CELIAC DISEASE identify untreated celiac disease and includes

immunoglobulin (Ig)A or IgG tissue transglutaminase

Benjamin Lebwohl, Peter H.R. Green
(tTG), IgA or IgG endomysium antibodies (EMAs), and
DEFINITIONS IgA or IgG deamidated gliadin peptide (DGP) antibodies.
(IgA or IgG antigliadin antibodies (AGAs) are generally
Celiac disease is a chronic, immune-mediated excluded because they are relatively nonspecific.)
enteropathy that is precipitated by dietary gluten in Nonceliac gluten sensitivity refers to symptoms or signs
genetically predisposed individuals.1 Gluten is the that develop upon gluten ingestion in people in whom a
commonly used term for the complex of water- diagnosis of celiac disease has been excluded. The Oslo
insoluble proteins from wheat, rye, and barley that is definitions for celiac disease and related terms provide
harmful to patients with celiac disease. Celiac disease is a more comprehensive elucidation of definitions
characterized by villus atrophy of the small intestinal currently used in celiac disease.
mucosa associated with malabsorption of nutrients,
clinical and subsequent histologic improvement after HISTORY OF CELIAC DISEASE
adoption of a gluten-free diet (GFD), and clinical and
Celiac disease was recognized as a clinical entity by
histologic relapse when gluten is reintroduced.2 Celiac
Aretaeus the Cappadocian in the first century ad. 3 The
disease exhibits a wide spectrum of clinical
name sprue was coined in the 18th century and is
presentations. In the past, typical celiac disease (now
derived from the Dutch word spruw, which means
called classical celiac disease) denoted a clinical
“aphthous disease,” so named because of the high
presentation with signs and symptoms of
prevalence of aphthous mouth ulcers in these patients.
malabsorption, such as diarrhea, steatorrhea, weight
In 1888, Samuel Gee published his paper “On the
loss, and nutritional deficiencies. The term is now
Coeliac Affection,” which described many of the clinical
questionable, however, because in modern clinical
features of celiac disease in patients of all age groups
practice, most patients do not present with these so-
and concluded, “If the patient can be cured at all it must
called typical manifestations. In contrast, presentations
be by means of the diet.”4 It was not until the middle of
previously described as atypical celiac disease and now
the 20th century, however, that the link between
termed nonclassical celiac disease (e.g., anemia, fatigue,
certain cereals and celiac disease was made by Willem
abdominal bloating and discomfort, osteoporosis,
Karel Dicke, a Dutch pediatrician. He became convinced
infertility) are now more common. Asymptomatic celiac
that the consumption of wheat flour was directly
disease (also called silent celiac disease) is usually
responsible for the deterioration in patients suffering
identified by screening using celiac disease-specific
from this condition.5 During the Dutch Famine in World
serology and is characterized by duodenal villus atrophy
War II, cereals used to make bread were severely scarce
in individuals who lack symptoms or signs of celiac
in the Netherlands and, during this time, children with
disease. Potential celiac disease denotes those with
celiac disease improved, only to relapse after the supply
normal small intestinal histology who are at increased
of cereal was reestablished at the end of the war. This
risk of developing celiac disease (usually identified by
observation confirmed Dicke’s previous observations
positive celiac disease-specific serology). Nonresponsive
that wheat ingestion exacerbated celiac disease.6
celiac disease (NRCD) is defined as ongoing or recurrent
Subsequent work by Dicke’s group showed that it was
symptoms or signs that suggest active celiac disease
the water-insoluble portion, or gluten moiety, of wheat
despite a strict GFD for more than 6 to 12 months.
