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Modulation of immune function by dietary lectins in rheumatoid arthritis


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Despite the almost universal clinical observation that inflammation of the gut is frequently associated with inflammation of the joints and vice versa, the nature of this relationship remains elusive. In the present review, we provide evidence for how the interaction of dietary lectins with enterocytes and lymphocytes may facilitate the translocation of both dietary and gut-derived pathogenic antigens to peripheral tissues, which in turn causes persistent peripheral antigenic stimulation. In genetically susceptible individuals, this antigenic stimulation may ultimately result in the expression of overt rheumatoid arthritis (RA) via molecular mimicry, a process whereby foreign peptides, similar in structure to endogenous peptides, may cause antibodies or T-lymphocytes to cross-react with both foreign and endogenous peptides and thereby break immunological tolerance. By eliminating dietary elements, particularly lectins, which adversely influence both enterocyte and lymphocyte structure and function, it is proposed that the peripheral antigenic stimulus (both pathogenic and dietary) will be reduced and thereby result in a diminution of disease symptoms in certain patients with RA.
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Review article
Modulation of immune function by dietary lectins in rheumatoid arthritis
Loren Cordain*, L. Toohey, M. J. Smith and M. S. Hickey
Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523, USA
(Received 2 March 1999 – Revised 5 July 1999 – Accepted 30 August 1999)
Despite the almost universal clinical observation that inflammation of the gut is frequently
associated with inflammation of the joints and vice versa, the nature of this relationship remains
elusive. In the present review, we provide evidence for how the interaction of dietary lectins with
enterocytes and lymphocytes may facilitate the translocation of both dietary and gut-derived
pathogenic antigens to peripheral tissues, which in turn causes persistent peripheral antigenic
stimulation. In genetically susceptible individuals, this antigenic stimulation may ultimately
result in the expression of overt rheumatoid arthritis (RA) via molecular mimicry, a process
whereby foreign peptides, similar in structure to endogenous peptides, may cause antibodies or T-
lymphocytes to cross-react with both foreign and endogenous peptides and thereby break
immunological tolerance. By eliminating dietary elements, particularly lectins, which adversely
influence both enterocyte and lymphocyte structure and function, it is proposed that the
peripheral antigenic stimulus (both pathogenic and dietary) will be reduced and thereby result
in a diminution of disease symptoms in certain patients with RA.
Rheumatoid arthritis: Lectins: Immune function
Rheumatoid arthritis (RA) is a complex autoimmune dis-
ease characterized by persistent inflammation of the syno-
vium, local destruction of bone and cartilage and a variety of
systemic manifestations which may ultimately result in
functional disability. Three major aspects of RA suggest a
fundamental autoimmune-mediated disease: (1) the pre-
sence of often massive lymphocytic infiltrates and activated
CD4+T-lymphocytes within the inflamed synovium;
(2) production of large amounts of rheumatoid factor (RF)
by B-lymphocytes and plasma cells in the synovium, and
(3) the observation that immuno-suppression influences the
course of RA (Williams, 1996). RA affects approximately 1%
of the adult population with females being two to four times
more susceptible than males (Grossman & Brahn, 1997).
Autoimmune diseases occur when the body loses the
ability to discriminate self proteins from non-self proteins.
This loss of tolerance ultimately results in the destruction
of self tissues by the immune system. Typically, auto-
immune diseases are characterized by the presence of
auto-antibodies and autoreactive T-lymphocytes acting
against specific self proteins (Dalton & Bennett, 1992).
Most autoimmune diseases are thought to develop via the
interaction of an environmental factor or factors with a
specific hereditary component. The genetic components
most closely associated with the expression of autoimmune
diseases are those genes which code for the human leuco-
cyte antigens (HLA). The mechanism (or mechanisms) by
which autoimmunity is manifested in genetically suscepti-
ble individualsvia environmental factors is not clearly defined,
however, it is increasingly being recognized that the process of
molecular mimicry (Fig. 1), by which a specific foreign antigen
may induce an immune cross-reaction with self antigens, may
be involved in a variety of autoimmune diseases (Oldstone,
1987; von Herrath & Oldstone, 1995) including RA (Albani
& Carson, 1996; Baum et al. 1996; Wilson et al. 1997).
In the present review, we propose that the interaction of
dietary lectins with enterocytes and lymphocytes facilitates
the translocation of both dietary and gut-derived bacterial
antigens to peripheral tissues, which in turn causes persis-
tent peripheral antigenic stimulation. In genetically suscep-
tible individuals, this antigenic stimulation may ultimately
result in the expression of overt RA via molecular mimicry
in which foreign peptides are similar enough in structure to
cause T-lymphocytes and antibodies to cross-react with endo-
genous peptides and break immunological tolerance. By elim-
inating dietary elements, including lectins, which adversely
British Journal of Nutrition (2000), 83, 207–217 207
Abbreviations: BSA, bovine serum albumin; HLA, human leucocyte antigens; Ig, immunoglobulin; PHA, phytohaemagglutinin; RA, rheumatoid arthritis;
RF, rheumatoid factor.
*Corresponding author: Dr Loren Cordain, fax +1 970 491 0445, email
influence both enterocyte and lymphocyte structure and func-
tion, it is proposed that the peripheral antigenic stimulus will be
reduced and thereby result in a diminution of disease symptoms.
Relationship of gut inflammation to rheumatoid arthritis
There is a strong relationship between gut inflammation and
joint inflammation which has been recognized for decades
in clinical practice and which has been substantiated in a
variety of animal models of arthritis. Approximately 20 %
of all patients with inflammatory bowel disease (Crohn’s
disease, ulcerative colitis) are complicated by joint inflam-
mation (Hazenberg et al. 1992). Conversely, occult intestinal
inflammation, which may be related to non-steroidal anti-
inflammatory drug therapy or may be disease associated, occurs
in approximately 67 % of patients with RA (Sartor, 1989).
Because gut inflammation is known to increase intestinal
permeability, it has been suggested that an increased uptake
of luminal bacterial components across the inflamed mucosa
leads to a systemic distribution of bacterially derived,
arthropathic products (Sartor et al. 1996). In support of
this notion is the observation that HLA-B27 transgenic rats
develop arthritis when raised in conventional environments,
but do not do so under germ-free conditions (Taurog et al.
1994; Rath et al. 1996). Further, treatment with metronida-
zole (an antibiotic preferentially acting on anaerobic bac-
teria) attenuates gastrointestinal inflammation and can
prevent reactivation of arthritis in animal models (Sartor
et al. 1996). It has been consistently shown that a single
intraperitoneal injection of cell-wall fragments of Eubacterium
aerofaciens, a main resident of the human intestinal flora,
can elicit both acute and chronic arthritis in a rat model
(Hazenberg et al. 1992; Kool et al. 1992). The main
constituents of the Eubacterium aerofaciens cell wall are
peptidoglycan–polysaccharide complexes, of which a
65kDa heat-shock protein is the smallest bioactive unit
(Klasen et al. 1994). These data point to the critical role
that gut-derived bacteria may play in eliciting RA.
In human subjects, as previously mentioned, intestinal
inflammation frequently accompanies RA (Sartor, 1989).
Further, there is considerable evidence to suggest that
intestinal permeability may be increased in patients with
RA (Katz & Hollander, 1989; Mielants, 1990), particularly
when joint disease is active (Smith et al. 1985). Patients with
RA have also been shown to maintain a high frequency of
small-intestinal bacterial overgrowth (Henriksson et al. 1993),
particularly with anaerobic bacterial species (Benno et al.
