces changes in local tissues without producing systemic responses. IL 1 affects mesenchymal tissue remodeling where it contributes to both destructive and repair processes. IL 1 activates lymphocytes and plays an important role in the initiation of the immune response. Receptors for IL 1 have been identified, but receptors are scarce and their affinities often do not match the potency of the biological response. The most consistent property of IL 1 is up-regulation of cellular metabolism and increased expression of several genes coding for biologically active molecules. IL 1 is a highly inflammatory molecule and stimulates the production of arachidonic acid metabolites. IL 1 also acts synergistically with other cytokines, particularly tumor necrosis factor. The multitude of biological responses to IL 1 is an example of the rapid adaptive changes that take place to increase the host's defensive mechanisms.
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To compare the titre of anti-ganglioside antibodies (AGA) to GM1 ganglioside in patients with central and peripheral neurological disease and pure motor and sensorimotor neuropathy, in patients with classic autoimmune diseases, and controls. AGA to GM1 were measured using an enzyme linked immunosorbent assay (ELISA) technique, highly purified bovine GM1 ganglioside, and sequential dilution of control and test sera. Antibody titre was calculated using the optical density readings of three consecutive serum dilutions multiplied by the dilution factor. A considerable overlap was evident in the titre of AGA to GM1 in control and test sera. High antibody titres were most frequent in patients with multifocal motor neuropathy with conduction block (MMNCB). Low AGA titre were observed in several patient groups. Compared with the controls, the median titre of AGA to GM1 was significantly higher in patients with multiple sclerosis, rheumatoid arthritis, primary Sjögren's syndrome and systemic lupus erythematosus. In contrast, the median titre in patients with diabetic peripheral neuropathy, motor neurone disease, sensorimotor neuropathy and chronic inflammatory demyelinating polyneuropathy was no different from that in normal control subjects. Estimation of AGA to GM1 may be helpful in the diagnosis of MMNCB in patients with a pure motor neuropathy but in few other conditions. Low titre AGA to GM1 are evident in several autoimmune conditions. The pathogenetic importance of AGA to GM1 in patients with neuropathy is not clear.
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In the present study we investigated the subcellular localization of squalene synthase (farnesyl-diphosphate:farnesyl-diphosphate farnesyltransferase, EC 2.5.1.21). Squalene synthase catalyzes the formation of squalene from trans-farnesyl diphosphate in two distinct steps and is the first committed enzyme for the biosynthesis of cholesterol. Recently, a truncated form of the enzyme from rat hepatocytes was purified, and monospecific antibodies for squalene synthase were produced. This enabled the subcellular localization of squalene synthase by three different methods: (i) analytical subcellular fractionation and measurements of enzyme activities; (ii) immunodeterminations of squalene synthase in the isolated subcellular fractions with a monospecific antibody; and (iii) immunoelectron microscopy. All three methods gave consistent results. The data clearly illustrate that squalene synthase enzymatic activity and squalene synthase are exclusively localized in the endoplasmic reticulum. In rat hepatic peroxisomes we were not able to detect any squalene synthase. In addition, we also demonstrated that squalene synthase in the microsomal fraction is dramatically regulated by a number of hypolipidemic drugs and dietary treatments.
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Objective: To describe the clinical and serologic features of women with silicone breast implants who were referred for symptoms of rheumatic disease. Design: A case series. Setting: University and private rheumatology practices. Patients: A total of 156 women with silicone breast implants and rheumatic disease complaints. Controls for the serologic studies included women with silicone implants and no rheumatic symptoms (n=12) and women with fibromyalgia without silicone implants (n=174). Measurements: Complete physical examination and testing for immunoglobulins; complement; C-reactive protein; rheumatoid factor, and autoantibodies by indirect immunofluorescence, immunodiffusion, and Western blot
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We investigated the safety and immunogenicity of a candidate HIV-1 vaccine, Env 2-3 (Chiron Biocine Co.), in combination with an adjuvant emulsion, MF59, with or without an additional immune modulator, MTP-PE, in 78 healthy HIV-1-seronegative adults. Sixteen subjects participated in a dose escalation study of MTP-PE in MP59 without Env 2-3, given at 0 and 1 months; 48 subjects participated in a study of a fixed dose of 30 mu g of Env 2-3 in MF59 with increasing doses of MTP-PE (0, 5, 10, 25, 50, and 100 mu g), and 14 subjects participated in a study of 100 mu g of Env 2-3 in MF59 without MTP-PE. Subjects were assigned to study groups under a randomized, double-blind allocation. Subjects received immunization at 0, 1, and 6 months, and had the option of receiving a fourth dose at 12-18 months. Env 2-3 in MTP-PE/MF59 was associated with significant reactogenicity, in that severe, although self-limited systemic and/or local reactions occurred in 15 of 30 vaccinees. In contrast, Env 2-3 in MF59 without MTP-PE was relatively well tolerated, and severe local and/or systemic reactions occurred in only 2 of 18 subjects, Env 2-3 stimulated serum antibodies to HIV-1 envelope protein (gp120) as detected by Western blot in 39 of 43 subjects and to HIV-1 virus lysate by EIA in 28 of 43 subjects after three injections. The majority of subjects also developed EIA antibodies to recombinant gp120 (SF-2), gp120 (LAI), and V3 peptide (SF-2). Neutralizing antibodies to the homologous SF-2 strain developed in 30 of 43 and 27 of 34 subjects, and fusion inhibition antibodies in 25 of 43 and 15 of 36 subjects after three and four injections, respectively, Lymphoproliferative responses to the immunogen, Env 2-3, were observed in over 80% of the vaccinees examined, and CD4+ cytotoxic T cell activity directed against HIV-1 was noted transiently in 2 of 20 vaccinees. Addition of MTP-PE to Env 2-3 or increasing the dose of Env 2-3 from 30 to 100 mu g did not augment immunogenicity. Env 2-3 in MF59 was well tolerated and immunogenic in HIV-1-seronegative individuals. The addition of MTP-PE significantly increased reactogenicity, but had little, if any, effect on immunogenicity.