that produced intestinal injury in patients with celiac
Refractory celiac disease (RCD, a subset of NRCD) is
disease.7 In 1954, Paulley provided the first accurate
defined as symptomatic, severe small intestinal villus
description of the characteristic intestinal lesion in
atrophy despite a strict GFD for more than 6 to 12
patients with celiac disease.8 With the development of
months. RCD is a diagnosis of exclusion that is not
effective peroral suction biopsy instruments in the late
explained by inadvertent gluten ingestion, other causes
1950s, Rubin and coworkers demonstrated that celiac
of villus atrophy, or overt intestinal lymphoma. Celiac
disease in children and idiopathic or nontropical sprue
disease serology denotes serology tests that specifically
in adults were identical diseases with the same clinical
and histopathologic features.9 Since the 1980s, we have
seen substantial advances in our understanding of the
genetic, immunologic, and molecular mechanisms
fundamental to the pathogenesis of celiac disease. In
1986, Howell and associates observed that celiac
disease was associated with specific HLA-DQ2
haplotypes.10 In 1993, Lundin and colleagues
demonstrated that HLA-DQ2 preferentially presents
gluten-derived gliadin peptides to activate intestinal
mucosal T cells in celiac patients.11 Subsequently, the
enzyme tTG (more specifically tTG type 2 [tTG2]) was
identified as a celiac autoantigen, which led to more
accurate serologic diagnostic tests.12 In 1998, Molberg
and colleagues reported that modification of gliadin by
host tTG2 enhances gliadin-specific celiac disease T-cell
responses.13 The identification of specific tTG-modified
DGPs as dominant α-gliadin T-cell epitopes highlighted
the pivotal role played by tTG2 in the pathogenesis of
celiac disease.14 Epidemiologic studies using EMA and
tTG serology have substantially increased estimates of
celiac disease prevalence in the USA as well as the
breadth of celiac disease prevalence worldwide.15-17
This in turn has led to renewed interest in potential
nondietary treatments including gluten detoxification,
glutenase therapy, modifiers of small intestinal tight
junction function, tTG2 inhibitors, and immune-based
interventions including attempts to reverse intolerance
to gluten.
EPIDEMIOLOGY
Epidemiologic studies using specific celiac serology
testing indicate that celiac disease has a wide
geographic distribution and affects individuals from
multiple and diverse ethnic and racial backgrounds. The
overall prevalence of celiac disease in Europe has been
estimated at 1%, with the highest reported prevalence
of 2.4% in Finland.21 Factors such as predominant HLA
haplotype, timing of introduction of gluten into the diet,
differences in the gliadin concentration of infant
formulas, and interobserver variation in interpreting
small intestinal biopsy findings might explain
differences in prevalence.22 Celiac disease is
particularly prevalent in the Punjab region of northwest
India, where wheat rather than rice has, for many
generations, been a staple of the diet.23 The condition
has been reported in blacks, Arabs, Hispanics, Israeli
Jews, Sudanese of mixed Arab-black descent, and
Cantonese and is particularly high among the Saharawi
population in northwest Africa.24 Peoples rarely
affected include those of purely sub-Saharan African,
African-Caribbean, or Southeast Asian (including
Chinese or Japanese) descent. Some authors have
noted a femaleto-male ratio of 2:1, whereas others
have reported equal prevalences in men and women.
Most studies measuring diagnosed celiac disease,
however, have found a female predominance,
suggesting that men are more likely to remain
undiagnosed. Studies in the USA indicate that the
prevalence of celiac disease is comparable with that in
Europe. A large multicenter study by Fasano and
coworkers15 determined the prevalence of EMAs in
more than 13,000 at-risk and not-at-risk American
subjects to be 1 in 22 and 1 in 39 among first-degree
and second-degree relatives of subjects with celiac
disease, respectively. Of most significance, these
investigators found a prevalence of antiendomysial
antibodies of 1:133 among 4126 “not-at-risk” subjects.
