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EUROPEAN JOURNAL OF INFLAMMATION
1721-727 (2008)
Copyright © by BIOLIFE, s.a.s.
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1
THE IMMUNOLOGY OF IMMEDIATE AND DELAYED HYPERSENSITIVITY
REACTION TO GLUTEN
A. VOJDANI, T. O’BRYAN1 and G.H. KELLERMANN2
Immunosciences Lab., Inc., Beverly Hills, CA; 1Davis Parkway, Warrenville, IL;
2NeuroScience, WI, USA
Received October 16, 2007 – Accepted January 18, 2008
Mailing address: Dr. Aristo Vojdani,
8693 Wilshire Blvd, Suite 200,
Beverly Hills,
CA 90211, USA
Tel: ++1 310 657 1077 Fax: ++1 310 657 1053
e-mail: immunsci@ix.netcom.com
EDITORIAL
The mechanism of oral tolerance to dietary proteins
Although mucosal surfaces are exposed to many
dietary proteins and infectious agents, the immune
system normally will not react to these antigens (1-
4). Unresponsiveness or tolerance to these antigens
is maintained by three principal mechanisms:
anergy or functional unresponsiveness; deletion
through programmed cell death or apoptosis; and
immune suppression by regulatory T cells (Tregs).
This induction of immune suppression or anergy to
gliadin is shown in Fig. 1.
Although HLA-DQ2 or HLA-DQ8, which are
tissue types known to be associated with celiac
disease, is found in roughly 30% of the western
population, celiac sprue is encountered in 1 out of
50 carriers. Most carriers of these genes, like the
rest of the population, harbor some form of immune
protection through regulatory T-cells.
The regulatory T cells are divided into two major
groups:
a. Natural Tregs, which act in a contact-dependent
fashion, and express CD25 and transcription
Vol. 6, no. 1, 0-0 (2008)
The immunology of gluten hypersensitivity and celiac disease has been pursued with signicant
interest in the past 20 years. For the prevention of systemic diseases, most pathogens that gain entry
into our bodies must be met with an effective immune response, yet in the gastrointestinal tract it is
equally important that commensal bacteria and a diverse collection of dietary proteins and peptides
be recognized without eliciting an active immune response or constant activation of the inammatory
pathway. This phenomenon of hyporesponsiveness to food antigens is known as oral tolerance. This oral
tolerance to dietary antigens is maintained by three different mechanisms: anergy, cell deletion and
immune suppression. However, in the presence of mechanical/chemical stressors and infections, this
tolerance may break down, and gut associated lymphoid tissues (GALT) will react to different luminal
antigens. The reaction of GALT to these antigens may lead to the production of pro-inammatory
cytokines, opening of tight junctions, entry of undigested antigens into the circulation, and the
subsequent production of IgA, IgG, IgM and IgE antibodies in blood and secretory components. Like
any other food hypersensitivity reaction, gluten sensitivity can be divided into immediate and delayed
hypersensitivities. In this review an attempt is made rst to differentiate immediate hypersensitivity to
gliadin, mediated by IgE, from delayed hypersensitivity, which is mediated by IgA and IgG. Furthermore,
we attempt to differentiate between gluten hypersensitivity with enteropathy (celiac disease) and gluten
hypersensitivity without enteropathy.
Key words: celiac disease, gluten hypersensitivity, delayed hypersensitivity, enteropathy
2
factor FOXP3;
b. Adoptive Treg Type 1 cells (TR1), which
function in a contact-independent manner and
may or may not express CD25 and FOXP3. The
TR1 and TH3 cells preferentially synthesize
immunosuppressive cytokines IL-10 and TGF-
β, respectively, in order to maintain homeostasis
of responses to foreign antigens, including
gliadin.