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Between August 1990 and March 1991, the United States deployed 697 000 troops to the Persian Gulf to liberate Kuwait from Iraqi occupation. Since the Gulf War, most veterans seeking medical care at Departments of Veterans Affairs and Defense medical facilities have had diagnosable conditions, but the symptoms of several thousand veterans have not been readily explained. The most commonly reported, unexplained complaints have been chronic fatigue, rash, headache, arthralgias/myalgias, difficulty concentrating, forgetfulness, and irritability. These symptoms have not been localized to any one organ system, and there has been no consistent physical sign or laboratory abnormality that indicates a single specific disease. Because of the unexplained illnesses being experienced by some Gulf War troops, a comprehensive clinical and research effort has been organized by the Departments of Veterans Affairs, Defense, and Health and Human Services to provide care for veterans and to evaluate their medical problems. To determine the causes and most effective treatments of illnesses among Gulf War veterans, a thorough understanding of all potential health risks associated with service in the Persian Gulf is necessary. These risks are reviewed in this article and include possible reactions to prophylactic drugs and vaccines, infectious diseases, and exposures to chemicals, radiation, and smoke from oil fires.(Arch Intern Med. 1995;155:262-268)
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EAE induced in Lewis rats by guinea-pig spinal cord and such lipid adjuvants as hexadecane or squalene (without the mycobacterial component) is more sensitive to lower doses of cyclophosphamide and some select immunosuppressive agents than the conventional EAE induced using Freund's complete adjuvant. In addition, these animals do not suffer from adjuvant arthritis which may be induced if the bacterial component is present. These modifications in the conventional assay have enhanced its ability to detect new, weaker and/or lower doses of known immunosuppressants.
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EAE induced in Lewis rats by guinea-pig spinal cord and such lipid adjuvants as hexadecane or squalene (without the mycobacterial component) is more sensitive to lower doses of cyclophosphamide and some select immunosuppressive agents than the conventional EAE induced using Freund's complete adjuvant. In addition, these animals do not suffer from adjuvant arthritis which may be induced if the bacterial component is present. These modifications in the conventional assay have enhanced its ability to detect new, weaker and/or lower doses of known immunosuppressants.
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We confirmed that, when immunized with a conventional complete Freund adjuvant (water in oil), Lewis rats were highly susceptible to adjuvant arthritis, Fisher rats were less susceptible, and Buffalo rats were much less susceptible. However, mycobacterial delipidated cells in squalane (squalane-type adjuvant) produced severe arthritis with almost 100% incidence even in the less susceptible rat strains except for Buffalo rats. With regard to an immune response, Freund complete adjuvant induced strong delayed hypersensitivity to purified protein derivative (PPD) and peptidoglycan (PG) in all rat strains used, Whereas the squalane-type adjuvant induced these hypersensitivities only in Lewis and Buffalo rats, but not in Fisher and Brown Norway rats. No correlation was found between development of arthritis and delayed hypersensitivity to either PPD or PG, or both. It seems that PPD hypersensitivity may be inherited differently from PG hypersensitivity.
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The homing and adhesion of circulating cells to target tissue vasculature precedes their subsequent invasion of inflamed tissue. Polymorphonuclear cells (PMNs), key players in most inflammatory events, are among the first cells to arrive. The present work, performed on CNS lesions from mice with experimental autoimmune encephalomyelitis, provides morphologic evidence for interactions between PMNs and unique, frondlike extensions from endothelial cells (EC) during early attachment. Platelets also were seen attached to these endothelial fronds. The structures projected into vessel lumina from the vicinity of tight junctions and were often branched and complex, the latter characteristics suggesting a possible role in cellular 'trapping'. Polymorphonuclear cells appeared to traverse the CNS vasculature between EC where the blood-brain barrier was severely compromised with junctional complexes reduced to simple contact points. The cells from which the fronds derived were often plump and possessed cytoplasm rich in organelles, perhaps indicative of activation. The present report contrasts with previous observations on lymphocytes in the same system where lymphocytic pseudopodia formed intimate contacts before their burrowing directly through the endothelium and where EC fronds were not involved.