1994; Eerola et al. 1994). Although the mechanism of action
is not entirely clear, there is convincing evidence to show that
antibiotic therapy has anti-rheumatic activity in many patients
with RA (Trentham & Dynesius-Trentham, 1995; O’dell et al.
1997). As in animal models, the human data are suggestive
that increased uptake of luminal bacterial components across
the inflamed mucosa leads to a systemic distribution of
bacterially derived, arthropathic products.
Translocation of intestinal antigens to the periphery
Common mucosal pathogens, particularly those found in the
gut, may play an important role in the aetiology of RA by
virtue of their ability to initiate an autoimmune response via
interaction with the immune system. Clearly implicit in this
model is the ability of intraepithelial pathogens and intact
proteins to escape enzymic digestion and to cross the
gastrointestinal barrier and enter peripheral circulation.
From a functional perspective, in healthy subjects the
contents of the gut lumen lie outside the body and contain a
toxic or antigenic load from which the body needs to be
protected. Protection is supplied by a number of mechan-
isms including: the intestinal mucosa, intestinal secretions
(primarily mucus and secretory immunoglobulin (Ig)A),
and intramural lymphocytes (Crissinger et al. 1990). The
primary intestinal barrier is supported by the liver, through
which all enterically derived substances must pass before
entering the peripheral circulation. Under normal circum-
stances in healthy subjects, the intestinal immune apparatus
208 L. Cordain et al.
amino acid sequence
of foreign antigen
amino acid sequence
of self antigen
Fig. 1. A schematic representation of simple two-way molecular mimicry in whichforeign
and self antigens may trigger T-cell cross-reactivity because of a shared sequence of
amino acids.
mounts rapid and potent effector responses to prevent
invasion by pathogenic viruses and bacteria (Mowat,
1987). Further, healthy, functionally intact epithelial
mucosa cells normally do not allow passage of more than
small amounts (approximately 2 %) of intact dietary pro-
teins (Mowat, 1987; Travie & Menzies, 1992). However,
translocation of viable bacteria from the gastrointestinal
tract to extra-intestinal sites (mesenteric lymph nodes, liver,
spleen, kidney and blood) has been shown to occur under
three circumstances: (1) disruption of ecological equili-
brium which allows intestinal bacterial overgrowth, (2)
deficiencies in host immune defences, and (3) increased
permeability of the intestinal barrier (Berg, 1992).
Undegraded dietary peptides have also been shown to enter
the peripheral circulation (Hurby et al. 1985), particularly
when intestinal permeability is increased by disease (Travis
& Menzies, 1992), non-steroidal anti-inflammatory drugs
(Travis & Menzies, 1992; Bjarnason & Peters, 1996), ethanol
(Bjarnason et al. 1984; Keshavarzian et al. 1994), acetic acid
(Fabia et al. 1993) and dietary lectins derived from legumes
and cereal grains (Liener, 1986; Pusztai, 1993).
Dietary lectins
Common dietary staples such as cereal grains and legumes
contain glycoproteins called lectins which have potent anti-
nutritional properties (Table 1) which influence the structure
and function of both enterocytes and lymphocytes (Liener,
1986; Pusztai, 1993). Wheat-germ agglutinin derived from
dietary wheat products is heat stable and resistant to
digestive proteolytic breakdown in both rats (Pusztai et al.
1993a) and human subjects (Brady et al. 1978) and has been
recovered intact and biologically active in human faeces
(Brady et al. 1978). Wheat-germ agglutinin and lectins in
general bind surface glycans on gut brush-border epithelial
cells causing damage to the base of the villi which includes
disarrangement of the cytoskeleton, increased endocytosis
and shortening of the microvilli (Liener, 1986; Sjolander
et al. 1986; Pusztai, 1993). The structural changes induced
by wheat-germ agglutinin on intestinal epithelial cells elicit
functional changes including increased permeability (Sjo-
lander et al. 1984) which may facilitate the passage of
undegraded dietary antigens into systemic circulation (Pusz-
tai, 1993). High-wheat-gluten diets have been shown to
induce jejunal mucosal architectural changes in normal
subjects (Doherty & Barry, 1981). In rats dietary wheat-
germ agglutinin is rapidly transported across the intestinal
wall into the systemic circulation where it is deposited in
blood and lymphatic vessel walls (Pusztai, 1993a).
Under normal circumstances, when the luminal concen-
tration of intact dietary proteins is low, absorbed proteins
generally elicit a minimal allergic response because of the
limiting influence of T-suppressor cells. Because of their
resistance to digestive proteolytic breakdown, the luminal
concentrations of lectins can be quite high, consequently
their transport through the gut wall can exceed that of other
dietary antigens by several orders of magnitude (Pusztai,
1989a), and absorbed dietary lectins can be presented by
macrophages to competent lymphocytes of the immune
system (Hurby et al. 1985; Pusztai, 1989a).
Not only do dietary lectins increase gut permeability
(Sjolander et al. 1984; Greer & Pusztai, 1985) thereby
allowing increased passage of dietary and gut-derived
bacterial antigens into the periphery (Liener, 1986; Pusztai,
1993), they may also cause a bacterial overgrowth which
facilitates the preferential growth of gut bacteria such as
Escherichia coli and Lactobacillus lactis (Banwell et al. 1988)
which are associated with the expression of RA because they
contain an amino acid sequence (Q(K/R)RAA) which is also
found in the gene products of the HLA system of a high
percentage of patients with RA (Auger & Roudier, 1997).
Phytohaemagglutinin (PHA), a dietary lectin derived from
kidney beans, causes accelerated enterocyte cell turnover
which leads to an increase in the proportion of juvenile cells
209Rheumatoid arthritis and diet
Table 1. A non-comprehensive list of edible plants containing lectins and the physico-chemical properties of their purified lectins (modified from
Liener, 1986)
Toxicity Molecular
Genus and species Common name Peritoneal* Oral† mass (Da) Sugar specificity
Arachis hypogaea
Peanut, groundnut ? ? 110000 Galactose
Canavalia ensiformis
Jack bean ++110000 Mannose, glucose
Macrotyloma uniflorum
Horse gram −+113000
Lablab purpureus
Hyacinth bean ++n.a. n.a.
Glycine max
Soyabean +−122000 Galactose,
Hordeum vulgare
Barley ? +40000
Lens culinaris
Lentil ? 52000 Mannose, glucose
Lotus tetragonolobus
Winged bean ? +120000 Fucose
Oryza sativa
Rice ? ? 10000
Phaseolus aureus
Mung bean ? n.a. n.a.
Phaseolus coccineus
Scarlet runner bean ? ? 120000
Phaseolus lunatus
Lima bean −+124000
Phaseolus vulgaris
Kidney bean ++120000
Pisum sativum
Garden pea, split pea −−53000 Mannose, glucose
Ricinus communis
Castor bean ++60000 Galactose,
Solanum tuberosum
Potato ? ? 46000 Diacetylchitobiose
Triticum vulgaris
Wheat ? +36000
Vicia faba
Horse bean, broad bean ? ? 50000 Mannose, glucosamine
n.a., not available.
*Death results from the intraperitoneal injection of crude seed extract or purified lectin.
Growth inhibition caused by adding purified lectin to the diet of experimental animals.