An analysis of the National Health and Nutrition
Examination Survey (NHANES) in 2009-2010 found that
the prevalence of celiac disease (diagnosed and
undiagnosed) in the USA was 0.7%.16 Within the USA,
prevalence of celiac disease varies by ethnicity, with
individuals of Punjab Indian ethnicity having the highest
prevalence.25 The population prevalence of celiac
disease appears to be increasing. In 1 USA study, tTG
seropositivity was 0.2% among 9133 subjects whose
blood samples were stored circa 1950 compared with
0.9% in comparable, modern-day sera, suggesting a
substantial (4-fold) increase in celiac disease prevalence
over time.26 The estimated prevalence of celiac disease
has also risen in Finland, from 1% in 1980 to 2% in
2000.27 The reason in the rise in seroprevalence has
not been identified, but environmental triggers of celiac
disease have been proposed (see section later,
Environmental Factors). Diagnosis rates appear to be
changing in the USA. Whereas greater than 80% of
cases were undiagnosed in the NHANES during 2009-
2010,16 fewer than 50% were undiagnosed in 2013-
2014.28 This may be due to increased awareness of
celiac disease and widespread interest in the GFD in the
population at large. Epidemiologic studies using celiac
serology indicate that asymptomatic or minimally
symptomatic celiac disease is more common than
diagnosed or symptomatic disease.29 A Finnish study of
3654 schoolchildren of ages 7 to 16 years, using 2
serologic screens with EMA and tTG antibodies,
demonstrated that 1 in every 99 children had biopsy-
proved celiac disease,30 although only 10 of 56 subjects
(18%) with a positive serology had overt symptoms of
celiac disease. Two subjects with elevated antibodies
and HLA-DQ2 haplotype had normal mucosa consistent
with potential celiac disease. Another study
demonstrated fluctuations in tTG2 serology positivity
over time in children with potential celiac disease.31 In
the latter study, 12 of 39 children (31%) with potential
celiac disease developed villus atrophy over 3 years of
follow-up. Thus, there appears to be individual variation
in the natural history of celiac disease, at least in
children, where tTG2 seropositivity and celiac
enteropathy may fluctuate over time.
PATHOLOGY
Celiac disease affects the mucosa of the small intestine.
The mucosal lesion can vary considerably in severity
and in extent.9 Examination under magnification of the
small intestinal mucosal surface in severe untreated
celiac disease reveals a flat mucosal surface with
complete absence of normal intestinal villi. Histologic
examination of tissue sections confirms this loss of
normal villus structure (Fig. 107.1A and B). The
intestinal crypts are markedly elongated and open onto
a flat absorptive surface. The total thickness of the
mucosa may be reduced only slightly, because crypt
hyperplasia compensates for the absence or shortening
of the villi. These architectural changes decrease the
amount of epithelial surface available for digestion and
absorption.9 The enterocytes, which appear columnar
in normal biopsy specimens, are cuboidal or, at times,
squamoid in celiac disease. Their cytoplasm is more
basophilic (i.e., RNA rich), the basal polarity of the
nuclei is disrupted, and the brush border is markedly
attenuated. When viewed by electron microscopy, the
microvilli of the absorptive cells appear shortened and
often fused. The number of free ribosomes is increased,
reflecting impaired differentiation and resulting in the
increased cytoplasmic basophilia evident on histologic
examination. Degenerative changes, including
cytoplasmic and mitochondrial vacuolization and the
presence of many large lysosomes, are also obvious.
Structural abnormalities of tight junctions between
damaged absorptive cells provide a morphologic
explanation for the increased permeability of the
mucosal barrier in celiac disease.32 The endoplasmic
reticulum is sparse, explaining the low level of synthesis
of digestive enzymes, including disaccharidases and
peptidases. Thus, mature absorptive cells are reduced
in number and functionally compromised. Unlike the
absorptive cells, undifferentiated crypt cells are
markedly increased in number in patients with severe
untreated celiac disease, and the crypts are therefore
lengthened. Moreover, the number of mitoses in crypts
is strikingly increased. Cytologic features and
histochemistry of the crypt cells are normal by both
light and electron microscopy. Studies of epithelial cell
kinetics in untreated celiac disease suggest that “villus
atrophy” is a misnomer because there is evidence for an
actual increase in enteropoiesis in the crypts. Wright
and colleagues33 estimated that intestinal mucosa from
patients with celiac disease produces 6 times as many
cells per hour per crypt as does normal small intestine,
and that the cell cycle time is halved, reflecting
premature cell shedding. The experimental evidence
suggests, therefore, that the central mechanism of villus
shortening in celiac disease is a toxic effect on maturing