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Adjuvants can be used with recombinant antigens to elicit cell-mediated immunity and antibodies of protective isotypes (IgG2a in the mouse and IgG1 in primates). Adjuvants should not produce reactions at injection sites, be pyrogenic or induce anterior uveitis or arthritis. Among 130 analogs of muramyl dipeptides tested, N-acetylmuramyl-L-threonyl-D-isoglutamine showed the greatest separation of potency as an adjuvant from potency in the production of side-effects. A stable emulsion of squalane and the Pluronic polymer L-121 provides a versatile vehicle for targeting of antigens to antigen-presenting cells. The combination of this emulsion with the threonyl analog of MDP is termed Syntex Adjuvant Formulation. This formulation increases the efficacy of influenza, hepatitis B virus, herpes simplex virus, lentivirus and tumor vaccines in experimental animals.
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Polyclonal and monoclonal antibodies to cholesterol are readily induced by injecting cholesterol-loaded liposomes containing lipid A as an adjuvant. Analysis of the literature reveals that conjugates of cholesterol, and conjugates of analogues of cholesterol, with heterologous proteins or lipids have been used as antigens in various studies since 1925, and this has led to successful development of immunoassays for steroid hormones. It is concluded that cholesterol is a highly immunogenic molecule. The ability of monoclonal antibodies to cholesterol to react with liposomes containing cholesterol to cause complement-dependent immune damage to the liposomes is strongly influenced by the lipid composition of the liposomes, the amount of cholesterol in the liposomes, and the reaction temperature. The antibodies also react with crystalline cholesterol in a solid-phase ELISA and, depending on the particular monoclonal antibody, immune reactivity may or may not be observed with cholesterol esters, cholesterol analogues, or steroid hormones. Analysis by ELISA has revealed that virtually all normal human sera contain varying levels of naturally occurring IgG and IgM autoantibodies to cholesterol. Naturally occurring autoantibodies to cholesterol are also observed in pigs, but not in guinea pigs. Possible implications of these investigations for theories of immune mechanisms that may have beneficial or detrimental roles in processes of aging, atherosclerosis, and vascular diseases are discussed.
MS and CIP are inflammatory diseases of the CNS and PNS that are characterized by focal demyelination. Both disorders are thought to involve autoimmune processes. The factors that lead to a chronic inflammatory process have not been completely defined, but the immune system is thought to play a prominent role as has been discussed in this chapter. The role of a persistent or recurrent viral exposure has not been reviewed here but may well be a contributing factor. Since chronic relapsing experimental encephalomyelitis in animal models is a T-cell-mediated disease that pathologically resembles MS, T cells are postulated to be of primary importance in human demyelinating diseases. Oligoclonal T-cell populations can be found in the CSF of MS patients, even though their antigenic specificity is not known. HLA associations (HLA Dw2 and HLA DR2 in MS and HLA Dw3 in chronic inflammatory neuropathy) might relate to the proposed immunopathogenesis, as class II antigens encoded by these loci might serve as restriction elements for T-cell recognition of an autoantigen by encephalitogenic cell populations. Humoral factors are thought to play an important role in the pathogenesis of CIP, as plasma exchange has been shown to be beneficial. Experimental work with an antimyelin glycoprotein monoclonal antibody demonstrates the in vivo demyelinating activity of antibodies as well as the importance of cellular elements in the demyelinating process. Finally, a number of immunoregulatory abnormalities have been demonstrated in MS patients that point to defects in immunoregulation, in particular in the generation of suppression. Decreases in AMLR in active MS might be of importance, as the AMLR is a reaction against self MHC determinants during which suppression is generated. Defects in suppression might allow self-reactive cells to escape regulation and cause inflammatory lesions in the nervous system.
Article
Interleukin 1 (IL 1), IL 6, and tumor necrosis factor (TNF) are typical examples of multifunctional cytokines involved in the regulation of the immune response, hematopoiesis, and inflammation. Their functions are widely overlapping but each shows its own characteristic properties. IL 6 was originally identified as a B cell differentiation factor, and thus one of the major functions of IL 6 is antibody induction. Transgenic mice have provided much needed information on the pathophysiological role of cytokines. With IL 6 transgenic mice, deregulation of the IL 6 expression was suggested to be involved in the generation of plasmacytoma/myeloma and mesangium proliferative glomerulonephritis. The cis-regulatory elements and trans-acting nuclear factor (or factors) for the IL 6 expression (NF-IL 6) have been identified. NF-IL 6 was shown to be a member of a C/EBP family, and the possible involvement of NF-IL 6 not only in the IL 6 regulation but also in the induction of various acute phase proteins was also observed. The findings suggest the presence of a positive regulatory loop in acute-phase reaction. IL 1 receptor belongs to an Ig superfamily, but the IL 6 receptor is a member of a newly identified cytokine receptor family. The IL 6 receptor system was shown to be composed of a ligand binding chain and a signal-transducing molecule. IL 6 was found to trigger the association of these two polypeptide chains. This unique mechanism may be applied to other cytokine receptor systems.
