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Published in final edited form as:

Gastrointest Endosc Clin N Am. 2012 October ; 22(4): . doi:10.1016/j.giec.2012.07.003.

Celiac Disease Pathophysiology

Sonia S. Kupfer and Bana Jabri
University of Chicago Celiac Disease Center

Keywords
celiac disease; HLA-DQ2 and HLA-DQ8; single nucleotide polymorphisms; intestinal
microbiome; gluten; deamidation; adaptive and innate immunity

Introduction
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Celiac disease is an intestinal inflammatory disease that is triggered by dietary gluten, a

protein found in wheat, barley and rye in genetically susceptible individuals.1 Descriptions
of a celiac disease-like phenotype can be traced back to the Greek physician Aretaeus in the
1st and 2nd century AD (reviewed in 2). Gluten was identified as the culprit of celiac disease
by Dutch physicians who observed that, during the 194445 famine when wheat and rye
were scarce, celiac children symptomatically improved.3 Subsequent studies characterized
many features of celiac disease, and, while disease pathogenesis and pathophysiology
remain incompletely understood, the disease is thought to arise from the interplay of genetic,
environmental and immunological factors (Figure 1). Importantly, understanding of celiac
disease pathophysiology, in which the trigger (wheat, rye and barley) is known, will
undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (e.g., type I
diabetes) that share many common pathogenic perturbations. In this review, we describe
seminal findings in each of the three domains of celiac disease pathogenesis: genetics,
environmental triggers and immune dysregulation with a focus on newer areas of
investigation such as non-HLA genetic variants, intestinal microbiome and the role of the
innate immune system.

Genetics
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Celiac disease has a strong hereditary component. Epidemiological studies show that up to
20% of first-degree relatives are affected by the disease6 with concordance rates of 7580%
in monozygotic twins and 10% in dizygotic twins7. The strongest and best-characterized
genetic susceptibility factors in celiac disease are human leukocyte antigen (HLA) class II
genes known as HLA-DQ2 and HLA-DQ8, molecules responsible for presentation of
antigens to immune cells. However, while HLA-DQ2 or DQ8 are necessary for disease to
develop, they are not sufficient implicating other genetic or environmental factors in disease
development. Approximately, 2530% of individuals of European descent carry HLA-DQ2
susceptibility, but only about 4% of these individuals will develop celiac disease in their
lifetime8 underscoring the role of additional factors. Recent large-scale genetics studies,
called genome-wide association studies (GWAS), have identified a number of common nonHLA genetic factors (many in genes involved in immunity) associated with celiac disease

Correspondence to: Sonia S. Kupfer, MD, Assistant Professor of Medicine, University of Chicago Medicine, Department of Medicine,
Section of Gastroenterology, Hepatology and Nutrition, 900 East 57th Street, MB#9, Chicago, IL 60637, 773-702-8076 (phone),
773-702-2281 (fax), [email protected].

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which, on their own, contribute a small amount to overall risk but have great potential in
discovering important and novel pathways involved in disease pathogenesis.

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HLA-DQ2 & -DQ8 genetics and disease risk

HLA is the name of the major histocompatibility complex (MHC) in humans.4 These genes
reside on chromosome 6 and are divided into three classes (IIII) (Figure 2). HLA-DQ is a
class II molecule on chromosome 6p21.3 responsible for presentation of peptides from
outside cells (compared with class I molecules that present peptides from within cells and
class III molecules that encode complement proteins). HLA-DQ is composed of a
heterodimer encoded by HLA-DQA1 and HLA-DQB1 genes respectively. The
heterodimer is a cell surface receptor located on APCs.

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The genetics of celiac disease is complex because the number, type and configuration of the
DQA1 and DQB1 alleles determine disease risk. Current WHO nomenclature is HLA
followed by a hyphen followed by the gene (e.g., DQA1, DQB1, etc), an asterisk
(separator), allele group (field 1), colon (field separator), protein (field 2).5 The isoform
encoded by a specific combination of DQA1 and DQB1 genes can be expressed as HLAx.y
where x refers to DQB1 and y to DQA1. For example, DQ2.5 is the protein encoded by
DQB1*02 and DQA1*05 inherited either in cis (on the same chromosome) or trans (on
different chromosomes). When these alleles are located on the same chromosome (i.e., in
cis), they are often inherited in a haplotype with another class II molecule DRB1*03 (DR3).
Figure 3 highlights HLA configurations associated with celiac disease. The highest risk
group are those that carry DQB1*02 on both chromosomes (i.e. homozygotes) known as
gene dose effect.6,7 DQB1*02 homozygosity (carrying two DQB1*02 alleles) has an
estimated prevalence of 2% in the population but represents 25% of all celiac patients due to
an estimated five-fold increased risk of celiac disease compared to heterozygotes (carrying
one DQB1*02 allele).8,9 Studies have shown that the CD4+ helper T cell response from
DQB1*02 homozygous individuals is stronger than the response from heterozygous
individuals.6,10 Moreover, DQB1*02 homozygosity may be associated with younger age of
onset11,12 and more complicated clinical course including refractory sprue. 13 DQ2.5
(DQB1*02/DQA1*05) heterozygotes are the most common HLA configurations and
represent up to 50% of the HLA types found in celiac disease patients. 9 While DQ2.2
(DQB1*02/DQA1*02) is highly homologous to DQ2.5, it alone carries little risk of celiac
disease due to decreased stability of bound peptides.14