In the absence of tolerance, gut associated
lymphoid tissues will react to luminal antigens,
which may lead to the production of IgA and
IgM antibodies, pro-inammatory cytokines
and subsequent inammation and tissue damage
or autoimmunity (5). Immediate and delayed
hypersensitivity to gluten are characterized by
IgE-mediated reaction or IgG, IgM, IgA plus T-
cell reaction to gluten when tolerance to gluten is
either not established properly or broken in these
conditions (1-6).
A. Immediate type hypersensitivity to gluten
Like any other food hypersensitivity reaction,
gluten hypersensitivity can be divided into immediate
or delayed. The immediate hypersensitivity to gluten
is IgE-mediated and may become life-threatening in
severe cases when combined with exercise or some
medication. This IgE-specic reaction may occur
with IgE-specic epitopes of ω-5 gliadin, glutenins
or allergenic epitopes of wheat formed after heat
inactivation, hydrolyzation or chemical processes
(6).
Food-dependent exercise or medication-induced
anaphylaxis (FDEIA) is a distinct form of a common
food allergy induced by a combination of causative
food ingestion (wheat), physical exercise, and/or
aspirin intake. Systemic allergic reactions such
as anaphylactic shock and generalized urticaria
are symptoms of FDEIA (7-8). This immediate
hypersensitivity reaction is not limited solely to
wheat antigen. Many kinds of foods such as shrimp,
shellsh, hazelnut, buckwheat, corn, apple and
orange have been reported to cause this type of food
allergic reaction (9-14). The mechanism for food
induction of IgE-mediated hypersensitivity is shown
in Fig. 2.
Diagnosis of FDEIA is normally done by an
exercise challenge test combined with ingestion of
food that is known to have given patients episodes
of anaphylaxis after its intake. The challenge test is
unsafe for patients since it can provoke anaphylactic
shock during testing. Therefore, an in vitro diagnostic
method predicting development of symptoms by
food and exercise challenge is a safer option for
testing. However, for accurate in vitro testing it is
necessary to identify IgE-binding epitopes (8).
This identication of IgE-binding epitopes of
gliadin and high molecular weight gluten subunit
was completed using sera from patients with
WDEIA and enzyme immunoassay. Twenty-nine
of thirty patients with wheat-dependent-exercise-
induced anaphylaxis had specic IgE antibodies
to these epitope peptides. Conversely, none of
the 25 sera from healthy subjects reacted to both
gluten and gluten peptides. These results indicate
that measurement of IgE levels specic to epitope
peptides of ω-5 gliadin and high molecular weight
gluten peptide is useful as an in vitro diagnostic
method for the assessment of patients with wheat-
induced exercise-induced anaphylaxis, baker’s
asthma and contact urticaria.
In addition, in many industries wheat isolates
have been produced by means of chemical and
enzymatic treatment. This treatment induces the
solubilization of gliadins in aqueous buffers by
means of deamidation (15). The high protein content
and solubility of treated gliadin in water provide
interesting technological properties for their use in
the food industry. The wheat isolates are used as
food emulsiers, gelling agents, lm formation aid,
stretchability agents in meat products, sauces, soups,
and as clarifying agents in red wines.
This extensive use of wheat isolates in the food
industry may be the major cause of hidden food
allergies, which can be extremely dangerous to
individuals with IgE-mediated allergy to wheat.
In fact, anaphylaxis to wheat isolates was recently
reported and proved by means of double-blind,
placebo-controlled food challenge. Interestingly, the
subject individual did not react to native wheat our,
but had very severe reaction to wheat antigens isolated
from meat products. It was therefore concluded that
treatments used for gluten deamidation generate new
allergenic epitopes. A case of contact urticaria was
recently attributed to hydrolyzed wheat in cosmetics
combined with a generalized urticaria induced with
A. VOJDANI ET AL.
3
Eur. J. Inamm.
the ingestion of sausages with lentils and a French
cassoulet. This patient could also eat cereal-based
products without any problem (15-17).