Article
Adjuvant-induced arthritis, an autoimmune disease similar to rheumatoid arthritis, was used to investigate possible mechanisms of immune system modulation of the reproductive system. This laboratory previously reported that arthritic male rats have reduced serum testosterone and elevated serum LH concentrations. In the experiments described here, serum prolactin levels were not significantly different in arthritic animals compared with non-injected control animals. Neither reduced food consumption of arthritic rats nor the injection vehicle appear to cause a reduction of serum testosterone. Serum corticosterone was significantly elevated in the arthritic group compared with both the non-injected or the vehicle-injected control animals. Testicular cells from arthritic animals secrete significantly less testosterone in vitro compared with cells from non-injected control animals, both basally and in response to dbcAMP and hCG. In summary, the reduced serum testosterone of arthritic animals appears to be the result of a testicular dysfunction.
Article
The intradermal administration of complete Freund's adjuvant (CFA) containing Mycobacterium butyricum to Sprague-Dawley (SD) and Lewis strain rats results in polyarthritis and uveitis. Over 90% of the eyes examined from the SD rats given CFA had histologic evidence of anterior uveitis, clinically evident in only 20 to 28%. Many rats developed arthritis without clinical uveitis, but uveitis was rare in the absence of arthritis. Histologically, the ocular inflammation was characterized by a polymorphonuclear, and later, a lymphocytic infiltration of the iris and ciliary body with cells and fibrinous exudate in the anterior chamber and cells in the vitreous. Antibodies and cellular immunity to ocular (S antigen, alpha crystallin), articular (type II collagen, proteoglycan) and bacterial components (MDP), were demonstrated in some rats, but positive tests did not correlate with either articular or ocular disease. Ten percent of rats given type II collagen in incomplete Freund's adjuvant developed uveitis. Thus, the pathogenesis of the arthritis and uveitis in the adjuvant model may be mediated by lymphocytes which exhibit crossreactivity with antigens in these structures, although the specificity of such antigens has not been identified in our studies.
Article
Cholesterol-dependent complement activation has been proposed as a factor that might influence the pathogenesis of atherosclerosis. Although antibodies to cholesterol conjugates have been reported, cholesterol is widely regarded as a poorly immunogenic substance. Monoclonal IgM complement-fixing antibodies to cholesterol were obtained in the present study after immunizing mice with liposomes containing high amounts of cholesterol (71 mol % relative to phosphatidylcholine) and lipid A as an adjuvant. Clones were selected for the ability of secreted antibodies to react with liposomes containing 71% cholesterol but not with liposomes containing 43% cholesterol. The antibodies also reacted with crystalline cholesterol in a solid-phase enzyme-linked immunosorbent assay. Binding of monoclonal antibodies to the surface of crystalline cholesterol was demonstrated by electron microscopy by utilizing a second antibody (anti-IgM) labeled with colloidal gold. The immunization period required to induce monoclonal antibodies was very short (3 days) and a high fraction of the hybrid cells (at least 70%) were secreting detectable antibodies to cholesterol. The results demonstrate that cholesterol can be a highly immunogenic molecule and that complement-fixing antibodies to cholesterol can be readily obtained.
Article
Human adjuvant disease or autoimmune disease after implantation of foreign material occurs subsequent to injection or implantation of paraffin/silicone and, possibly, silicone polymers. Patients develop signs, symptoms, and laboratory abnormalities suggestive but not diagnostic of a connective-tissue or autoimmune disease. The purpose of this paper is to present a thorough review of the literature, case studies, and guidelines for the possible identification of these patients. While previously reported in the Japanese literature, at the present time there are still many questions surrounding this disorder. The condition has not as yet been well-established, and further research is needed to explore these relationships in the U.S. population.
Article
Genetic control over sensitivity to experimental adjuvant arthritis was studied in different strains of inbred, recombinant and congeneic mice. The development of adjuvant arthritis is genetically regulated, with sensitivity to adjuvant arthritis controlled by H62-complex. The genes controlling sensitivity to adjuvant arthritis were shown to be located in (S-region) H-2 system.
Article
Acute joint inflammation was produced in BALB/c mice by a single intravenous injection of synthetic muramyl dipeptide (MDP), its stereoisomers and 6-O-acyl derivatives of MDP. Four adjuvant-active, but not five adjuvant-inactive MDP analogs induced acute swelling and erythema of the ankles and wrists which were detected around 6-10 hr, reached the maximum severity by 18-24 hr and subsided by days 3 to 4 after injection. Introduction of the stearoyl group, but not the alpha-branched long chain fatty acid group into the C-9 hydroxyl group of MDP enhanced and prolonged the joint lesions compared with MDP.
Article
We evaluated the antiarthritic activity of gold sodium aurothiomalate (GSTM) and auranofin (AF) against experimental polyarthritis induced in 3 rat strains using 3 different adjuvants. These 2 gold drugs were found to either stimulate, inhibit or have no effect upon the development of arthritis, dependent upon the rat strain and/or the adjuvant used. The ambivalent antiarthritic activities of GSTM and AF did not appear to be associated with any variations in serum gold levels. These results highlight the need for caution in studying gold drugs using the adjuvant polyarthritic model in the rat and, if used, the need to define clearly the strain/adjuvant/gold drug combination. Within these constraints however, our findings support the concept that GSTM and AF have different mechanisms of action.