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A small minority of celiac patients carry only one of the alleles of the risk HLA-DQ2
heterodimer: HLA-DQA1*05 (05:01 or 05:05) or HLA-DQB1*02 (02:01 or 02:02). This is
called the half-heterodimer. The European Genetic Cluster on Celiac Disease typed over
1000 celiac patients and found that 6% carried neither HLA-DQ2 nor DQ8. Of these
patients, 93% (57/61) carried the DQ2.5 half heterodimer with almost three-quarters
carrying only the DQB1*02 allele. 15 The prevalence of individuals carrying only one copy
of DQB1*02 was increased in celiac patients compared with controls, while those carrying
only one DQA1*05 was higher in controls compared to patients indicating a negative
association for the DQA1*05 half heterodimer.9
DQ8 is a heterodimer composed of -chains encoded by DQA1*03:01 and -chains encoded
by DQB1*03:02. When they are inherited on the same chromosome, they are found on a
haplotype with DRB1*04 notated as DR4-DQ8. The prevalence of HLA-DQ8 in the general
population varies geographically with higher rates in individuals from the Middle East and
South America.16 In celiac disease overall, HLA-DQ8 is found in 510% of patients.9,15 As
with DQ2, risk of disease with HLA-DQ8 follows a gradient. The highest risk appears to be
in individuals who inherit DQ8 and DQ2; though, the overall prevalence of carrying both
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DQ8 and DQ2 is low at 2.5%.9 In individuals with HLA-DQ8 and DQ2.2 or DQ2.5, risk is
estimated at 1:24, while those with HLA-DQ8 but not DQ2.2 or DQ2.5, risk is estimated at
1:89.9 DQ8 homozygosity confers increased risk compared to DQ8 heterozygotes.17
Development of celiac disease in individuals who are HLA-DQ2 and -DQ8 negative is
extremely rare. In a large European collaborative study, only 4 of 1008 patients (0.4%)
fulfilled criteria for celiac disease but did not carry DQ2 (including half heterodimer) nor
DQ8.15 No other class I or II associations were identified in this small group. In support of
these findings, two additional studies in the US and Italy found the prevalence of DQ2/8
negativity in celiac disease to range from 0.160.9%. 9,17 Thus, in a very small group of
patients, if clinical suspicion is high with supporting serological and histological findings,
celiac disease can be diagnosed in the absence HLA-DQ2 or -DQ8. However, the overall
risk of celiac disease in individuals who do not carry DQ2 or DQ8 is very low. These
findings support the use of HLA testing for its high negative predictive value (Figure 4).
HLA peptide binding

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HLA-DQ2 and DQ8 play a key role in celiac disease due to their physiochemical
properties and binding of specific peptides deamidated by tissue transglutaminase 2 (tTG2).
Both HLA-DQ2 and DQ8 contain positively charged pockets with a preference for binding
negatively charged particles. Specifically, in DQ2, the lysine position at 71 has a
preference for binding negatively charged residues at positions P4, P6 and P7 (Figure 5). 18
The DQ8 57 polymorphism creates a basic environment with a preference for binding the
negatively charged residue at P9 (Figure 5).19
In celiac disease, these HLA molecules on APCs present gluten peptides to CD4+ T cells
thereby activating them.20,21 The size of the peptide fragment defines stimulatory activity
with larger fragments showing increased CD4+ T cell stimulation compared with smaller
fragments.2226 While deamidation favors binding to HLA-DQ2 or DQ814, studies have
suggested that it is not absolutely required for stimulation of CD4+ T cells especially in the
case of HLA-DQ8.19,27 The mechanism for recognition of native peptides is that the
polymorphism at position 57 allows DQ8 to switch from interaction with a negatively
charged residue in TCR to one in the peptide.19
Non-HLA genetic susceptibility factors and role in disease pathogenesis