Because food isolates or deamidated gluten are
new food ingredients, when allergy to wheat is
suspected, immune reaction to wheat isolates should
be tested for a nal determination of allergy to wheat
or its chemically modied antigens.
B. Delayed type hypersensitivity to gluten
Delayed type hypersensitivity to gliadin is IgG,
IgA or T-cell mediated. This reaction to gluten
develops because of the loss or failure of the
tolerance mechanism, or intolerance to ingested
gluten. When this immune reaction to gluten occurs
with the involvement of tissue transglutaminase in
genetically susceptible individuals who present
chronic inammation in the small intestine, villous
atrophy and attening of the mucosa, it is called
celiac disease. However, this immune reaction to
gliadin and glutenin peptides of gluten may also
occur in an individual without the involvement of
genetic makeup and tissue transglutaminase, being
induced instead by a loss of immune tolerance to
gluten peptides and by enhanced gut permeability
(18-19). If this loss of tolerance to gluten peptides
does not involve enteropathy and is accompanied
by intestinal barrier dysfunction, followed by
the entry of these peptides into the circulation
and systemic IgG and IgA response to gluten,
then for this delayed type hypersensitivity we
suggest the terminology gluten sensitivity without
enteropathy.
B1. Celiac disease or gluten sensitivity with
enteropathy
Celiac disease (CD) is a typical complex
inammatory disorder in which crucial genetic and
environmental factors have been identied. It is
an acquired disorder occurring in both adults and
children. The condition is characterized by sensitivity
to gluten that results in inammation and atrophy of
the mucosa of the small intestine. Similar protein
components of related grains such as barley, rye, oat,
kamut and spelt also cause an immune response in
patients with CD. The clinical presentation of CD
is very non-specic, and may vary from patient
to patient. Patients may complain of abdominal
cramps, bloating, diarrhea, and/or excessive gas
production after meals. They may also note general
malaise, lassitude, weakness, undesired weight loss,
constipation, anemia (B12 deciency), osteoporosis/
osteopenia, poor dentition, peripheral neuropathy,
seizures/ataxia with cerebral calcications,
irritability or poor growth in children, birth defects
in infants, small stature, and amenorrhea/infertility/
recurrent miscarriage in females (18-21).
Diagnosis of celiac disease
Because CD presentation varies so greatly,
many affected individuals do not suspect they
have the disease and therefore do not seek medical
attention. Even when medical attention is sought, if
patients have atypical symptoms, CD may not be
diagnosed unless the physician suspects and tests
for it. Therefore, diagnosed celiac disease is most
likely the ‘tip of the iceberg’ accounting for only
approximately 12% of total cases. Characteristic
villous atrophy and symptoms of intestinal
malabsorption are present in the classic form of the
disease (22); however, now many newly-diagnosed
patients have milder, atypical symptoms often
without diarrhea or malabsorption (“atypical CD”)
or have no symptoms at all (“silent CD”).
Recently, serological testing has been increasingly
used to test patients with suspected gluten-sensitive
enteropathy as well as for monitoring dietary
compliance. Both IgG and IgA antibodies are
detected in sera of patients with gluten-sensitive
enteropathy (5). IgA antibodies are less sensitive but
more specic markers of the disease. IgG antibodies
appear to be more sensitive but less specic
markers of disease than IgA. It is recommended
that both antibodies should be measured due to
the high incidence of IgA deciency among celiac
patients, which may mask the disease. Antibody
testing is also important in detecting individuals
who are at risk of having celiac disease but have
no symptomology, in individuals with atypical
symptoms or extraintestinal manifestations of celiac
disease (gluten sensitivity without enteropathy), and
in individuals with presumed celiac disease who
fail to respond to a gluten-free diet. Patients with
positive antibody tests must undergo small intestine
biopsy to conrm the diagnosis and assess the degree
of mucosal involvement (23-25).