(containing high levels of membrane polymannosylated
receptor glycans) on the small-intestinal villi (Pusztai,
1993). Because Escherichia coli preferentially binds to man-
nose receptors on enterocytes, the increase in the number of
mannose receptors via increased juvenile enterocytes allows
Escherichia coli bacteria to successfully out-compete other
resident gut micro-organisms. It is likely that PHA and other
dietary lectins operate in the same manner to induce similar
changes in other gut floral species (Pusztai et al. 1991).
Legume and cereal lectins alter the microflora of the gut
(Liener, 1986; Banwell et al. 1988; Pusztai et al. 1993b),
causing both inflammation (Wilson et al. 1980; Liener,
1986; Pusztai et al. 1993b) and increased intestinal perme-
ability (Greer et al. 1985) which in turn facilitates the
translocation of gut pathogens to the periphery. Kidney-
bean lectin (PHA) is lethally toxic for conventional rats
when given in high doses (Wilson et al. 1980), but is non-
toxic for germ-free animals (Rattray et al. 1974). Thus,
PHA’s toxic effects could be directly attributed to its ability
to increase the translocation of gut-derived bacteria to the
periphery. In the case of RA, dietary lectins may operate in a
similar manner to indirectly increase the expression of the
disease by facilitating movement of bacterial antigens with
arthrogenic properties to the periphery.
Because dietary lectins are able to cross the gastrointestinal
barrier rapidly and enter the circulation intact (Pusztai et al.
1989), they may also be able to interact directly with synovial
tissues. Although not a characteristic model of RA with all of
its symptoms, a rabbit model of arthritis has shown that the
direct injection of legume-derived dietary lectins into the knee
joint induces the development of severe arthritis.Specifically,
single injections of Lens culinaris lectin (derived from lentils),
Pisum sativum lectin (derived from peas), or the lectin
concanavalin A derived from the jack bean (Canavalia
ensiformis) were able to induce severe arthritis characterized
by an amplification of the initial inflammatory response due to
T-lymphocyte stimulation (Brauer et al. 1985).
Other legume-derived lectins such as soyabean aggluti-
nin, concanavalin A, and lectins derived from other
Phaseolus (bean) species have been demonstrated to influ-
ence intestinal structure and function negatively (Liener,
1986), as have lectins derived from groundnuts (Ryder et al.
1992). Legumes are almost always consumed in the cooked
state, and it is often assumed that cooking eliminates lectin
activity. However, Grant et al. (1982) have demonstrated
that residual lectin activity is present in kidney beans
(Phaseolus vulgaris) even when cooked at 858for 6 h or
at 908for 3h. Lectin activity has been demonstrated in
wheat, rye, barley, oats, maize (Liener, 1986) and rice
(Tsuda, 1979). Maize, like wheat, can alter intestinal
epithelial structure and function (Mehta et al. 1972). The
biological activities of cereal lectins are similar because
they are closely related to one another both structurally and
immunologically (Peumans & Cammue, 1986).
Clinical and experimental evidence implicating diet in
rheumatoid arthritis aetiology
The control of RA by dietary manipulation has been
infrequently tested and has not always yielded convincing
results (Shatin, 1964; Ziff, 1983; Darlington et al. 1986;
Buchanan et al. 1991), probably because the gastrointestinal
tract may not play a pathogenic role in all cases of RA and
because most previous clinical trials have only controlled for
single, rather than multiple dietary elements which may
simultaneously influence disease expression and progression.
Van de Laar & van der Korst (1992) demonstrated
symptomatic improvement in a subset of patients with RA
who were seropositive for RF when they were placed on
elemental diets (protein-free diets consisting of essential
amino acids, glucose, trace elements and vitamins). Twice
as many of the food-sensitive patients showed improvement
during a milk-free leg of the trial, and all food-sensitive
patients showed marked disease exacerbation during food
re-challenge. The authors concluded: ‘The existence of a
subgroup of patients in whom food intolerance influences
the activity of rheumatoid factor seropositive rheumatoid
arthritis deserves serious consideration’. In support of this
conclusion is a more recent experiment which showed a
significant (P=004) improvement in the number of sore
joints in a group (n10) of patients with RA who followed an
elemental diet for 3 weeks (Haugen et al. 1994). Further, in
the only controlled study of elemental diets in the treatment
of RA, patients experienced improvements in grip strength
(P=0008) and Ritchie score (P=0006) that relapsed
following food re-introduction (Kavanaghi et al. 1995). In
Crohn’s disease approximately 20 % of the patients experi-
ence joint inflammation together with gut inflammation
(Hazenberg et al. 1992). Elemental diets have been shown
to be as effective as corticosteroids in treating the disease,
and most subjects (84 %) achieve disease remission with
elemental diets (Riordan et al. 1993). The most frequent
food intolerances were to cereals, dairy products and yeast
(Riordan et al. 1993).
In coeliac disease there is a characteristic T-cell-mediated
destruction of the intestinal villi which results in malabsorp-
tion and increased intestinal permeability (Hamilton et al.
1982). All symptoms of coeliac disease are eliminated
following removal of gluten-containing cereals (wheat,
rye, barley and oats). RA has frequently been demonstrated
to occur concurrently with coeliac disease (Collins & Maki,
1994; Lepore et al. 1996). Multiple studies of arthritic
patients have demonstrated elevated antibody levels for
gliadin (O’Farrelly et al. 1988; Lepore et al. 1993), and
gluten-free diets have been shown to be effective in redu-
cing arthritic symptoms in coeliac patients (Bourne et al.
1985; Charkravarty & Scott, 1992; Lepore et al. 1993).
These studies support the concept that wheat-containing
diets can increase intestinal permeability and thereby allow
gut-derived antigens access to the periphery. Because
removal of gluten-containing grains not only eliminates
coeliac disease, but also symptoms of arthritis, such diets
may be of benefit for some patients with RA. No large clinical
trials have been undertaken specifically to examine the effec-
tiveness of gluten-free diets in the treatment of RA, however,
there are numerous case studies reporting alleviation of RA
symptoms with grain-free diets (Shatin, 1964; Williams,
1981; Beri et al. 1988; Lunardi et al. 1988). Additionally,
complete withdrawal of food during fasting reduces objective
and subjective indices of the disease (Kjeldsen-Kragh et al.
1991). Collectively, these studies suggest that modulation of
intestinal physiology by dietary substances may allow both
210 L. Cordain et al.
dietary and pathogenic antigens access to the periphery,
thereby causing persistent immune system stimulation.
Milk and dairy products have frequently been implicated
in the aetiology of RA. O’Farrelly et al. (1989) demon-
strated that fifty-three of ninety-three patients with RA had
elevated circulating IgG antibodies to milk, wheat or both
dietary proteins. Bovine serum albumin (BSA), a milk
protein, contains an amino acid sequence homologous
with human collagen type I, C1q, and sera from RA patients
displayed reactivity to synthetic peptides containing the
BSA residues responsible for the homology (Perez-
Maceda et al. 1991). Additionally, exogenous BSA peptides
have been found to be bound to RA HLA-DR susceptibility
alleles (Chicz et al. 1993). Case studies have shown that
elimination of milk and dairy products from the diets of
patients with RA improved symptoms, and the disease was
markedly exacerbated on re-challenge (Parke & Hughes,
1981; Panush et al. 1986). No large-scale controlled trial
testing the effect of dairy products on RA development and
progression has been undertaken. In animal models of RA,
disease symptoms are routinely induced in dogs (Ohashi et
al. 1996), rats (Griffiths, 1992) and rabbits (Thomsen et al.