enterocytes that results in their premature loss into the
intestinal lumen and a compensatory increase in cryptal
enterocyte replication. Such a mechanism would
explain many of the histologic abnormalities described
previously. The cellularity of the lamina propria is
increased in the involved small intestine. The cellular
infiltrate consists largely of plasma cells and
lymphocytes. The number of IgA-, IgM-, and IgG-
producing cells is increased 2-fold to 6-fold, but, as in
normal mucosa, IgA-producing cells predominate.34
Polymorphonuclear leukocytes, eosinophils, and mast
cells also can contribute substantially to this increased
cellularity. The number of intraepithelial lymphocytes
(IELs), often reported per 100 enterocytes, is increased
in untreated celiac disease.9 In normal small intestinal
mucosa, lamina propria T cells are predominantly CD4+
(helper/ inducer) cells, whereas the IELs are mainly
CD8+ (cytotoxic/ suppressor) cells. In untreated celiac
disease, this distribution of lamina propria T cells is
maintained, but the density of cells in both
compartments is increased. Marsh pioneered the
theory of sequential progression of the celiac lesion in
the small intestinal mucosa.35 Starting with a normal,
pre-infiltrative (stage 0) mucosa, the initial observed
event is an increase in IELs, followed by infiltration of
the lamina propria with lymphocytes (stage 1). Crypt
hyperplasia (stage 2) precedes villus atrophy (stage 3)
and is observed only in the presence of lamina propria
lymphocytosis, suggesting that IELs are not sufficient to
induce intestinal architectural changes in celiac disease.
Finally, total mucosal atrophy (stage 4) develops and is
characterized by complete loss of villi, enhanced
apoptosis, and crypt hyperplasia. Marsh classification
stages had previously been subdivided according to the
degree of villus atrophy, with scores of 3a, 3b, and 3c
corresponding with partial, subtotal, and total villus
atrophy, respectively. However, because of low
interobserver reproducibility for these substages, a
quantitative approach to reporting the villus
height:crypt depth ratio has been proposed.36 This
classification, termed Quantitative-Mucosal Algorithmic
Rules for Scoring Histology (Q-MARSH), has the
potential to be used as an outcome when assessing
interventions in the treatment of celiac disease. The
length of small intestinal involvement by the celiac
disease lesion varies among untreated individuals.
When the intestinal lesion does not involve the entire
length of small bowel, the proximal intestine is usually
the most severely involved; sparing of proximal
intestine with involvement of the distal small intestine
can occur, but is uncommon.9 An increase in IEL count
alone is not sufficient for a histologic diagnosis of celiac
disease. This finding is nonspecific and is seen in many
other conditions including SIBO, peptic duodenitis, Hp
infection, NSAID use, and in autoimmune disorders.
Thus, some shortening of the villi, crypt hyperplasia,
cytologically abnormal surface cells, and increased
lamina propria cellularity must be present to establish
the diagnosis firmly. When the duodenal bulb is the
only involved portion of the small intestine, the term
“ultra-short celiac disease” has been used.37 Treatment
with a GFD results in significant improvement in
intestinal structure (see Fig. 107.1C). The cytologic
appearance of the surface absorptive cells improves
first, often within a few days. Tall, columnar absorptive
cells with basal nuclei and well-developed brush
borders replace the abnormal, immature cuboidal
surface cells; the ratio of IELs to absorptive cells
decreases. Subsequently, villus architecture reverts
toward normal, with lengthening of the villi and
shortening of the crypts; the lamina propria decreases
in cellularity. The mucosa of the distal small intestine
improves more rapidly than that of the more severely
involved proximal bowel.35,38 In some patients,
months to years of gluten withdrawal may be required
before the mucosa reverts to normal; indeed, some
residual abnormality, which may range from subtle to
striking, often persists, possibly because of inadvertent
gluten ingestion.39,40 Finally, the mucosal lesion of
celiac disease can be histologically identical to the
mucosal response to injury typical of a wide range of
other enteropathies (see “Differential Diagnosis”).
PATHOGENESIS
The interaction of the water-insoluble protein moiety
(gluten) of certain cereal grains with the mucosa of the
small intestine in susceptible persons is central to the
pathogenesis of celiac disease. Celiac disease is
considered an immune disorder that is triggered by an
environmental agent (gliadin) in genetically predisposed
persons. The wide spectrum of clinical manifestations is
the result of a complex interplay of varying
environmental, genetic, and immune factors. How these
factors control the varied expression of celiac disease
and passage from latent to overt disease remains
unknown.