Article
The incidence and prevalence rates of connective tissue disease syndromes in Rochester, Minnesota, from 1950 through 1979 are reported. The incidence of definite systemic lupus erythematosus (SLE) has not increased since 1960. The incidence of SLE in the elderly population was higher than that in previous reports. Rates of SLE and discoid lupus erythematosus were approximately equal. Other diagnoses (in decreasing order of frequency) were suspected lupus erythematosus, scleroderma, drug-induced lupus, and overlapping connective tissue disease syndromes. The 10-year survival of patients with definite SLE was decreased, and the survival of patients with suspected SLE was the same as that of the general population.
Article
Over a hundred compounds and natural materials were examined for their ability to induce arthritis in rats when mixed with heat killed delipidated Mycobacteria tuberculosis. Many of these materials were also assessed for (CMI) adjuvant activity by their ability to induce allergic encephalomyelitis (EAE) in rats when mixed with guinea pig spinal cord, both with and without added M. tuberculosis. Cyclization and/or the presence of oxygen atoms, or double bonds reduced (or abolished) the arthritogenic potential and adjuvanticity of alkanes > C 10. Esters/triglycerides of fatty acids > C 12, retinol acetate (not palmitate) and vitamins E and K showed coarthritogenic and adjuvant activity. Other active lipids included squalene and cholesterol oleate, which are both present in human sebum. Sebaceous lipids may therefore perhaps function as natural adjuvants if resorbed during abrasion and infection. Squalane (perhydrosqualene), pristane and hexadecane were excellent substitutes for mineral oil in preparing arthritogenic adjuvants from various mycobacteria, C. rubrum and N. asteroides. These oily compounds were also very effective adjuvants per se, in the absence of bacterial material or emulsifier, for inducing EAE in Lewis rats.
Article
When Lewis rats were immunized by intradermal injection into the parietal scalp rather than into the footpad with mycobacterial delipidated cells in squalene, arthritis could be produced in the temporomandibular joint (TMJ) with a maximum incidence of 60%, accompanied by systemic polyarthritis. Other methods of immunization including intradermal injection into the tail, posterior cervical region, or intra-inguinal lymph nodes did not induce arthritis in the TMJ. A combination of this inoculation and hemiocclusal loss markedly increased the incidence of arthritis in the TMJ. This arthritis in the TMJ was, however, milder than that in other joints and was apparent only histologically. The group given intradermal injection of adjuvants into the parietal scalp showed definite suppression of body weight gain. Since the method of intradermal injection into the parietal scalp can induce a high incidence of arthritis in the TMJ, our study presents a unique experimental model for study of arthritis in the TMJ.
Article
The absorption and metabolic fate of dietary squalene was investigated on the rat by administering a single oral dose of 3H-squalene and 14C-cholesterol. Experiments on rats with cannulated thoracic duct revealed that 3H-squalene was, like 14C-cholesterol, absorbed through the lymphatic vessels and that ca. 20% of absorbed 3H-squalene was cyclized to sterols during the transit through the intestinal wall. Feces contained 3H-sterols, indicating that newly synthesized mucosal sterols had been secreted into the gut lumen. In intact animals, 3H-squalene appeared in the circulation more rapidly than 14C-cholesterol and did not persist to any significant extent in the squalene-rich adipose and muscle tissues. The increase in dietary squalene load (8-48 mg) decreased the absorption percentage of 3H-squalene (45-26%) but did not affect the absorption of 14C-cholesterol (47%). Determination of fecal steroids revealed that during the first days absorbed 3H-squalene was eliminated to a significantly higher extent than 14C-cholesterol as fecal bile acids (34% vs 11%). The experiments indicate that the rat intestine has a marked capacity for absorbing dietary squalene and that the absorbed squalene is preferentially converted to bile acids in the liver.
Article
To study a role for T cells in nonspecifically induced arthritis, rats were injected intraarticularly into ankle joints with mineral oils including 2,6,10,15,19,23-hexamethyltetracosane (squalene) and incomplete Freund's adjuvant. The results showed that moderate joint inflammation had developed by Day 6 after the nonspecific stimulation. This was then followed by induction of severe arthritis, reaching a peak on Day 21. Histologically, the early phase of arthritis was associated with edema of synovial tissues containing many polymorphs and monocytes/macrophages and the late phase of the joint inflammation with marked hyperplasia of synovial membrane with dense infiltration of CD5+ and alpha beta+ T cells. Depletion of alpha beta+ T cells by a monoclonal antibody against TCR alpha beta suppressed both induction and progression of the late phase of arthritis. Thus, pathogenic T cells appear to be recruited to joint tissues following nonspecific stimulation.