1985) by injecting the synovium with BSA. Further, milk
drinking is known to induce rheumatoid-like joint lesions in
rabbits drinking cows’ milk (Welsh et al. 1985).
Immunological and molecular mechanisms of
rheumatoid arthritis
Genetic susceptibility
Inherited susceptibility to RA is associated with the genes
found on the short arm of chromosome 6 which code for
the HLA system. On chromosome 6, the HLA system is
sub-divided into class I (HLA-A, HLA-B, HLA-C) and class
II segments (HLA-DR, HLA-DQ, HL-DP). Within the class
II segment, the HLA-DRB1 genes, which encode the HLA-
DR4 and HLA-DR1 molecules, convey enhanced sus-
ceptibility to RA. The specific function of HLA molecules
is to bind internally processed antigens (both exogenous
and endogenous in nature) and to present them to
T-lymphocytes. Thus, the relationship between HLA sus-
ceptibility haplotypes and RA indicates an antigen-driven
response (Weyland & Goronzy, 1997). More specifically, it
has been observed that most (76%) of the HLA alleles
associated with RA contain, in the third hypervariable
region of their bchains, an amino acid sequence composed
of the amino acid motif Q(K/R)RAA (glutamine-(lysine/
arginine)-arginine-alanine-alanine) (Rowley et al. 1997).
Not only does the Q(K/R)RAA motif increase the prob-
ability of RA, it increases the severity of destruction (Larsen
score.162) and the likelihood of developing early erosive
disease (Wagner et al. 1997). How the Q(K/R)RAA motif
increases RA susceptibility or severity is still controversial.
However, a multistep molecular mimicry model (Fig. 2) has
been proposed where the Q(K/R)RAA sequence is an
antigenic epitope exhibited on several gut microbial pro-
teins (Escherichia coli,Lactobacillus lactis,Brucella ovis,
Proteus mirabilis), and patients with RA respond more
strongly to these antigens than healthy subjects (Albani
& Carson, 1996; La Cava et al. 1997; Auger & Roudier,
Molecular mimicry
HLA molecules themselves are frequently processed and
presented by antigen-presenting cells and these HLA-
derived peptides sometimes represent the majority of
211Rheumatoid arthritis and diet
Escherichia coli
heat-shock protein
Lactobacillus lactis
heat-shock protein
Brucella ovis
heat-shock protein
Putative auto-antigen?
Homologous amino acid motif
Fig. 2. Rheumatoid arthritis may arise from three-way molecular mimicry in which the Q(K/
R)RAA (glutamine-lysine/arginine-arginine-alanine-alanine)amino acid susceptibility motif
is shared by gut bacterial proteins, by self human leucocyte antigen (HLA) proteins and by
a putative tissue auto-antigen. Bacterial peptides containing the Q(K/R)RAA sequence
and entering the periphery (facilitated by dietary lectins) may stimulate T-cells causing
them to cross-react with the putative auto-antigen.
peptides presented by the antigen-presenting cells (Cao et al.
1995). It has been suggested that thymically selected T-cells
with weak affinity for self HLA peptides may subsequently
be stimulated by peripheral exposure to microbial peptides
which mimic the HLA amino acid sequence (Baum & Staines,
1997). Specifically, the T-cell repertoire which is positively
selected during embryonic development, with weak affinity
for the Q(K/R)RAA motif expressed on HLA-DR molecules,
may subsequently be stimulated by peripheral exposure to
Escherichia coli,Lactobacillus lactis,Brucella ovis and
Proteus mirabilis containing the mimicking epitope. The
Q(K/R)RAA motif, whether expressed on HLA-DR mole-
cules, synthetic peptides, bacterial or viral proteins represents
a strong epitope for B-lymphocytesresponsible for serological
cross-reactivity among Q(K/R)RAA-containing peptides
(Roudier et al. 1989; Albani et al. 1992).
The Q(K/R)RAA motif is also the basis for T-lympho-
cytes involved in the positive and negative selection of the
T-cell repertoire in the thymus during embryonic develop-
ment. The T-lymphocyte repertoire in most cases is entirely
defined before exposure to environmental pathogens (Bevan
et al. 1994), and immature T-lymphocytes are positively
selected in the thymus by virtue of their low-affinity binding
with HLA peptides presented by cells of the thymic epithe-
lium. These positively selected T-lymphocytes undergo
maturation and become part of the pool of mature, naive
T-lymphocytes that, after birth, are recruited in specific
immune responses (Jameson et al. 1995). Immature T-
lymphocytes in the thymus that bind with high affinity to
HLA self peptide complexes have a high self-reactive
potential and are eliminated (negative selection) (Nossal,
1994). Therefore, thymically selected T-lymphocytes which
have been positively selected by virtue of their low affinity
interactions with HLA-DR1B alleles containing the Q(K/
R)RAA motif, may be later triggered in the periphery on
exposure to foreign peptides with homologous amino acid
sequences (Albani & Carson, 1996).
Rheumatoid factor
Approximately 70–80 % of patients with RA have RF
present in their blood and synovial fluid (Grossman &
Brahn, 1997). RF is an autoantibody since it has specificity
for the Fc (C g3 and C g2 domains) receptor of IgG
(Williams, 1992). Recent work utilizing crystal structure
analysis of the RF–IgG Fc, antibodyantigen complex
suggests that RF may have another entirely different speci-
ficity separate from IgG Fc and that the reactivity with IgG
Fc probably occurs because of similarities with an unin-
dentified antigen (Sutton et al. 1998). Consistent with this
notion is earlier work indicating that viral and bacterial
proteins also bind IgG Fc receptors via microbial receptors
which resemble the IgG Fc receptor (Nardella et al. 1985,
1988). Further, RF Ig genes show clear evidence of somatic
mutation, indicating that RF production by B-lymphocytes
is a T-lymphocyte-dependent, antigen-driven process (Gor-
onzy & Weyland, 1993). More recent studies utilizing
computer modelling and crystallographic studies suggest
that the mechanisms that operate on RF selection in RA
synovia are similar to immune responses to exogenous
antigens (Mageed et al. 1997). Collectively, these data
suggest that RF production may occur principally in
response to foreign proteins and secondarily in response to
self proteins.
There is some evidence to suggest that RF production
may be influenced by dietary proteins. O’Farrelly et al.
(1989) showed that fifty-three of ninety-three patients with
RA had raised levels of IgG antibodies to milk and/or wheat
proteins. Of the fifty-three patients positive for dietary
proteins, forty-eight (90 %) had raised levels of IgA RF
whereas only seven (17 %) of the remaining forty non-diet-
sensitive RA patients had detectable levels of IgA RF. These
data are suggestive of a breakdown in gastrointestinal
tolerance to dietary antigens in this group of patients, and
indicate that RF production may occur in response to
gastrointestinally related antigens.