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HLA is the best-characterized genetic susceptibility factor in celiac disease, but does not
account for all disease heritability suggesting that additional genetic factors play a role.
Genome-wide association studies (GWAS) have identified a number of candidate genetic
susceptibility factors in celiac disease. The results of GWAS shed light on new genes and
genetic pathways involved in disease pathogenesis. The immediate challenge is to identify
variants within these regions that are functionally important in order to elucidate their role in
celiac disease pathogenesis. To date, non-HLA genetic loci harboring 115 genes have been
associated with celiac disease using GWAS.2831 Of these genes, 28 are immune-related
which can be broadly grouped into categories based on function and pathways. (Reviewed
in 32,33). Enrichment analysis indicates that these genes are broadly involved in adaptive and
innate immune response among others (Figure 6). Taken as a whole, these results underscore
the importance of immune dysregulation in celiac disease by confirming the role of the
adaptive immune response as well as highlighting pathways involved in innate immune
response. Post-GWAS studies will need to focus on elucidating the functional basis of these
genetic variants; in particular, the role of regulatory variation.
An intriguing finding to emerge from GWAS is the overlap of variants identified in a
number of diseases and traits including several immune-related diseases. Common loci have

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been identified with type 1 diabetes, rheumatoid arthritis and Crohns disease suggesting
common genetic backgrounds for these immune-related diseases. However, non-HLA loci in
celiac disease are estimated to account for a small portion of overall genetic risk. The reason
for missing heritability is still under investigation and could be explained by the
contribution of highly penetrant genetic variants with lower allele frequencies than those
studied in GWAS. These rare variants may have greater impact on disease susceptibility
than common variants discovered to date and, as large-scale sequencing studies are
completed, it will become clear what role rare genetic variants play in celiac disease
pathogenesis. Moreover, the role of gene-gene and gene-environment interactions need to be
explored further in celiac disease.

Environment

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Environmental factors clearly play an important role in celiac disease pathogenesis. The
primary trigger in the disease is gluten, and, over the past decade, many studies have
contributed to our understanding of gluten biochemistry and antigenic epitopes, transport
through the small intestinal epithelium, modification by tTG, and binding to antigen
presenting cells in the lamina propria with subsequent activation of adaptive immunity.
Moreover, it has become clear that gluten is associated with innate immune responses in the
gut epithelium and that cytotoxic intraepithelial lymphocytes appear to play a central role. In
addition, emerging data implicates microbiota (both commensal and pathogenic) in disease
pathogenesis, while epidemiological studies have suggested that early (and possibly late)
gluten introduction to children, ceasarean section delivery as well as lack of breast-feeding
are important risk factors for development of celiac disease.
Gluten and epithelial transport of peptide fragments
Wheat, rye and barley belong to the same tribe called triticeae that diverged from oats
belonging to the aveneae tribe. (Figure 7) While gluten is used as the general term to
describe the trigger of celiac disease, gluten technically refers to the disease-activating
peptides found only in wheat. Gluten comprises two different protein types, gliadins and
glutenins, capable of triggering disease.3436 The peptides in barely and rye, hordeins and
secalins respectively, are also capable of activating disease.37 In contrast, oats, comprised of
more distantly related peptides called avenins, rarely trigger celiac disease.38 Gliadins,
glutenins, hordein and secalins contain high contents of prolines and glutamines which
makes them resistant to degradation by gastric acid, pancreatic and brush border enzymes
because these are lacking in prolyl endopeptidase activity.39,40 There is ongoing interest in
leveraging certain bacterial or fungi endopeptidase activities as a therapeutic strategy.3942

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Transport of peptide fragments across the small intestinal epithelium and intestinal
permeability have been areas of intense research in celiac disease, though their primary role
in disease pathogenesis remains incompletely understood. Peptide fragments that have been
resistant to degradation can be transported across the epithelium primarily by transcellular
pathways (reviewed in 43). Tight junctions play a role in peptide transport and genome-wide
association studies in celiac disease have found susceptibility SNPs in tight junctionassociated genes.29,44,45
However, it is unclear whether altered intestinal permeability is a primary cause or a
consequence of intestinal inflammation. Moreover, the role of tight junction blockade as a
therapeutic strategy has been studied using pre-haptoglobin-2, an analogue of the zonnula
occludens toxin.4648 However, this study did not directly measure intestinal permeability
and, therefore, the mechanism of action remains unclear. An alternate mechanism of
transcellular transport of gliadin involves abnormal retro-transport of IgA-gliadin by the
CD71 receptor.49 CD71, a transferrin receptor, was shown to be upregulated and apically
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expressed in active celiac disease leading to escape of gliadin degradation and translocation
to the lamina propria known as the so-called Trojan Horse phenomenon.49 Further study is
required to determine the role of peptide fragment transport and intestinal permeability in
pathogenesis.
Microbiota
An emerging field of investigation is the role of the human microbiome in human health and
disease.50 The human intestine harbors a vast number and variety of commensal
microorganisms that are complex and dynamic (reviewed in 51). In the past 5 years, there
have been important technological developments in high-throughput sequencing that have
enable investigators to characterize the human microbiome using culture-free methods
known as metagenomics.52 While an individuals microbiome is unique, there is evidence of
sharing among family members.53 The microbiome is influenced by diet54, and the interplay
between diet and the microbiome affects metabolic function.55 Importantly, there are
important interactions between the gut microbiome, diet and the immune system that appear
to contribute to phenotypes such as obesity53, inflammatory bowel disease56 and celiac
disease.