4
Immune mechanism in celiac disease
Gluten is composed of two proteins, gliadin and
glutenin. Gliadin, the alcohol-soluble component, is
the preferred substrate of tissue transglutaminase, an
enzyme that deamidates or removes an amino group
from gliadin and adds the remainder of the peptide
into existing proteins as part of the normal repair
process. Transglutaminase is present in the cytoplasm
of most cells in an inactive state, but inammation
and mechanical injury activate and release it into the
intracellular matrix. It is present in high concentrations
in the connective tissue of the small intestinal wall,
especially surrounding smooth muscle cells in
the lamina propria. Transglutaminase complexes
with gliadin to form a “neoantigen” recognized as
immunogenic by patients with celiac disease. The
neoantigen is processed by antigen-presenting cells
such as macrophages, which then present it to CD4+ T-
lymphocytes. The CD4+ T-lymphocytes then activate
to produce interferon-γ and to proliferate. Interferon-
γ, produced by T cells, is thought to be primarily
responsible for injuring and killing mucosal epithelial
cells (19-20). This immunological mechanism
underlying celiac disease in individuals with specic
HLA subtype is shown in Fig. 3.
In addition to mechanical stress, chemical
injury, infectious agents, macrophages and CD4+
T-lymphocytes, other lymphocyte subsets are also
involved in the immune response in CD. Early
in celiac disease, certain “toxic” small gliadin
peptides generated by transglutaminase activity
stimulate secretion of IL-15 by epithelial cells and
lamina propria macrophages. These gliadin peptides
also increase mucosal permeability, enhancing
lymphocyte inltration. IL-15 is a key inammatory
mediator that stimulates intraepithelial lymphocytes.
The humoral immune mechanism is activated when
sensitized CD4+ T cells stimulate B cells to make
anti-gliadin and anti-transglutaminase antibodies.
B-lymphocytes mature into increased numbers of
plasma cells in the intestinal submucosa where
they produce the antibodies characteristic of CD.
The presence of T cells that recognize deamidated
gluten peptides in celiac disease might be relevant to
autoimmunity and the implication of celiac disease
in many autoimmune diseases (26-29).
C. Delayed hypersensitivity to gluten without
enteropathy or gluten sensitivity without
enteropathy
The terms gluten sensitivity and celiac disease
(also known as gluten-sensitive enteropathy) have
thus far been used synonymously to refer to a disease
process affecting the small bowel and characterized
by malabsorption and gastrointestinal symptoms.
Yet, gluten sensitivity can exist even in the absence
of an enteropathy. The systemic nature of this
disease, the overwhelming evidence of an immune
pathogenesis and the accumulating evidence of
diverse manifestations involving organs other than
the gut, such as the skin, heart, bone, pancreas,
joints, nervous system, liver, uterus and other
organs necessitate a re-evaluation of the belief that
gluten sensitivity is solely a disease of the gut (30).
This involvement of multi-organ system disorder
could be independent of HLA type and production
of antibodies against tissue transglutaminase (26,
30). The immune reaction to gliadin peptide and
its cross-reaction with different tissues might
result from a breach in oral tolerance to gliadin
and the induction of intestinal barrier dysfunction
by environmental factors such as xenobiotics and
infections (rotaviruses).
Indeed, human rotaviruses are the most frequent
etiologic agents of gastroenteritis in infants and
young children in most parts of the world. Anti-
gliadin peptide antibodies from patients with gluten
sensitivity recognize the viral product, suggesting
a possible link between rotavirus infection and
gluten sensitivity. It has also been demonstrated that
puried rotavirus peptide antibodies are capable of
cross-reacting with gliadin peptide, tight junction
protein (desmoglein peptide) and monocytes toll-like
receptor-4 peptide. These ndings further implicate
alteration of cell permeability in gluten sensitivity
and autoimmunity (26, 31-32).