Article
In vivo and in vitro studies, case reports and population studies show that: (1) silicone is immunogenic; (2) silicone is biodegradable and transported via the reticuloendothelial system to distant locations; (3) silicone breast implants "leak" and in turn silicone migrates outside the breast tissue; (4) case reports and population studies document an autoimmune reaction and immunological dysfunction in patients with silicone breast implants; (5) these immunological abnormalities and symptoms are reversible upon removal of the breast implants (in 50-70% of cases). The criteria to establish medical causation are defined, and based on those criteria it is concluded that silicone breast implants cause immunological disease.
Article
To study the existence of autoimmunity against the cerebellum in patients with sporadic cortical cerebellar atrophy. The presence of autoantibodies against the cerebellum in the serum and cerebrospinal fluid samples that were obtained from patients with sporadic cortical cerebellar atrophy and control patients was investigated by using immunohistochemical techniques. University hospital and research laboratory in Lyons, France. Eight patients with cortical cerebellar atrophy that was associated with or without other neurological symptoms; 350 patients with various neurological diseases; and 33 normal, healthy subjects. Serum and cerebrospinal fluid anti-cerebellar autoantibodies were investigated by using indirect immunofluorescence techniques in rat cerebellum. To characterize antigen labeled by patient's serum, we used an immunotrapping enzyme activity assay of glutamate decarboxylase. Serum and cerebrospinal fluid samples that were taken from one patient with sporadic cortical cerebellar atrophy associated with peripheral neuropathy and slow eye movements contained anti-glutamate decarboxylase autoantibodies. These results suggest a participation of autoimmunity in the pathogenesis of some cases of sporadic cerebellar cortical atrophy and the involvement of the cerebellar gamma-aminobutyric acid-ergic system in the pathogenesis of this disease.
Autoreactive B- as well as T-lymphocytes are often integral parts of the normal immune system and are not per se pathogenic. Also activation of these autoreactive lymphocytes may in many cases occur without ensuing pathology. In the current paper is discussed two situations whereby unspecific inflammatory stimuli in the form of immunological adjuvants may either by themselves cause arthritis, or may change a non-pathogenetic to a destructive and chronic inflammatory disease.
Article
The appearance of joint inflammation (JI) 14 days after the injection of adjuvant (AJ) in the tail of rats is associated with a cachectic syndrome which is characterised by marked weight loss (WL). The degree of weight loss was examined in relation to the extent of change in other markers of inflammation including increased plasma copper (pCu), decreased plasma zinc (pZn) and increased hepatic metallothionein (hMT). At 14 days post-AJ injection, arthritic rats showed the following changes, relative to the controls: body weight, 12% decrease, pZn, 50% decrease; pCu, 90% increase and hMT, 11-fold increase (allp<0.001). Significant relationships were observed between JI, WL, pZn and hMT. The following coefficients of determination (r 2) were observed; JI and WL,−0.530, JI and pZn,−0.485; JI and hMT, 0.286; WL and hMT, −0.510 (allp<0.007). There was a strong relationship between the decreased pZn and increased hMT;r 2=−0.456 (p<0.001). While increased pCu was clearly associated with AJ-arthritis in these rats, there was no quantitative relationship between the extent of change in pCu and the other parameters measured (r 2 all<0.01). The highest correlation observed was between pZn and WL (r 2=0.637,p<0.001)., While the initial depression of pZn may be the result of increased hepatic hMT levels, longer term reductions in pZn levels are linked to systemic inflammation, the degree of arthritis and associated weight loss.
Article
We have studied serum cytokine profiles in BALB/c mice after immunization with influenza vaccine alone or combined with the following adjuvants: alum; MF59 emulsion; MF59 containing the muramyl peptide N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2- dipalmitoyl-sn-glycero-3-(hydroxyphosphoryloxy)) ethylamide (MTP-PE); MF59 plus the lipid A analogue monophosphoryl lipid A; MF59 plus the Quil A saponin fraction LTC; or LTC alone. Pooled mouse sera were analyzed by ELISA at various times after immunization for IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IFN-gamma, and TNF-alpha. In naive mice, vaccine alone induced low levels of IL-3 and IL-5 only; vaccine plus alum induced a low IL-6 response as well. The MF59-based adjuvants significantly increased the IL-5 and IL-6 levels, whereas Quil A LTC induced strong IFN-gamma and measurable IL-2 responses, in addition to moderate IL-5 and IL-6. In previously infected mice, MF59 and MF59/MTP-PE were capable of generating IFN-gamma responses, as well as IL-5 and IL-6. All of the cytokine responses were rapid (peaking 3 to 12 h postimmunization) and short lived. In naive mice, the MF59 adjuvants induced serum cytokine profiles that are consistent with a primarily Th2-type response, whereas the Quil A LTC induced cytokines associated with both Th1 and Th2 responses. Ab analyses indicated that, although the adjuvants strongly affected the magnitude of the humoral response, there was no obvious correlation between the cytokine profile observed and the subclasses of Ab induced.