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Studies of the gut microbiome in celiac disease are still in their early stages and have yielded
conflicting results likely due to different experimental approaches on fecal or biopsy
samples in various patient populations from different countries. All of these factors can bias
microbiome results. In 2004, a study identified rod-shaped bacteria in intestinal biopsies of
celiac patients suggesting a role for the microbiome in celiac disease.57 Further studies
analyzed samples for metabolic readouts of the gut microbiome (e.g., short chain fatty acid
and volatile compounds) in celiac patients58,59 as well as first-degree relatives of celiac
patients60 and found significant differences compared to controls. Additional studies using
various methodologies found differences in fecal and/or mucosal-associated composition
primarily of Bacteroides, Clostridium, Bifidobacteria, Lactobacillus, Escheheria coli and
Staphylococcus59,6165 between celiac patients (both untreated and treated) and controls.
Differences in microbial composition were also found between adult and children with
celiac disease.66 However, other studies have failed to find differences in the microbiome
among cases and controls.67 A recent paper hypothesized that the intestinal microbiome as a
whole determines the switch from tolerance to immune response in genetically susceptible
infants and found a lack of Bacteroidetes and increased abundance of Firmicutes in a
longitudinal study of at-risk infants followed from birth to 24 months.68 Further studies
using combined genomic approaches are needed to clarify the role of the microbiome in
celiac disease.

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Consistent with the role of diet in modulating the gut microbiome, the gluten free diet alone
in healthy individuals led to decreases in Bifidobacterium and Lactobacillus.69 Moreover,
animal and human studies suggest possible interactions between commensal bacteria and
immune responses in celiac disease.70,71 Animal studies have suggested that the microbiome
in celiac disease might alter intestinal permeability thereby contributing to disease
pathogenesis.72 To date, probiotic studies in celiac disease investigated the proteolytic
activity of VSL#3 or sourdough lactobacilli42,73, but none has studied the role in modulating
commensal flora, although there is data of therapeutic effect of probiotics in irritable bowel
syndrome.74 Animal and human studies in this area are ongoing.
Despite technological advances in studying the human intestinal microbiome, many
questions remain to be answered about the role of commensal bacteria in immune-mediated
gastrointestinal diseases such as celiac disease or inflammatory bowel diseases (reviewed
in 75). First, and perhaps most important, among these is whether the intestinal microbiota is
a cause or a consequence of intestinal inflammation. There is evidence to support both sides
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and additional studies are needed to elucidate cause and effect. Moreover, there is interest in
how microbial alterations could be used for therapeutic interventions, though clinical trials
are lacking in celiac disease. There are questions about how diet impacts and alters intestinal
microbiota as well as the effect of different microbes on immune function. Finally, the role
of commensal fungi and viruses has not been studied in celiac disease.
Other environmental risk factors
Besides the commensal microbiome, a number of other factors including childhood
infections notably rotavirus, mode of delivery, gluten introduction to infants, and breastfeeding have been studied in celiac disease. The data on these factors stems primarily from
epidemiological and ecological studies, and their role in disease pathogenesis remains to be
fully elucidated.

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The role of pathogenic organisms in celiac disease had been suggested in the 1980s when
Kagnoff et al described a 12 amino acid sequence homology between A-gliadin and the E1b
protein from human adenovirus type 1276 and that celiac patients had a significantly higher
rate of previous adenovirus type 12 infection compared to controls.77 It was hypothesized
that there may be immunological cross-reactivity between antigenic elements shared by
viruses and -gliadin.78 However, follow-up studies are inconsistent in their findings
regarding adenovirus type 12 and celiac disease.7981 The finding of a seasonal pattern of
higher rates of summer births in children with celiac disease also suggests a role for
infectious agents.82 More recent studies implicate rotavirus in celiac disease pathogenesis.
Stene et al prospectively followed children with HLA risk and determined that frequent
rotavirus infections (as measured by rotavirus antibody titers) showed a moderate, but
statistically significant increased risk of celiac disease.83 Zanoni et al used a peptide library
approach using sera of active celiac patients and found an autoantigen peptide recognize
rotavirus serotype 1 major neutralizing protein VP7 as well as HSP60, desmoglein 1 and
toll-like receptor4 (TLR4).84 Anti-peptide antibodies altered intestinal permeability and
activate monocytes via TLR4 signaling suggesting a role of innate immunity and viral
infection in disease pathogenesis.