Therefore, since afnity-puried rotavirus
peptide antibody not only binds to gliadin peptide
but also recognizes endomysial structure, activates
TLR4, and alters epithelial cell permeability, it
suggests that the rotavirus epitope may be important
in determining an anti-virus immune response’s
ability to cross-react with self-antigens. This cross-
reaction between rotavirus peptide and human tissue
antigens has functional consequences on TLR4,
tight junction proteins and intestinal permeability. It
A. VOJDANI ET AL.
5
Eur. J. Inamm.
is likely, then, that a molecular mimicry mechanism
may be involved in the pathogenesis of gluten
sensitivity with or without enteropathy (33-37).
The gliadin peptide also shares homology with
other self-antigens such as heat shock protein-60
(HSP60), glutamic acid decarboxylase, myotubularin-
related protein-2 and toll like receptors. Heat shock
proteins are highly conserved proteins synthesized
when cells are exposed to stress stimuli, such as
infection and inammation. Increased expression
of HSPs has been observed in jejunal epithelial cells
in patients with CD. Antibodies against the celiac
peptide cross-react with HSP60 and may therefore
induce epithelial cell cytotoxicity, thus amplifying
the damage of the intestinal mucosa with increased
intestinal permeability (37).
Matrix metalloproteinase-2 (MTMR2) belongs
to the protein-tryrosine phosphatase family. Defects
in MTMR2 are the cause of Charcot-Marie-Tooth
disease type 4, which is an autosomal recessive
demyelinating neuropathy. A demyelinating nervous
system disease can be observed in patients with CD.
Finally, TLRs are type I transmembrane proteins
involved in innate immunity by recognition of
conserved microbial structures. Activation of
antigen presenting cells via innate immune receptors
such as TLR4 can break self-tolerance and trigger
the development of autoimmunity (38-40). The anti-
gliadin peptide antibodies bind TLR4 on monocytes
and induce both the expression of activation
molecules such as CD83 and CD40 and the production
of pro-inammatory cytokines similar to the action
of bacterial antigens. The mimicry mechanism by
which rotaviruses or other environmental factors
are involved in the pathogenesis of gluten sensitivity
without enteropathy is shown in Fig. 4.
1
Fig. 1. Cellular and molecular induction of immune tolerance to dietary proteins
(gliadin). In the absence of major mechanical and chemical stress or infection (A), no
damage is done to fibroblasts and epithelial cells, and only small quantities of tissue
transglutaminase are released into the environment (B). Since under these conditions the
tight junctions are in perfect shape (C), only a few gliadin molecules may survive
digestion and be transported across the mucosal epithelium (D). If these molecules of
gliadin are deamidated by transglutaminase (E), the key regulator of the immune system
called dendritic cells or antigen-presenting cells (F) prime T cells for anergy or
tolerance. Early exposure to dietary proteins and bacterial antigens such as LPS (G) can
activate regulatory T cells to produce TGF-
�
and IL-10, inducing activation of
tolerogenic DCs (H) to control immune response to dietary proteins (gliadin). Further
activation of TR1, TH3 and natural Treg (I) by IL-10 results in induction of central or
peripheral tolerance (J).
Fig. 1. Cellular and molecular induction of immune tolerance to dietary proteins (gliadin). In the absence of major
mechanical and chemical stress or infection (A), no damage is done to broblasts and epithelial cells, and only small
quantities of tissue transglutaminase are released into the environment (B). Since under these conditions the tight
junctions are in perfect shape (C), only a few gliadin molecules may survive digestion and be transported across the
mucosal epithelium (D). If these molecules of gliadin are deamidated by transglutaminase (E), the key regulator of the
immune system called dendritic cells or antigen-presenting cells (F) prime T cells for anergy or tolerance. Early exposure
to dietary proteins and bacterial antigens such as LPS (G) can activate regulatory T cells to produce TGF-β and IL-10,
inducing activation of tolerogenic DCs (H) to control immune response to dietary proteins (gliadin). Further activation
of TR1, TH3 and natural Treg (I) by IL-10 results in induction of central or peripheral tolerance (J).