Article
To describe neurologic and neurophysiologic (NP) outcome in patients with systemic lupus erythematosus (SLE) followed prospectively and to determine predictors of change in NP status. Clinical examination, laboratory and NP tests (brain stem auditory and visual evoked responses, peripheral nerve conduction studies) were performed in 18 unselected patients with SLE attending a general rheumatology clinic at enrollment into the study (baseline) and after a 2-year (mean) period of followup. Fifty percent (9/18) and 83% (15/18) of patients had neurological abnormalities at baseline and followup, respectively, the most common of which were headache and peripheral neuropathy. NP abnormalities were found in 56% (10/18) and 61% (11/18) of patients at baseline and followup. The most frequent abnormalities at both visits were of peripheral nerve conduction [33% (6/18) and 56% (10/18), respectively] and abnormalities of brainstem and/or visual evoked responses were found in 28% (5/18) and 22% (4/18) of patients at both visits. At baseline, vasculitis was significantly increased in patients with NP abnormalities (p = 0.04). NP status deteriorated between visits in 8 patients (44%), 6 of whom acquired peripheral abnormalities. Improvement in NP status was only noted in patients (2/18, 11%) who had NP abnormalities restricted to the central nervous system. Associations were seen between elevated dsDNA antibodies, vasculitis, and lymphopenia, and the risk of acquiring new NP abnormalities. Patients with SLE had many neurological and NP abnormalities. NP deficits acquired were most often of peripheral nerve conduction. The ability to identify and classify clinical and subclinical neurological abnormalities in patients with SLE using NP tests may enhance our understanding and management of their neurological disease.
Article
To investigate the incidence, prevalence and clinical features of systemic sclerosis (SS) in Iceland. All patients diagnosed with SS from 1975-90 were included. Retrieval for the study began in 1980 and was carried out by computerised search from registers of all hospitals and health care clinics and death registration files, and with personal communication with doctors in Iceland. Over a 16 year period from 1975-90, 15 new cases were found with an incidence of 0.7 and 0.05/100,000, for females and males at risk respectively, and 0.38 for both sexes. At the end of 1990 there were 18 patients alive with SS, 13 with limited and five with diffuse cutaneous involvement. The age standardised prevalence was 11.9 and 1.5/100,000 for females and males at risk respectively. The crude prevalence rate for both sexes was 7.1/100,000. There were five deaths, two patients died of SS related causes, one had SS renal disease. The relative risk of death was similar to that in the general population. The calculated five year survival rate was 100% and the 10 year survival rate 81%. No HLA antigen association was found. Compared with previous surveys this study shows a low incidence of systemic sclerosis and a high proportion of patients with limited cutaneous involvement.
Article
A variety of mechanisms can be proposed to explain the potential effects of silicone and silicone by-products on the immune response. In this paper, we discuss information on the chemistry of silicon and silicone gels/elastomers, and the manufacture of silicone breast implants as they pertain to the bioreactivity of silicone. Moreover, with reference to silicone-mediated human adjuvant disease, an overview of experimental adjuvant-induced arthritis is presented; comparisons with graft-versus-host disease and chemically induced autoimmunity then follow. Particular attention is paid to similarities in the characteristics of silicone and classic lipid adjuvants. For example, macrophage activation is presumed to be a central event in silicone-induced autoimmunity. Since those genes uniquely expressed in macrophages activated by plastic adherence are similar to those induced by lipopolysaccharide, adherence to silicone rubber may initiate an inflammatory response by the same mechanism. Macrophage effects would also include the erosion of implants through the generation of oxidants and localized pH changes. The degradation products of silicone are also implicated in the adjuvant effects of silicone implants. There is evidence to suggest that oxidants produced by inflammatory cells preferentially inactivate CD8+ suppressor T cells. This could then lead to an inflammatory state, perhaps through oxidant-induced transcription factors such as NF-kB, resulting in a long-term pro-oxidant imbalance that manifests itself as a breakdown in immunological self-tolerance. The authors hypothesize that autoreactivity following oxidant stress evolved to enhance inflammatory repair mechanisms after tissue, cell or molecular damage by oxidants.
Article
The potential use of vaccines for treatment of chronic or persistent virus infections is an area of great interest and controversy. Previous experiments have shown that the incidence and severity of spontaneous recurrent genital herpes in latently infected guinea pigs could be significantly reduced by vaccination with herpes simplex virus glycoprotein subunit vaccines. The current study shows the critical role of adjuvant in an effective formulation. Immunization of previously infected guinea pigs with a subunit vaccine containing a muramyl peptide derivative, MTP-PE, in a low-oil emulsion as adjuvant reduced the incidence of recurrent disease up to 80% compared with formulations lacking MTP-PE. Vaccines containing adjuvant alone failed to modify recurrences. Alum, the traditional adjuvant, was not effective. Glycoprotein subunit vaccines elicited high-titer ELISA and neutralizing antibody responses far greater than those generated by virus infection. However, neither antibody titers nor lymphoproliferative responses reproducibly correlated with the pattern of recurrent disease.