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Mode of delivery has also been studied as a possible risk factor for celiac disease perhaps
due to altered exposure to commensal bacteria in the perinatal period. While not confirmed
in all studies85, cesaerean section, particularly performed electively, is associated with a
modest increased risk of later celiac disease.86,87 Intriguingly, a recent study found that
children born vaginally have microbiota in various tissues that resemble their mothers
vaginal flora including Lactobacillus, Prevotella and Sneathia spp, while children born by
cesearean section harbored flora resembling skin bacterial communities such as
Staphylococcus, Corynebacterium and Propionibacterium spp.88 Additional work is needed
to correlate neonatal bacterial colonization with future risk of celiac disease.
The effect of timing of gluten introduction on risk of celiac disease came to the forefront
with the Swedish celiac epidemic in the 198090s. Prospective, population-based data
noted that, in 1985, there was a four-fold increase in celiac disease incidence in children
under age 2 that precipitously dropped to pre-1985 rates a decade later.89,90 Ten years later,
the prevalence of celiac disease in Swedish children born during the epidemic remains three
times higher than the population prevalence.91 This rapid rise and decline in disease
incidence correlated with changes in infant feeding practices including younger age of
gluten introduction, increase amount of gluten in diet and reduced breast-feeding.89,92 A
prospective, ten year observational study in children at risk for celiac disease noted a fivefold increased risk of celiac disease autoimmunity when gluten was introduced in the first 3
months compared to 46 months of life further evidence that early gluten introduction is a

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risk factor.93 Despite these ecological and epidemiological studies, reasons why early gluten
introduction causes higher risk of celiac disease remains unexplained.

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Breast-feeding has also been shown in some studies to be protective against celiac disease.
A meta-analysis pooled five case-control studies and found a 52% reduction in celiac
disease correlating to duration of breast-feeding.94 Hypotheses for the protective effect of
breast-feeding on celiac disease include avoidance of early gluten introduction, protection
against infections, decreased immune response due to IgA antibodies in breast milk and T
cell-specific suppressive effects. Mothers with at-risk infants are therefore counseled to
continue breast-feeding as long as possible and introduce gluten between 46 months.95

Immune Dysregulation
Introduction

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While celiac disease requires genetic susceptibility (primarily HLA-DQ2 or DQ8) as well
as environmental exposures (foremost gluten ingestion), these alone are insufficient to
trigger the disease and do not explain ongoing small intestinal inflammation. Immune
dysregulation, therefore, is a core feature of celiac disease pathogenesis and has been the
subject of intense research over the last few decades. The role of tTG in the deamidation of
specific toxic epitopes as well as the initiation of gluten-specific T cell adaptive immune
responses have been elucidated. Moreover, the role of innate immune responses in disease
pathogenesis has recently received attention especially in small intestinal epithelial damage
via CD8+CD4- intraepithelial lymphocytes.
Toxic epitopes and tissue transglutaminase
Once undigested peptide fragments from wheat, rye and barley are transported to the lamina
propria, they are subject to deamidation by tTG2 which converts glutamine to glutamate
thereby introducing negative charges that have stronger binding affinity for HLA-DQ2 and DQ8 on APCs. tTG2 belongs to a family of calcium-dependent transamidating enzymes that
catalyze covalent and irreversible cross-linking of proteins expressed in all cell types. In an
inactive, closed form, tTG2 is located intracellularly and is enzymatically inactive.96 For
reasons that are incompletely understood, tTG2 is transported extracellularly, where, in the
presence of calcium, tTG2 is in an open reduced form and is enzymatically active.97 Under
normal physiological conditions, tTG2 is rapidly inactivated via oxidation. While in a
reducing environment such as ongoing inflammation, tTG2 remains active extracellularly
which might facilitate ongoing tTG2 activity (Figure 8).98