Interaction of dietary lectins with immune function
It is apparent that dietary lectins from both cereal grains and
legumes increase the translocation of gut-derived bacterial
and dietary antigens to the periphery by: (1) causing an
intestinal bacterial overgrowth and (2) increasing intestinal
permeability. Additionally, dietary lectins have the ability to
interact with components of the immune system which may
facilitate the autoimmune process. Table 2 lists these
212 L. Cordain et al.
Table 2. Influence of dietary lectins on gastrointestinal and immunological function
Effect Reference
1. Facilitate preferential growth of bacteria such as
Escherichia coli
and Liener, 1986; Banwell
et al
. 1988; Pusztai
et al
. 1993
Lactobacillus lactis
which contain the Q(K/R)RAA susceptibility motif
2. Bind surface glycans on gut brush-border epithelial cells causing Liener, 1986; Sjolander
et al
. 1986; Pusztai, 1993
disarrangement of the cytoskeleton, increasedendocytosis and
shortening of the microvilli
3. Increase gut permeability allowing increased passage of both dietary and Sjolander
et al
. 1984; Greer & Pusztai, 1985; Liener, 1986
bacterial antigens to the periphery
4. Amplify HLA class II expression in intestinal epithelial cell lines Weetman
et al
. 1985
5. Stimulate T-cell proliferation Uder
et al
. 1980; Clevers
et al
. 1986
6. Stimulate IFN-g, causing HLA class II expression Piccinini
et al
. 1987; Lowes
et al
. 1992
7. Cause abnormal expression of ICAM in T-cells Koch
et al
. 1994; Shingu
et al
. 1994
8. Stimulate the production of inflammatory cytokines (IL-1, TNFa) Firestein
et al
. 1990; van den Bourne
et al
. 1997
HLA, human leucocyte antigens, IFN-g, interferon-g; ICAM, intracellular adhesion molecules; IL-1, interleukin-1; TNFa, tumour necrosis factor a.
multiple effects, and Fig. 3 shows schematically how dietary
lectins may facilitate the expression of RA via their
interaction with the gut and the immune system.
Dietary lectins including both wheat-germ agglutinin
(Pusztai et al. 1993a) and PHA (Pusztai et al. 1989) have
been shown to cross the gastrointestinal barrier rapidly and
enter the peripheral circulation. In rats dosed with PHA, up
to 10% of the lectin is found in circulation 3h after feeding
(Pusztai et al. 1989). Thus, PHA is a powerful oral immuno-
gen which produces a high titre of IgG anti-PHA antibodies
in animals and probably man (Pusztai, 1993). Antibody
development to PHA becomes measurable 10 d after the first
dose and further feeding or re-introduction results in
booster effects (Pusztai, 1993). Thus, the gut anti-lectin
IgA system is ineffective against PHA since it cannot
prevent its absorption after its re-introduction (Pusztai,
1989b). This abrogation of the gut IgA response to PHA
and possibly to other lectins has important consequences in
autoimmune disease because it would allow dietary lectins
continuous access to T-lymphocytes at the gut mucosal
Further, because dietary lectins increase intestinal perme-
ability, they would promote increased activity between the
immune system and gut bacteria. The interaction of the
systemic immune system with bacterial and dietary antigens
at the gut mucosal surface could lead to activation of
previously quiescent Q(K/R)RAA-specific T-lymphocytes
which react with the Q(K/R)RAA amino acid motif of gut
pathogens (Albani & Carson, 1996). Normally, these acti-
vated T-lymphocytes would return to the intestinal mucosa
and would not travel to peripheral sites, such as the
synovium, without abnormal expression of intracellular
adhesion molecules (Albani & Carson, 1996). Numerous
in vitro experiments have demonstrated that PHA is a potent
stimulator of intracellular adhesion molecule expression in
RA (Koch et al. 1994; Shingu et al. 1994). Thus, lectin-
induced intracellular adhesion molecule expression in auto-
reactive T-lymphocytes would allow them to travel to
peripheral sites in the joint and to persist in the synovial
Immunogenic foreign antigen fragments could be brought
to the inflammatory sites by synovial type A macrophages
and by B-cells recruited and activated by the inflammatory
stimuli (Albani & Carson, 1996). Therefore RF-producing
B-cells, because of their ability to bind and ingest antigens
trapped in immune complexes, would represent powerful
213Rheumatoid arthritis and diet
Immune system activation
T-cell receptor
Putative auto-antigen
HLA molecule loaded with putative auto-antigen
Target tissue (joint connective tissue)
Fig. 3. A diagrammatic illustration of how dietary lectins may hypothetically interactwith the gut and immune system to influence the expression of
rheumatoid arthritis. Dietary lectins may: (1) facilitatepreferential growth of bacteriasuch as
the Q(K/R)RAA susceptibility motif, (2) increase gut permeability allowing increased passage of both dietary and bacterial antigens to the
periphery, (3) amplify human leucocyte antigen (HLA) class II expression in intestinal epithelial cell lines, (4) stimulate T-cell proliferation,
(5) stimulate interferon-g, (6) cause abnormal expression of intracellular adhesion molecules in T-cells, and (7) stimulate the production of
inflammatory cytokines (interleukin-1,tumour necrosis factor a).
antigen-presenting cells, and their presence would partially
regulate the amplification of the inflammatory process
(Albani & Carson, 1996).
In addition to maintaining elevated levels of intracellular
adhesion molecules, RA is also characterized by elevated
levels of the inflammatory cytokines, interleukin 1, and
tumour necrosis factor a(Odeh, 1997). Numerous in vitro
experiments show that PHA is a potent stimulator of both
cytokines in peripheral blood mononuclear cells (Firestein
et al. 1990; van den Bourne et al. 1997). To date no trials
have been conducted to determine if in vivo administration
of dietary lectins in human subjects is able to elicit similar
responses. However, such responses seem likely since intact
PHA is present in the peripheral circulation following its
ingestion (Pusztai et al. 1989).
Molecular mimicry of dietary antigens with self proteins
We have outlined the hypothesis that the homologous amino
acid motifs among bacterial antigens, the HLA-DRB1 genes
and putative auto-antigens in joint tissue may induce RA in
genetically susceptible individuals by virtue of immuno-
logical cross-reactivity in a three-way model of molecular
mimicry. In addition to bacterial antigens, viral antigens,
including the Epstein-Barr virus, may also induce cross-
reactivity in RA via three-way molecular mimicry (Albani
& Carson, 1996; Baum et al. 1996). Less well appreciated
are the homologous amino acid motifs which may occur
between dietary peptides and self and which have been
implicated in the aetiology of RA.
Perez-Maceda et al. (1991) showed that the sera from
patients with RA recognized BSA from cows’ milk and that
a sequence of BSA (residues 141–157) was highly homo-
logous with human collagen type I and the plasma com-
plement protein, C1q. In support of the immunogenicity of
this BSA fragment, sera from patients with RA displayed a
specific reactivity for a synthetic peptide containing the
BSA residues responsible for the homology (Perez-Maceda
et al. 1991). Chicz et al. (1993) have demonstrated that
exogenous BSA proteins can be bound to various HLA
alleles, including DR4 molecules, suggesting that BSA
proteins may have a significant role in the development of
autoimmunity via molecular mimicry.
Ostenstad et al. (1995) have demonstrated that glycine-
rich cell-wall protein (GRP 1.8), which is a ubiquitous
storage protein found in virtually all cereal grains and
legumes, contains significant amino acid homologies with
both fibrillar collagen, procollagen and Epstein-Barr virus
nuclear antigen-1. A synthetic fifteen amino acid sequence
derived from GRP 1.8 stimulated T-lymphocytes taken from
the synovial fluid of patients with RA and caused a pre-
ferential expansion of synovial T-cells bearing V a2.1/V b
5.5 gene products, thereby indicating the involvement of
HLA complex-restricted auto-antigen recognition (Osten-
stad et al. 1995). The T-cell expansion caused by the GRP
1.8 analogue could be blocked by the addition of anti-DR
antibodies (Ostenstad et al. 1995), providing further evi-
dence of the potentiating role of molecular mimicry in the
aetiology of RA.