Article
A Plasmodium falciparum circumsporozoite protein (PfCSP) recombinant fusion protein, R32NS1(81), formulated with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane (Detox) was administered to 12 volunteers. One volunteer had malaise and self-limited painful induration at the injection site after the second dose and declined further immunization. The other 11 volunteers tolerated the three doses of 1,230 micrograms of vaccine, but most complained of sore arms; in five cases the pain or malaise was severe enough to interfere with work or sleep. Two weeks after the third dose of vaccine, four of the 11 immunized volunteers had > or = 14 micrograms/ml of antibodies to the repeat region of the PfCSP in their serum. Two of these four volunteers did not develop P. falciparum parasitemia when challenged by the bite of five mosquitoes carrying P. falciparum sporozoites. The seven volunteers with lower levels of antibodies and 11 of 11 controls developed parasitemia. These data are consistent with other studies, and indicate that vaccine-induced antibodies against the repeat region of PfCSP can prevent effective sporozoite infection of hepatocytes in humans. The challenge is to improve the immunogenicity of PfCSP-based vaccines, and to develop methods for including PfCSP peptides as components of multitarget malaria vaccines.
Article
Serum squalene, a non-steroid intermediate of cholesterol biosynthesis, originates mainly from endogenous cholesterol synthesis and partly from diet, especially in populations consuming a lot of olive oil rich in squalene. Its postabsorptive metabolism has not been studied in detail in humans. Its presence in chylomicrons and VLDL suggests that the removal of dietary squalene may reflect the metabolism of intestinal lipoproteins. Accordingly, we studied the postabsorptive metabolism of 1 g dietary squalene in 16 healthy subjects with apolipoprotein (apo) E 3/3 phenotype and in five type III hyperlipidemic apo E 2/2 homozygotes known to have a retarded chylomicron remnant removal, and compared the results with vitamin A fat load test. About 40% of the basal and 90% of the postabsorptive squalene was in lipoproteins < 1.019 g/ml. The peak concentrations of chylomicron squalene were at 6 h, and of triglyceride-rich nonchylo-fraction at 9-12 h in the controls. The peak values occurred later than those of vitamin A. At 24 h the levels still exceeded the basal ones. In type III dyslipoproteinemia, most of the basal and postabsorptive squalene was in lipoproteins of density less than 1.019 g/ml, the peak postabsorptive values occurred later than in the controls and the serum values remained above the control levels for up to 24 h. The squalene and vitamin A areas under the incremental response curves (AUC) were higher than in the control group. The AUCs of the two markers in chylomicron were correlated negatively and those in LDL+HDL were correlated positively with fasting HDL cholesterol levels, the respective correlations being opposite with fasting VLDL triglycerides. The postabsorptive profile of squalene levels resembled that of vitamin A in both groups, except that the squalene curves were shifted to a later time period. Thus, a delayed clearance of chylomicron remnants could be detected by analyzing serum squalene 6-24 h after the squalene-supplemented fat meal.
Article
The safety of licensed influenza virus vaccine (IVV) combined with a novel adjuvant containing muramyl tripeptide (MTP) conjugated to phosphatidylethanolamine (PE) was evaluated in a randomized pilot study. Ten healthy 23-30-year-old men were given a single intramuscular dose of IVV combined with saline (n = 5) or with 100 micrograms of MTP-PE in the MF59 adjuvant emulsion (MF59-100) (n = 5). Evaluations were performed on days 0, 1, 2, 4, 7 and 28 after inoculation. IVV alone was well tolerated. All volunteers immunized with IVV/MF59-100 experienced moderate to severe local and systemic reactions which interfered with usual activities. Discomfort at the injection site was first noted at 2-6 h; induration (5/5), erythema (3/5), and regional adenopathy (3/5) persisted for up to 4 days. Systemic symptoms including chills (5/5), fever (3/5), nausea (3/5) and/or dizziness (2/5) developed within 12 h of inoculation and resolved by 48 h. Elevated white blood cell count (days 1 and 2), erythrocyte sedimentation rate and serum fibrinogen were transiently observed. Although peak serum neutralizing antibody titres versus influenza A/H3N2 and influenza B antigens were higher in the group given IVV with MF59-100, these unexpected reactions indicate that this dose of adjuvant is unsuitable for use in combination with this IVV.
Article
Neurologic complications of both the central and peripheral nervous systems occur frequently in patients with primary Sjögren's syndrome (primary SS), but the underlying cause of these complications is unknown. We studied the presence of antineuronal antibodies in relation to neurologic complications in a consecutive series of 45 patients with primary SS. Twenty-five patients had neurologic complications: 12 patients with polyneuropathy, three with psychiatric disorders, four with carpal tunnel syndrome, seven with migraine, seven with myalgia, and four with other complications (transverse myelitis, stroke, Bell's palsy, and pyramidal signs). Ten patients had more than one neurologic complication. Eleven patients had major and 14 had minor complications according to criteria used for rating neurologic complications in patients with systemic lupus erythematosus. Antineuronal antibodies were present in six of 11 (55%) patients with major neurologic complications and in four of 34 (11%) of patients without major neurologic complications (p = 0.001). This difference could be attributed mainly to the group of patients with polyneuropathy. Three of the 10 sera of patients with positive antineuronal antibodies had antibodies reacting with a 38-kd neuronal protein on immunoblotting, identical to the anti-Hu antibody reactivity in paraneoplastic neurologic disease associated with small-cell lung cancer.