6
Based on this mechanism of action, we should
think about the immunology of gluten sensitivity
beyond the gut and emphasize laboratory testing for
celiac disease and gluten sensitivity beyond gliadin
and transglutaminase antibodies.
CONCLUSIONS
Immediate type hypersensitivity to gluten is IgE
mediated. This IgE-mediated reaction to gluten
may become life-threatening if wheat ingestion is
combined with exercise or with medication, such as
aspirin.
Strenuous exercise, medications and xenobiotics,
by increasing splanchnic blood ow, may cause an
increase in mucosal permeability and the entry of
gliadin into the circulation, hence, antibody response
against gliadin polypeptides.
2
Fig. 2. Schematic presentation of the pathophysiology of the immediate hypersensitivity
reactions (Type I allergy) of the intestine. Hypersensitivity reaction occurs by the binding
of dietary peptides (gluten) to low affinity IgE receptor CD23, which is expressed on the
epithelium of the small intestine (A), facilitating uptake of antigen in an IgE-independent
manner (B). Gluten cross-links to IgE on the surface of MAST cells to induce
degranulation (C). This MAST cell degranulation could be induced by strenuous
exercise, alcohol and medication (aspirin) (D), causing injury to gastrointestinal mucosa
and an increase in mucosal permeability (E). Under these conditions, parts of gluten that
are resistant to processing by luminal and brush-border enzymes will survive digestion
and be transported across the mucosal epithelium as polypeptides. Upon activation of
transglutaminase in the subepithelial region (F), many gliadin peptides form high
molecular weight complexes with transglutaminase (G) that can be transferred into the
circulation and the skin, leading to urticaria (H). These complexes can also bind to IgE
receptors on MAST cells and induce further degranulation (I). Finally, infiltration of
granulocytes, mononuclear cells and their cytokines can contribute to late phase
responses, which result in the impairment of epithelial barrier function (J). Also,
products released from MAST cells, including histamine, serotonin, prostaglandins,
tryptases and chymases (K), have been shown to have direct and indirect effects (via
activation of the enteric nerve) on epithelial ion secretion, barrier function, and intestinal
motility.
Fig. 2. Schematic presentation of the pathophysiology of the immediate hypersensitivity reactions (Type I allergy) of the
intestine. Hypersensitivity reaction occurs by the binding of dietary peptides (gluten) to low afnity IgE receptor CD23,
which is expressed on the epithelium of the small intestine (A), facilitating uptake of antigen in an IgE-independent manner
(B). Gluten cross-links to IgE on the surface of MAST cells to induce degranulation (C). This MAST cell degranulation
could be induced by strenuous exercise, alcohol and medication (aspirin) (D), causing injury to gastrointestinal mucosa
and an increase in mucosal permeability (E). Under these conditions, parts of gluten that are resistant to processing
by luminal and brush-border enzymes will survive digestion and be transported across the mucosal epithelium as
polypeptides. Upon activation of transglutaminase in the subepithelial region (F), many gliadin peptides form high
molecular weight complexes with transglutaminase (G) that can be transferred into the circulation and the skin, leading
to urticaria (H). These complexes can also bind to IgE receptors on MAST cells and induce further degranulation (I).
Finally, inltration of granulocytes, mononuclear cells and their cytokines can contribute to late phase responses, which
result in the impairment of epithelial barrier function (J). Also, products released from MAST cells, including histamine,
serotonin, prostaglandins, tryptases and chymases (K), have been shown to have direct and indirect effects (via activation
of the enteric nerve) on epithelial ion secretion, barrier function, and intestinal motility.
A. VOJDANI ET AL.
7
Eur. J. Inamm.
Clinicians should be aware that during food
processing many wheat isolates are produced by
chemical and enzymatic treatment and used in many
food products. Therefore, some patients may have
immune reaction to treated gliadin used in sausage,
but not to gluten or wheat itself.