A third dietary antigen which may also induce RA via
molecular mimicry is the a-gliadin component of wheat
which shares significant amino acid sequences with calre-
ticulin, an endoplasmic reticulin chaperone protein (Karska
et al. 1995). Anti-calreticulin antibodies have been found in
patients with RA (Routsias et al. 1993), and HLA-DR4
molecules from arthritic patients are known to present a
peptide fragment derived from calreticulin (Verreck et al.
In summary, dietary peptide fragments, derived from
both milk proteins and cereal grain and legume proteins,
maintain significant amino acid homologies with collage-
nous tissues found in the synovium and are capable of
stimulating T-cells in an HLA restricted manner. Because
of the inherent lectin-induced permeability and floral changes
induced by cereal and legume consumption on the intestinal
epithelial cells, dietary antigens (with molecular mimicking
potential) which normally would not enter into the systemic
circulation, are rendered capable of doing so.
We have provided extensive evidence linking dietary sub-
stances to the development of RA. Dietary glycoproteins, as
well as other elements, can influence intestinal structure
and function so as to allow increased translocation of both
pathogenic and dietary antigens to the periphery causing
persistent immunological stimulation. Because of shared
amino acid motifs among exogenous peptides, HLA-derived
peptides and self tissue, cross reactivity may occur thereby
breaking immunological tolerance and resulting in the
expression of RA. It is proposed that by eliminating certain
dietary elements, including lectins, which adversely influ-
ence both enterocyte and lymphocyte structure and function,
the peripheral antigenic stimulus will be reduced and
thereby result in a diminution of disease symptoms in
some but not all patients with RA.
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qNutrition Society 2000
217Rheumatoid arthritis and diet
... agricultural and medical research applications (77). Studies have revealed new evidence of potential light in lectins, particularly cereal lectins in the etiology of human disorders like rheumatoid arthritis and cardio vascular diseases (CVDs) (79). Plant Lectins administered orally may have an extensive impact on varied types of tumors. ...
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Humans are constantly facing multiple health challenges from both communicable and non-communicable diseases that significantly affect their health. Additionally, drug resistance or failure has made the situation even worse and poses serious challenges for researchers to develop new drugs. Hence, to address these problems, there is an urgent need to discover and develop timely and long-term-based therapeutic treatments from different sources. One such approach is harnessing the potential of plant secondary metabolites. Plants have been utilized for therapeutic purposes in addition to being used for nutritional benefits. In the last two decades, plant-based drug developments have been one of the effective means of treating human diseases owing to their multiple functions. More recently, anti-nutritional factors (ANFs) have emerged as one of the important targets for novel plant-based drug development due to their multifaceted and potential pharmacological properties. However, their anti-nutritional properties have been the major setback for their limited success in the pharmacological sector. In this review, we provide an overview of ANFs and their beneficial roles in preventing human diseases with multiple case studies. We also highlight the recent developments and applications of ANFs in the food industry, agriculture, and pharmaceutics with future perspectives. Furthermore, we evaluate meta-analyses on ANFs from the last 30 years in relation to their function in human health benefits. This review is an endeavor to reevaluate the merit of these natural compounds and explore their potential for both human and animal health. KEYWORDS anti-nutritional factors (ANF), nutritional deficiency, plant-based foods, secondary metabolites, human diseases
... A pathophysiological reasoning approach to Personalized Nutrition practice uses signs, symptoms, and health issues to identify which pathophysiological mechanisms may be a priority for the individual, and then determines which interventions have mechanisms of actions which may ameliorate those health issues (74). Mechanisms of pathophysiology in RA such as dysbiosis, IP and inflammation, have been identified above along with interventions targeting these (Appendix A, [75][76][77][78][79][80][81][82][83][84] . ...
This review aims to investigate the role of intestinal permeability (IP) in rheumatoid arthritis (RA), following the hypotheses that leakage of intestinal microbes can influence increased citrullination of peptides leading to anti-citrullinated protein antibody (ACPA) production and inflammation in RA; and that leaked microbes can migrate to the peripheral joints, leading to immune responses and synovitis in peripheral joints. This review explored the evidence for the link between microbial dysbiosis and increased IP in the inflammatory state in RA, as well as the role of increased citrullination and bacterial translocation in the link between microbiota and immune responses in RA. Furthermore, this research aims to evaluate the potential effect of probiotics on RA symptoms and pathogenesis via proposed mechanisms, including the support of microbial balance and suppression of inflammatory factors in RA. A systematic literature search was conducted in three tranches (review, mechanism, intervention). 71 peer-reviewed papers met the inclusions criteria and are summarized in a narrative analysis. Primary studies were critically appraised, synthesized and their relevance to clinical practice evaluated. Evidence found in this mechanism review consistently supported intestinal dysbiosis and increased IP in arthritis. An altered intestinal microbiome was demonstrated in RA with specific microbes such as Collinsella and Eggerthella correlating with increased IP, mucosal inflammation, and immune responses. Hypercitrullination and ACPA production correlated with arthritic symptoms and intestinal microbes were shown to influence hypercitrullination. Some in vitro and animal studies demonstrated a link between leakage of microbes and bacterial translocation, but further research is needed to elucidate the link between IP and citrullination. Probiotic intervention studies evidenced reductions in inflammatory markers IL-6 and TNFα, associated with proliferation of synovial tissue and pain perception in RA joint inflammation. Despite some conflict in the literature, probiotics may present a promising nutritional intervention in the suppression of both, disease activity and inflammatory markers.Key teaching pointsThere is evidence for a dysbiotic profile of the RA gut with specific RA-associated microbes.Increased intestinal permeability and leakage of PAD enzyme facilitates citrullination of peptides.Hypercitrullination and ACPA production correlate to arthritic signs.Microbial leakage and translocation plays a role in the pathogenesis of RA.Probiotics (e.g. L. Casei 01) may reduce inflammation and ameliorate RA symptoms.
... Legumes and nightshades (tomatoes, white potatoes, eggplant, peppers, and seed species) contain lectin. Lectins can increase intestinal permeability and increase innate immune cell activation, which may be associated with rheumatoid arthritis (RA) symptoms (Cordain et al., 2000). Soybean meal-based diets alter TJ protein mRNAs and decrease protein absorption, induce intestinal neutrophil turnover, and increase intestinal permeability in zebrafish (Solis et al., 2020). ...
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Dysfunction of gut barrier is known as “leaky gut” or increased intestinal permeability. Numerous recent scientific evidences showed the association between gut dysfunction and multiple gastrointestinal tract (GI) and non‐GI diseases. Research also demonstrated that food plays a crucial role to cause or remedy gut dysfunction related to diseases. We reviewed recent articles from electronic databases, mainly PubMed. The data were based on animal models, cell models, and human research in vivo and in vitro models. In this comprehensive review, our aim focused on the relationship between dietary factors, intestinal permeability dysfunction, and related diseases. This review synthesizes currently available literature and is discussed in three parts: (a) the mechanism of gut barrier and function, (b) food and dietary supplements that may promote gut health, and food or medication that may alter gut function, and (c) a table that organizes the synthesized information by general mechanisms for diseases related to leaky gut/intestinal permeability and associated dietary influences. With future research, dietary intervention could be a new target for individualized disease prevention and management. This review summarizes current literature, mainly from PubMed, on the mechanisms of gut barrier and function, including food and dietary supplements or medications that promote or alter gut health. It also provides a comprehensive and clear table about basic mechanisms for disease‐related leaky gut/increased intestinal permeability with associated dietary influences.