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Certain glutamine residues, so-called toxic epitopes, have higher specificity for tTG2
deamidation in the small intestine. Peptides derived from wheat, rye and barley are
heterogeneous populations. Gliadin peptides are sub-divided intro -, -, and -gliadins,
while glutenins are characterized as high molecular weight or low molecular weight. Among
gliadin, glutenin, hordein and secalin peptides (as well as a few avenin peptides derived
from oats), toxic epitopes composed of a nine amino acid core sequence elicit glutenspecific T-cell responses in celiac disease dependent on HLA type. A nomenclature system
has been proposed recently for celiac disease-relevant gluten epitopes based on specific
criteria.99
A hallmark of celiac disease is the presence of anti-tTG2 antibodies that can be detected in
the serum by ELISA. Anti-tTG2 antibodies (especially IgA) are highly sensitive and specific
for the disease.100 However, the mechanism of auto-antibody formation remains
incompletely understood (reviewed in 101). Furthermore, there is controversy about the role
of anti-tTG2 antibodies in disease pathogenesis (reviewed in 102,103). A recent study104
provided evidence favoring a T cell-dependent model of antibody formation in celiac
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disease suggesting that tTG-specific B cells act as APCs for the gluten-specific T cell
immune response. Additional studies suggest that auto-antibodies could modulate small
intestinal biology by enhancing passage of gliadin peptides49, inhibiting angiogenesis105,106,
or alter tTG2 activity;104110 although there is conflicting data as to whether tTG2 activity is
inhibited or enhanced. Support for a role of auto-antibodies in disease pathogenesis is
provided by extra-intestinal manifestations of celiac disease notably dermatitis
herpetiformis. In this dermatological condition associated with celiac disease, anti-tTG3
antibodies are expressed in the dermal papillae and are thought to mediate lesion
formation.111
Adaptive immune response

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The role of the adaptive immune system in the gut is to distinguish between harmful and
beneficial antigens derived from microorganisms (commensal and pathogenic) as well as
ingested food peptides. As a result, the intestinal mucosa holds a large proportion of all
immune cells in the body that reside in gut-associated lymphoid tissue (GALT) where nave
T and B cells are found (reviewed in 112). Immune cells residing in the lamina propria and
epithelial layer, in contrast, have effector and memory function. APCs patrol areas of nave
B or T cells and give costimulatory signals that induce T- or B-cell differentiation that, in
turn, leads to elimination of harmful antigens or tolerance of harmless antigens.
Maintenance of an adaptive tolerogenic T-cell response to a soluble protein antigen is
termed oral tolerance. Under normal physiological conditions, oral tolerance is maintained
in an environment of retinoic acid along with the cytokine TGF- that together induce
development of regulatory T cells to suppress pro-inflammatory effector T cells. 113,114
However, in celiac disease, it appears that retinoic acid, in the context of high IL-15,
promotes destructive immune responses to gluten rather than oral tolerance.115 These
findings also underscore the close association between adaptive and innate immunity in
celiac disease pathogenesis (see section on innate immunity below). An integrative model of
immune dysregulation in celiac disease is shown in Figure 9.

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The role of adaptive immunity in celiac disease pathogenesis was first described in the
1970s when Ferguson and MacDonald116,117 reported an association of celiac disease with a
lymphocyte-mediated immunity to gluten in the small intestine and that T cell-mediated
immunity led to characteristic pathological changes such as villous atrophy in an allograft
rejection model. Further studies found that T cells recognize gluten peptides presented by
HLA-DQ2 or DQ8 molecules on APCs in the lamina propria.118,119 Gluten-specific T cells
from small intestines of celiac patients reveal high levels of interferon- (IFN-)120 and
messenger RNA for IFN- was high in biopsies from celiac patients treated with short-term
gluten in vitro.121 In celiac disease, IFN- is produced by TH1 cells induced by IL-15, IFN and possibly IL-18.115,122,123 IFN-, in particular, is highly expressed in small bowel
from celiac patients, and it likely plays an important role in differentiation of
proinflammatory dendritic cells. In support of this hypothesis, clinical observations have
been made of celiac disease development after IFN- treatment for hepatitis C124 and higher
risk of celiac disease in patients with Downs syndrome in whom IFN- receptor expression
and type I IFN response are increased as chromosome 21 harbors the IFN- receptor. 125,126
Innate immune response
While gluten-specific CD4+ T cells play a central role in celiac disease, they are not
sufficient to produce characteristic epithelial damage and villous atrophy. This is mediated
by innate immune signals with intraepithelial lymphocytes (IELs) playing a primary role
(reviewed in127). IELs are a prominent histological feature in the spectrum of celiac disease
and aberrant IEL populations underlies refractory sprue (polyclonal in type I and
monoclonal in type II) as well as enteropathy-associated lymphoma (EATL).128 Intestinal

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IELs are a heterogeneous population composed primarily of TCR+ CD8+ cells but also
TCR+ and few natural killer(NK)-like cells.129