Unlike immediate type hypersensitivity to gluten,
which occurs within minutes, the delayed type
hypersensitivity to gluten may occur hours or days
after ingestion of wheat.
Delayed type hypersensitivity to gluten is an
antibody- (IgG, IgA) and T-cell-mediated reaction.
Immune reaction to gluten occurs in genetically
susceptible individuals with the involvement
of tissue transglutaminase, resulting in chronic
inammation of the small intestine. This delayed
type hypersensitivity to gluten is called celiac
disease or gluten sensitivity with enteropathy.
3
Fig. 3. Depiction of the intestinal mucosa with emphasis on the factors involved in the
development of celiac disease in individuals with HLA-DQ2/DQ8 positive. Infection,
mechanical and chemical stress (A) can impair mucosal integrity (B). The parts of gluten
that are resistant to brush-border enzymes will survive digestion and can be transported
across the epithelial barrier as polypeptides (C). Tissue transglutaminase in the intestinal
mucosa (lamina propria) become activated and deamidate gluten peptides. Some of the
deamidated gliadins may cross-link to transglutaminase and form complexes of gliadin
with tTG (D). Deamidated gliadin peptide by itself, deamidated gliadin peptide cross-
linked to tTG, and released tight junction proteins are presented by dendritic cells or
antigen-presenting cells as well as B cells (E) which carry HLA-DQ2 or DQ8 molecules
to the CD4+ T cells in the lamina propria (F). It is believed that this antigenic
presentation is enhanced in an individual with later-in-life exposure to bacterial antigens
whose mature dendritic cells produce significant amounts of interleukin-12 (G). This
antigenic presentation results in driving the CD4+ cell response either towards TH1
reaction, production of inflammatory cytokines (H), mucosal cell destruction and
autoimmunity, or, toward TH2 response B-cell activation (I), and antibody production
against deamidated gluten, transglutaminase, gliadin cross-linked to transglutaminase,
and different tissue antigens (J). - Deamidated gliadin peptide; - deamidated gliadin
peptide cross-linked to tTG; - tight junction proteins; - transglutaminase; T-
different tissue antigens.
Fig. 3. Depiction of the intestinal mucosa with emphasis on the factors involved in the development of celiac disease in
individuals with HLA-DQ2/DQ8 positive. Infection, mechanical and chemical stress (A) can impair mucosal integrity
(B). The parts of gluten that are resistant to brush-border enzymes will survive digestion and can be transported across
the epithelial barrier as polypeptides (C). Tissue transglutaminase in the intestinal mucosa (lamina propria) become
activated and deamidate gluten peptides. Some of the deamidated gliadins may cross-link to transglutaminase and form
complexes of gliadin with tTG (D). Deamidated gliadin peptide by itself, deamidated gliadin peptide cross-linked to tTG,
and released tight junction proteins are presented by dendritic cells or antigen-presenting cells as well as B cells (E)
which carry HLA-DQ2 or DQ8 molecules to the CD4+ T cells in the lamina propria (F). It is believed that this antigenic
presentation is enhanced in an individual with later-in-life exposure to bacterial antigens whose mature dendritic cells
produce signicant amounts of interleukin-12 (G). This antigenic presentation results in driving the CD4+ cell response
either towards TH1 reaction, production of inammatory cytokines (H), mucosal cell destruction and autoimmunity, or,
toward TH2 response B-cell activation (I), and antibody production against deamidated gluten, transglutaminase, gliadin
cross-linked to transglutaminase, and different tissue antigens (J). - Deamidated gliadin peptide; - deamidated
gliadin peptide cross-linked to tTG; - tight junction proteins; - transglutaminase; T - different tissue antigens.
8
Gluten sensitivity without enteropathy may occur
in individuals without the involvement of genes,
tissue transglutaminase and presence of inammation
in the small intestine. Gluten sensitivity without
enteropathy is induced mainly by enhanced gut
permeability due to infection (rotavirus), stress or
chemical injuries.