Gluten as Antigen
Celiac disease is a model for autoimmune diseases with
a defined environmental trigger (Fig. 107.2). Early work
that involved physiologic digestion with pepsin and
trypsin, followed by separation according to solubility
properties, identified several wheat proteins as being
responsible for the grain’s toxicity in celiac disease.
Wheat protein exists in a number of storage forms that
can be categorized into 4 general groups based on
solubility characteristics: prolamins (soluble in ethanol),
glutenins (partially soluble in dilute acid or alkali
solutions), globulins (soluble in 10% NaCl), and albumins
(soluble in water). The term gluten encompasses both
the prolamins and the glutenins. Although most toxicity
studies have been performed with prolamins, there are
data to indicate that glutenins also may damage the
celiac intestinal mucosa.41 The prolamins of wheat are
referred to as gliadins. Prolamins from other cereals
also are considered to be gluten and are named
according to their source (secalins from rye, hordeins
from barley, avenins from oats, and zeins from corn).
The taxonomic relationships of the major cereal grain
families provide a framework on which their toxicities in
celiac disease can be predicted (Fig. 107.3).42 Wheat,
rye, and barley belong to the tribe known as Triticeae,
and oats belong to a neighboring tribe known as
Aveneae. Avenin is genetically less similar to gliadin
than gliadin is to secalin and hordein. Despite their
genetic differences, however, prolamins from barley,
wheat, and rye still have immunologic cross-reactivity
because of their common ancestry.43 Grains that do
not activate disease (rice, corn, sorghum, and millet) are
separated still further from wheat, rye, and barley in
terms of their derivation from the primitive grasses.
Gliadin can be separated electrophoretically into 4
major fractions that range in molecular weight from 20
to 75 kd and exist as single polypeptide chains. These
have been designated α-, β-, γ-, and ω-gliadins, and all 4
fractions appear to be toxic to patients with celiac
disease.44 The complete amino acid sequences of
several of the gliadins and related prolamins in grains
other than wheat are known.41 Anderson and
colleagues14 identified a partially deamidated peptide,
consisting of amino acids 56 to 75 of α-gliadin as a
dominant epitope, responsible for activation of T cells in
celiac disease. However, patients with celiac disease can
respond to a diverse repertoire of gluten peptides.45
Furthermore, nongluten proteins in wheat appear to
contribute to immune activation in patients with celiac
disease.46 The release of intracellular tTG leads to the
deamidation of gluten proteins and an enhancement of
T-cell responses to the resulting DGPs.14 The reason
oats are tolerated by the majority of patients with celiac
disease is not obvious, because the prolamin fraction of
oats contains the same amino acid sequences (QQQPF,
where Q = glutamine, P = proline, and F =
phenylalanine) that in wheat gliadin have been shown
to be toxic.47 A possible explanation for this paradox is
that oats contain a relatively smaller proportion of this
toxic prolamin moiety than do toxic gluten-containing
cereals. Although a feature common to prolamins of
wheat, rye, and barley is a high content of glutamine
(≈30%) and proline (≈15%), the prolamins of oats have
an intermediate content of these amino acids, and the
nontoxic prolamins of rice, corn, and millet have an
even lower content of them.48 This hypothesis is
supported by collectively considering the studies on oat
challenge in patients with celiac disease; these studies
suggest that tolerance to oats might depend at least in
part on the total amount consumed.49 A systematic
review and meta-analysis found that adding oats to a
GFD did not adversely affect symptoms, histology, or
serologic abnormalities in patients with celiac
disease.50 Because most commercially-produced oats
are harvested in a way that is conducive to
contamination by gluten-containing grains, patients
with celiac disease should be advised to restrict their
oat consumption to uncontaminated oats that are
labeled gluten-free. The data on oats also highlight the
important relationship between the amount of gluten
consumed and the severity of disease manifestation. A
5- to 10-fold higher incidence of overt celiac disease in
children from Sweden compared with Denmark (2
populations with similar genetic backgrounds) has long
been cited as evidence of the importance of
environmental over genetic factors in pathogenesis of
celiac disease. Subsequent studies found as much as a
40-fold difference in the gliadin concentration of
Swedish compared with Danish infant formula.22 This
finding suggests that early exposure of the immature
immune system to significant amounts of gliadin may
be a relevant cofactor for the development of overt
celiac disease. The timing and/or quantity of gluten
introduction in infancy may play an important role in
facilitating gluten tolerance or intolerance. A cohort
study found that introduction of gluten during the
fourth through sixth month was associated with a
decreased risk of celiac disease.51 This, in addition to
the concerns that high quantity of gluten at first
exposure may play a role in the Swedish epidemic,52
formed the rationale for 2 randomized trials of infant
feeding strategies. One trial evaluated the intervention
of gluten introduction at 4 months and the other
evaluated gluten introduction at 12 months; both trials
used gluten introduction at 6 months as the
comparator.53,54 Neither the early nor delayed
strategy yielded a decreased risk of celiac disease
compared with introduction at 6 months. Thus, the
optimal timing of gluten introduction is yet to be
established.