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Epithelial stress can be triggered by inflammation, infection and gluten peptides leading to
expression of stress signals on enterocytes primarily MHC class I-related chain A and B
(MICA and MICB) molecules and HLA-E.130 (Figure 9) In healthy intestine, IELs typically
express inhibitory CD94/NKG2A receptors. In celiac disease, on the other hand, IELs
express NK receptors NKG2D131 and CD94/NKG2C132 that recognize MICA and MICB133
and HLA-E on epithelial cells134 which mediate epithelial destruction. IL-15 plays a key
role here by upregulating NK receptors on cytotoxic IELs and enables T-cell receptor
independent killing.131,135,136 Cytokine secretion (e.g. IFN-) and proliferation is mediated
by CD94-NKG2C.132 Activation of cytotoxic IELs might also be induced by gluten-specific
CD4+ T cells through IL-21123,137 and IFN-.121,138

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In refractory sprue, IELs acquire a highly activated NK-like phenotype.128 In this condition,
the inflammatory state in the small intestine persists despite avoidance of wheat, rye and
barley. There are two types (RCD I and II) characterized by their IEL phenotypes(reviewed
in 139). In RCD type I, IELs express CD3 and CD8 as well as TCR- similar to that found in
celiac disease. In these cases, prognosis is good with immunsuppressive therapy.128,140
RCD type II, on the other hand, lack CD8, CD4 and TCR-, have intracellular CD3, have
a clonal TCR gene rearrangement and carry a dismal prognosis.140 The NK-like phenotype
of IELs in refractory sprue is promoted and maintained by elevated IL-15 expression in the
small intestinal epithelium. 141,142

Unanswered questions and future directions

We have come a long way in our understanding of celiac disease pathogenesis since Dickes
first clinical observations in the 1950s. However, several questions remain unanswered in all
three domains of genetics, environment and immmunology. In celiac disease genetics, there
has been an explosion in the number of susceptibility variants identified due to technological
improvements in genotyping. The next phase of study will need to elucidate the functional
consequences of these variants and their contribution to disease pathogenesis. The full
impact of rare variants in celiac disease has not yet been studied and could explain some of
the missing heritability. In addition, the role of epigenetics (e.g., methylation) has not been
investigated in celiac disease and could play an important role in disease susceptibility.
Finally, the application of genetics discoveries in clinical practice remains undetermined.
Presently, HLA genetic testing is used primarily for its negative predictive value, and it is
not clear if additional, low or moderately penetrant susceptibility variants will alter clinical
diagnosis and management.

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Regarding environmental factors, it remains unclear how microorganisms (both commensal

and pathogenic) contribute to disease. To date, investigators have been unable to tease apart
cause versus consequence in microbiome studies in celiac disease. Moreover, it remains to
be studied how modulation of the microbiome through use of probiotics, for example, could
alter disease onset or course. Importantly, the role of viruses and fungi has been
understudied in celiac disease to date. While epidemiological studies suggest certain
protective factors such as breast-feeding and timing of gluten introduction, mechanistic
underpinnings of these observations remain incompletely understood.
Our immunological understanding of celiac disease now encompasses both adaptive and
innate immunity. However, questions remain about transport of gluten peptides across the
epithelium into the lamina propria. Moreover, the pathogenic role of anti-TG antibodies
continues to be debated. In addition, the role of TCR+ IELs in disease pathogenesis

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remains unexplored. Improved understanding of celiac disease pathogenesis is crucial to

development of novel and effective treatment strategies.

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Key Points

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Celiac disease results from the interplay of genetic, environmental and

immunological factors.

HLA-DQ2 and DQ8 are the strongest and best-characterized genetic

susceptibility factors in celiac disease, although recent genome-wide association
studies have identified additional susceptibility variants many involved in the
immune system and overlapping with other immune-mediated disease.

Environmental factors implicated in disease pathogenesis include gluten,

commensal and pathogenic microorganisms, timing of gluten introduction,
mode of delivery and length of breast-feeding; however, the mechanisms
underlying these associations are incompletely understood.

Both the adaptive and innate immune systems are dysregulated in celiac disease
pathophysiology.

Improved understanding of celiac disease pathophysiology will help uncover

new potential therapeutic targets and provide insight into disease mechanisms
relevant to other immune-mediated disease such as type I diabetes.

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Figure 1. Factors involved in celiac disease pathophysiology

Celiac disease is thought to arise from the interplay of genetic, environmental and
immunological factors. This review highlights seminal findings in each of these domains.

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Figure 2. Class II HLA-DQ

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The genes encoding for HLA molecules are found in the major histocompatibility (MHC)
complex on chromosome 6. HLA molecules involved in celiac disease are encoded in a
region known as class II; by genes known as -DQ (other class II genes include -DR and
DP). Class II HLA-DQ genes encode for - and -chains that are associated as heterodimers
on the surface of antigen presenting cells and form a cleft that binds antigens. HLA-DQA1
genes code for two -chains (1 & 2) and HLA-DQB1 genes code for two -chains (1 &
2).