Impaired mucosal integrity results in the entry of
gliadin peptides, tight junction proteins and others
to the submucosa, regional lymph nodes, and the
blood. The entry of gliadin peptides, tight junction
proteins and infections in the blood results in the
production of antibodies against them.
The cross-reaction of these antibodies with
different tissue antigens such as heart, kidney,
adrenal gland, ovary, thyroid, parathyroid, prostate,
4
Fig. 4. Depiction of immunological mechanisms underlying gluten sensitivity and its
immunopathological consequences. Precipitation of gluten sensitivity without
enteropathy appears to be preceded by acute gastroenteritis symptoms induced by
infections such as rotavirus and others (A). Rotavirus and its super-antigens can break
down mucosal IgA directly (B) or indirectly by the local production of anti-rotavirus
antibody. Due to partial linear homology or cross-reactivity between rotavirus protein
and a-gliadin, the anti-rotavirus antibody binds to gliadin and forms complexes with it
(C). The combination of infection antibody cross-reactivity with gliadin and additional
stressors can severely impair mucosal integrity (D) and the entry of gliadin peptides,
tight junction proteins and other antigens into the submucosa, regional lymph nodes, and
the blood (E). Gliadin peptides, rotavirus antigens, rotavirus antibody bound to gliadin,
and tight junction proteins are presented by dendritic cells with or without HLA-
DQ2/DQ8 to CD4+ cells (F). This antigenic presentation results in driving the cell
CD4+ response either towards TH1 reaction (G), the production of proinflammatory
cytokines, which contributes to autoimmunity (H); or towards TH2 response B-cell
activation (I) and antibody production against gluten, rotavirus, and tight junction
proteins (J). Cross-reaction of these antibodies with cell receptors such as toll-like
receptors on monocytes and the release of IL-6, IL-12 and TNF-
�
(K), and tissue antigens
such as heart, kidney, adrenal gland, ovary, prostate, brain and others (L) results in
further tissue damage and multi-organ system disorders (M). - Gliadin peptides; -
rotavirus antibody bound to gliadin; - tight junction proteins.
Fig. 4. Depiction of immunological mechanisms underlying gluten sensitivity and its immunopathological consequences.
Precipitation of gluten sensitivity without enteropathy appears to be preceded by acute gastroenteritis symptoms induced
by infections such as rotavirus and others (A). Rotavirus and its super-antigens can break down mucosal IgA directly
(B) or indirectly by the local production of anti-rotavirus antibody. Due to partial linear homology or cross-reactivity
between rotavirus protein and a-gliadin, the anti-rotavirus antibody binds to gliadin and forms complexes with it (C).
The combination of infection antibody cross-reactivity with gliadin and additional stressors can severely impair mucosal
integrity (D) and the entry of gliadin peptides, tight junction proteins and other antigens into the submucosa, regional
lymph nodes, and the blood (E). Gliadin peptides, rotavirus antigens, rotavirus antibody bound to gliadin, and tight junction
proteins are presented by dendritic cells with or without HLA-DQ2/DQ8 to CD4+ cells (F). This antigenic presentation
results in driving the cell CD4+ response either towards TH1 reaction (G), the production of proinammatory cytokines,
which contributes to autoimmunity (H); or towards TH2 response B-cell activation (I) and antibody production against
gluten, rotavirus, and tight junction proteins (J). Cross-reaction of these antibodies with cell receptors such as toll-like
receptors on monocytes and the release of IL-6, IL-12 and TNF-γ (K), and tissue antigens such as heart, kidney, adrenal
gland, ovary, prostate, brain and others (L) results in further tissue damage and multi-organ system disorders (M). -
Gliadin peptides; - rotavirus antibody bound to gliadin; - tight junction proteins.
A. VOJDANI ET AL.
9
Eur. J. Inamm.
brain and others results in multi-organ disorder,
which will be discussed in a subsequent article.
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