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Glycoalkaloids are abundantly found among the members of the Solanaceae family. Potatoes (Solanum tuberosum L.), tomatoes (Solanum lycopersicum L.), and eggplant (Solanum melongena L.) are the most common sources of glycoalkaloids. The most predominant glycoalkaloids present in potatoes are α-solanine and α-chaconine, and several other glycoalkaloids such as β-chaconine, γ-chaconine, β1-solanine, β2-solanine, and γ-solanine are also present in small quantities. Tomatoes contain α-tomatine and dehydrotomatine, and eggplant contains solasonine and solamargine as their main glycoalkaloids. Glycoalkaloids, especially from potatoes e.g., α-solanine and α-chaconine, are known to cause gastrointestinal problems such as gastritis, gastrointestinal disturbance, nausea, vomiting, diarrhea, fever, low blood pressure, and, in high doses, cause a fast pulse rate along with neurological and occasional death in humans and farm animals. In recent years, an increasing number of toxicological events were reported by food contaminations with glycoalkaloids. Hence, it becomes very important to identify, analyze, and characterize different types of glycoalkaloids present in food items. This book chapter comprehensively covers sources, chemistry, pharmacological, and toxicological actions of glycoalkaloids present in food items.
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Nuclear magnetic resonance (NMR) spectroscopy is a robust method, which can rapidly analyze compounds or their mixtures in complex matrices without separating or purifying them. This makes the technique ideal for analysis of foods and related products. NMR continues to be an underutilized methodology in the area of food authentication and analysis, mainly due to the high cost, relatively low sensitivity, and the lack of NMR expertise among food analysts. The aim of this chapter is to explore the role of NMR methodologies in the field of food science with a special focus on analysis of food toxins. An introduction of the basic principles of NMR related to the study of foods and nutrients is given. This is followed by a detailed description of metabolomics studies. NMR with metabolomics studies together make a powerful methodology to address the challenges faced in food science. Furthermore, a comprehensive overview of their recent applications in the areas of compositional analysis, food authentication, quality control, and human nutrition is provided. In addition, use of NMR techniques in the analysis of potential food toxins is discussed. Finally, future perspective of the use NMR-based studies in the identification and characterization of food constituents and toxins is presented.
Food toxins of natural origin cover a wide diversity of macromolecules; generated by plants, algae, fungi, or degraded products of metabolism with destructive effects even at very low concentration/dose or when consumed in sufficient quantities. These toxins have diverse chemical structures and may serve definite purposes in plants or are developed as biochemical protectant against predators, insects, or microbes. Glycoalkaloids, cyanide-generating compounds, enzyme inhibitors and lectins, and mycotoxins are some important examples of natural food toxins. The toxicity of food toxins relies on the level of toxins available as well as susceptibility of a given population. These toxins may lead to acute and chronic health issues whose clinical indications may range from minor gastrointestinal distress, neurological indications, and respiratory paralysis to fatality. Analysis of food toxins requires authentication of analytical techniques for screening, quantification, and identification of contaminants. Undeniably, chromatographic analytical approaches can analyze numerous natural food toxins in a given period of time, in a sensitive and selective manner, yielding toxins concentration accurately. Even though extensively used, these approaches are costly, consume a lot of time, and deliver data following a noteworthy time lapse. Furthermore, samples (food toxins) are damaged by analytical procedures. Thus, alternative approaches/substitutes such as IR spectroscopy are actually progressively advanced to deliver simple and rapid procedures for the detection of food toxins. IR spectroscopy is a non-destructive procedure; employed to authenticate and characterize samples in high throughput. The usefulness of IR spectroscopy has directed its usage in numerous applications which comprises chemistry of soil, cereals, agricultural produce, medicine, and so forth. Since it reviews the interactions between radiation and matter, IR spectroscopy is a suitable tool for carrying out analysis of food toxins in finished foodstuffs. This chapter delivers the advancement and potential prospective of IR spectroscopy as an alternate/substitute to prevailing techniques for the assessment of food toxins.
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Alkaloids are the most important class of secondary plant metabolites that have been considered as the major source of phytomedicine. These alkaloids are a group of phytochemicals that contains two fused, five-membered rings that share a bridgehead nitrogen atom, forming a tertiary alkaloid. Pyrrolizidine alkaloids are known for their hepatotoxic activities, but are also reported to cause cancer. They are abundantly found in plant families such as Apocynaceae, Asteraceae, Boraginaceae, Compositae, Fabaceae, Leguminosae, Ranunculaceae, and Scrophulariaceae. Several medicinal plants contain pyrrolizidine alkaloids such as comfrey (Symphytum officinale), coltsfoot (Tussilago farfara), and petasites (Petasites japonicus), etc. Pyrrolizidine alkaloids are also present in milk (cows and goats), honey, staple foods, herbal teas, and herbal medicines. In recent years, an increasing number of toxicological reports revealed food contaminations with pyrrolizidine alkaloids. Hence, it becomes very important to identify, analyze, and characterize different types of pyrrolizidine alkaloids present in food items. In this book chapter, sources, chemistry, pharmacological, and toxicological actions of pyrrolizidine alkaloids will be discussed.
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Yetersiz beslenme ve engellilik durumu birçok ortak noktası nedeniyle yakından ilişkili iki kavramdır. Besine ulaşmanın zor olduğu durumlarda ya da yüksek düzeyde besin çeşitliliğinin bulunduğu fakat yetersiz beslenmenin yaygın olduğu ülkelerde yaşamını sürdüren çocuklarda gelişimsel bozukluklar, gecikmeler ve engellilik oranlarının yüksek olduğu bildirilmektedir. Bu oranların açıklayıcısı veya iki kavramın bağının oluştuğu noktalar ise yetersiz beslenmenin çocuklarda çeşitli farklı engellilik durumlarına neden olması veya katkıda bulunması ile birlikte; engellilik durumlarının da yetersiz beslenmeye neden olması veya katkıda bulunmasıdır. Özel gereksinimli çocuklarda beslenmenin önemi, gebelik döneminde annenin beslenmesine kadar dayandırılmaktadır. İlk 1000 gün boyunca, yani gebelikten 2. doğum gününe kadar optimal düzeyde beslenmenin, yeni doğanın sağlıklı gelişimi ve yaşamı için kritik öneme sahip olduğu yönünde görüş birliği vardır .......