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Figure 3. HLA configurations in celiac disease. A) HLA-DQ2 homozygotes, heterozygotes and

half-heterodimers, and B) HLA-DQ8 homozygotes, heterozygotes and DQ8/DQ2

Red boxes denote the DQA1 gene encoding the alpha-chain and orange boxes denote the
DQB1 gene encoding the beta-chain (see figure 2). Shown in the boxes are the specific
alleles for each gene. Current WHO nomenclatures uses an asterix followed by the allele
group (e.g., 05), a colon then the protein group (e.g., 01). An empty box refers to other HLA
alleles not associated with celiac disease. Shown below the genes are the isoforms. cis
acting (i.e. on the same chromosome); trans acting (i.e. on opposite chromosomes);
risk of celiac disease for DQ2 half heterodimers is lower than the general population
especially individuals carrying only DQA1*05 (ref 15)

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Figure 4. Clinical application of HLA testing

HLA testing should be considered for screening, disease exclusion or to support a diagnosis.
Testing is unaffected by a gluten-free diet. Providers should ensure that both DQ2 alpha and
beta chains are tested. If a patient carries HLA-DQ2 or DQ8, they carry a risk factor (or
varying magnitude) for celiac disease and additional work-up should be considered.
Individuals carrying HLA-DQ2 half-heterodimers, are also at risk for celiac disease (albeit
substantially lower than other HLA-DQ2 and DQ8 positive patients). If HLA-DQ2 and
DQ8 are not present, then celiac disease risk is highly unlikely and antibody screening is not
necessary.

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Figure 5. MHC class II-gluten peptide complexes

MHC class II molecules HLA-DQ2 and DQ8 preferentially bind a glutamate residue of the
gluten peptide at position 6 and position 1/9 respectively. This binding is enhanced by a
negatively charged glutamate and positively charged pocket of the HLA molecule.

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Figure 6. Enrichment analysis of non-HLA genes associated with celiac disease

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We used GeneTrail to test for enrichment of functional annotations among non-HLA genes
associated with celiac disease from genome-wide association studies published through
2012. In this graph is shown the fold enrichment (y-axis) and significantly enriched
biological functions (x-axis). Background expectations were based on all human genes. Pvalues were calculated using a hypergeometric distribution using the approach by Benjamini
& Hochberg to control the false discovery rate. P-values for enrichment shown here ranged
from 4.8 102 to 3.2 1011.

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Figure 7. Divergence of oats from wheat, rye and barley

Wheat, rye, barley and oats belong to the same grain family (Poaceae) and subfamily
(Pooideae). However, they belong to distinct tribes: wheat, rye and barley (Triticeae) and
oats (Avenae). The prolamins from the triticeae tribe are immunogenic and contribute to
celiac disease, while avenins from pure, uncontaminated oats are safe for the vast majority
of celiac patients.

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Figure 8. Active and inactive states of tissue transglutaminase (tTG2)

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tTG2 is active in an open conformation in a reduced state. In presence of GTP and in the
absence of Ca2+ (i.e. intracellular environment), tTG2 is in a reduced, closed state and the
enzyme is inactive. Upon release to the extracellular environment with low GTP and high
Ca2+, tTG2 takes on an open conformation and is active. Usually oxidizing conditions in the
extracellular environment render tTG2 inactivated in its open conformation by the formation
of a disulphide bond between two vicinal cysteine residues in the enzyme. Upon creation of
reducing conditions (i.e. inflammation), the disulphide bond is reduced and the enzyme can
again take an active open conformation.

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Figure 9. Immune dysregulation in celiac disease

a) In health, gluten is tolerated in the presence of anti-gluten Foxp3+ regulatory T cells.

Moreover, intraepithelial lymphocytes (IELs) express inhibitory natural killer (NK)
receptors that prevent uncontrolled T cell activation.
b) With inflammation (e.g., celiac disease shown here) or infection, HLA-DQ2 or DQ8
bind gluten on antigen presenting cells and present to T cells leading to an anti-gluten T cell
response which release IFN- and possibly IL-21 leading to epithelial damage. The
upregulation of IL-15 and IFN- in the lamina propria induce dendritic cells to acquire a
pro-inflammatory phenotype. The innate immune system is also dyregulated in celiac
disease in that IELs undergo reprogramming to acquire a natural killer phenotype
characterized by upregulation of NKG2D and CD94/NKG2C receptors that recognize
MICA, MICB and HLA-E on epithelial cells mediating tissue damage. IL-15 upregulates
NK receptors and promotes T-cell receptor independent killing as well as blocking Foxp3+
regulatory T cell action on IELs. Finally, the humoral immune system produces glutenspecific antibodies that mediate systemic manifestations notably dermatitis herpetiformis.

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