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OSB, yaşamın ilk yıllarında ortaya çıkmakta ve etiyolojisi kesin olarak bilinmemektedir. OSB oluşumunda tek bir faktörden çok, genetik ve çevresel faktörlerin çoklu mekanizmalar halinde etkili olduğu ileri sürülmektedir (Risch & ark.,2014). Bir meta-analizde, genetik faktörlerin OSB oluşumunda %74-93 oranında katkıda bulunmakla birlikte yine de tek başına yeterli olmadığı belirlenmiştir (Tick & ark.,2016). Ebeveyn yaşının ileri olması, endokrin bozucu kimyasal ve radyasyon maruziyeti, ilaç alımı, civa/kurşun/alimünyum gibi çevresel toksinlerin OSB oluşumunda etkili olabileceği bildirilmiştir (Lyall vd., 2017 & Cekici ve Sanlier., 2019). Prematüre doğum, annenin gebelik boyunca başta folik asit olmak üzere yeterli vitamin ve mineral alamaması, bozulmuş otoimmünitenin OSB oluşumunda etkili mekanizmalar arasında sayılmaktadır (Lyall & ark., 2017; Cekici & Sanlier., 2019). Anne-çocuk arasındaki psikososyal bağın yetersiz olmasının da OSB gelişiminde etkili olabileceği düşünülmektedir (Özeren,2013). İlk 6 ay ve 2. yaşa kadar elzem olan anne sütü tüketiminin, OSB riskini azalttığını gösteren bulgular mevcuttur (Say, Babadağı & Karabekiroğlu, 2015; Huang & ark., 2021)...........
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Naturally processed peptides were acid extracted from immunoaffinity-purified HLA-DR2, DR3, DR4, DR7, and DR8. Using the complementary techniques of mass spectrometry and Edman microsequencing, > 200 unique peptide masses were identified from each allele, ranging from 1,200 to 4,000 daltons (10-34 residues in length), and a total of 201 peptide sequences were obtained. These peptides were derived from 66 different source proteins and represented sets nested at both the amino- and carboxy-terminal ends with an average length of 15-18 amino acids. Strikingly, most of the peptides (> 85%) were derived from endogenous proteins that intersect the endocytic/class II pathway, even though class II molecules are thought to function mainly in the presentation of exogenous foreign peptide antigens. The predominant endogenous peptides were derived from major histocompatibility complex-related molecules. A few peptides derived from exogenous bovine serum proteins were also bound to every allele. Four prominent promiscuous self-peptide sets (capable of binding to multiple HLA-DR alleles) as well as 84 allele-specific peptide sets were identified. Binding experiments confirmed that the promiscuous peptides have high affinity for the binding groove of all HLA-DR alleles examined. A potential physiologic role for these endogenous self-peptides as immunomodulators of the cellular immune response is discussed.
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The antigenic determinant on the Fc region of human IgG for two IgG rheumatoid factors (IgG-RF) from patients with rheumatoid arthritis were investigated in detail. The RF did not interact with IgG fragments that contained the C gamma 2 or C gamma 3 region alone, but required the presence of both regions for binding. The RF binding to solid-phase IgG were poorly inhibited by the IgG3 subclass and strongly inhibited by staphylococcal protein A (SPA) (42 kD), and fragment D of SPA (7 kD), indicating that the binding site is most likely the same as the Ga antigenic determinant described for IgM-RF, and is in the same location as the site on IgG that binds SPA. pH titration studies of the RF binding to IgG indicated the involvement of histidine and lysine or tyrosine side chains. Chemical modification studies showed the histidines were involved on the Fc side of the interactions, and tyrosines were involved on both the antigenic and antibody sides of the interactions. Lysines were not involved. The above information, and the knowledge of the number and position in space of the amino acid residues involved in the C gamma 2-C gamma 3 interface region of IgG, the binding site for SPA, and the amino acid substitutions in IgG3 that account for its inability to bind protein A, allowed the identification of the site on IgG that bind IgG-RF. This binding site involves some of the same amino acid side chains, His 435, Tyr 436, and one or both His 433 and 310, and is in the same location as the site that binds SPA. The same site is likely to be a common antigenic determinant for other RF. Furthermore, the described molecular mimicry suggests a biological relationship between bacterial Fc-binding proteins and the production of RF in rheumatoid arthritis.
Previous studies of the cytokine profile of rheumatoid arthritis (RA) have been primarily limited to the assessment of the levels of these mediators in synovial fluid (SF) or synovial tissues (ST) by biologic or immunologic assays. We have studied cytokine gene expression in RA by in situ hybridization of SF cells, enzymatically dispersed ST cells, and frozen sections of ST. RA ST cells (n = 7) were studied and a high percentage of cells hybridized to the following anti-sense probes: IL-6 = 19 +/- 3.3%; IL-1 beta = 9.9 +/- 1.7%; TNF-alpha = 5.8 +/- 1.4%; granulocyte-macrophage-CSF = 2.2 +/- 0.8%; transforming growth factor-beta 1 = 1.3 +/- 0.2% (p less than 0.05 for each compared to sense probes). Similar results were found using osteoarthritis ST cells, although the percentage of cells expressing the IL-6 gene (7.1 +/- 2.5%) was significantly less in osteoarthritis compared to RA. RA ST cells did not significantly bind the IFN-gamma probe (0.2 +/- 0.1% positive), although they were capable of expressing the IFN-gamma gene if stimulated with PHA. The OKM1+ population of ST cells (i.e., macrophage lineage cells) was greatly enriched for IL-1 beta and TNF-alpha, whereas the OKM1- population (lymphocytes, fibroblasts, and type B synoviocytes) was enriched for IL-6. The vast majority of cells expressing the IL-6 gene were non-T cells. Furthermore, hybridization to RA ST frozen sections localized IL-6 mRNA to the synovial lining layer, which is comprised of type A and type B synoviocytes. In contrast to the high level of cytokine gene expression observed in ST, SF cells did not hybridize significantly to any of the cytokine probes. If stimulated with LPS or PHA, SF cells expressed IL-1 beta or IFN-gamma genes, respectively.
Differentiation of αβ T cell receptor (TCR)-expressing T cells involves an obligatory interaction with self-major histocompatibility complex (MHC) molecules in the thymus. This process, called positive selection, both rescues thymocytes from programmed cell death and induces their differentiation into mature T cells. Another critical event in thymic development is to prevent maturation of hazardous autoreactive T cells; thus, mechanisms exist to eliminate T cells with self-reactive receptors (negative selection). How can these two pathways be distinguished? This question, which has long taxed immunologists, is more opposite because many features of the interactions in positive and negative selection are shared: Both processes are exquisitely MHC-allele specific, they involve MHC-bound peptide recognition, and employ at least some overlapping signal transduction pathways. However, resolution of this paradox has become much more feasible with the advent of powerful systems for withdrawing and reconstituting individual components involved in positive selection. This review describes recent advances in our understanding of the cells, receptors, ligands, and signaling pathways involved in this process. A pivotal part of this puzzle is the basis for discrimination between TCR ligands that induce positive vs negative selection. Recent work suggests that the peptide/MHC ligand for positive selection may bind with low avidity to the TCR. The implications of these data for the nature of T cell recognition during positive selection are discussed below.
The absorption into the blood of ovalbumin (OA) and beta-lactoglobulin (BLG) was investigated in eight healthy adults. Enzyme immunoassays showed up to 10.5 ng OA/ml serum in seven out of eight individuals 2-3 h after a test meal, whereas no BLG was demonstrated. The apparent size distribution of the absorbed OA was investigated by high-pressure liquid gel permeation chromatography fractionalion, followed by enzyme-linked immunosorbemt assay, which in the fractionated sera showed OA in all eight individuals. OA was found at the elution volume of intact OA and, in addition, was present in high molecular weight fractions, as part of the immune complexes. The serum concentrations of OA could not be clearly correlated to levels of serum and secretory anti-OA antibodies. No significant alterations of the levels of circulating immune complexes could be demonstrated by two antigen-nonspecific assays. The presented data indicate that, for certain dietary proteins, low-grade absorption of apparently undegraded protein into the blood occurs regularly in healthy adults.