Other Environmental Factors
The rise in celiac disease prevalence in recent decades
has led to efforts to identify environmental cofactors for
triggering its development. Recurrent rotavirus
infection was found to be associated with an increased
risk of subsequent celiac disease in a cohort study55
and receipt of the rotavirus vaccine may be protective
against celiac disease.56 Reovirus infection, when
introduced simultaneously with gluten, was shown to
induce a pro-inflammatory milieu and AGAs in a mouse
model, and patients with celiac disease do have higher
titers of antibodies to reovirus compared with healthy
controls.57 Gastric colonization with Hp is inversely
associated with celiac disease, raising the possibility
that the ongoing decline in Hp prevalence is
contributing to the rise in celiac disease.58 Other
proposed environmental risk factors include northern
latitude (in the USA),59 elective Caesarian section,60
and antibiotic use.61
Genetic Factors
Family studies that demonstrate frequent intrafamilial
occurrence of celiac disease reflect the importance of
genetic factors in its pathogenesis.62 Concordance for
celiac disease in first-degree relatives ranges between
8% and 18% and estimates for concordance in
monozygotic twins range from 49% to 83%.62,63 Our
understanding of the nature of this genetic
predisposition began with the observation that celiac
disease was associated with specific HLA-DQ2
haplotypes.10 HLA class II molecules are glycosylated
transmembrane heterodimers (α and β chains) that are
organized into 3 related subregions—DQ, DR, and DP—
and encoded within the HLA class II region of the major
histocompatibility complex on chromosome 6p. An
important link to a genetic predisposition was provided
by the isolation of gliadinspecific HLA-DQ2-restricted T-
cell clones from celiac disease mucosa.11,64 The HLA
class II molecule DQ2 is present in more than 90% of
persons with celiac disease compared with
approximately 35% of the general white population.
DQ2 is a heterodimer composed of either α1*0501
(DQ2.5) or, less commonly, α1*0201 (DQ2.2) together
with β1*02. The DQ α1*0301, β1*0302 heterodimer,
known as HLA-DQ8, is found in almost all of the
remaining patients with celiac disease.65 Occasional
cases of celiac disease have been reported in patients
who are DQ2 and DQ8 negative but nonetheless carry a
single DQ2 allele. Thus, in some cases, typing of
individual celiac-associated alleles may be helpful in
addition to determining DQ2 and DQ8 status. A gene
dose-effect also has been identified, whereby persons
who are homozygous for DQ2 are at greater risk than
heterozygotes for developing celiac disease. It is now
known that after gluten is absorbed, lamina propria
antigen-presenting cells (probably dendritic cells) that
express HLA-DQ2 or HLA-DQ8, present gliadin peptides
on their α/β heterodimer antigen-presenting grooves to
sensitized T lymphocytes expressing the α/β T-cell
receptor (TCR). These lymphocytes then activate B
lymphocytes to generate Igs and other T lymphocytes to
secrete cytokines, including interferon (IFN)-γ, as well as
interleukin (IL)-4, IL-5, IL-6, IL-10, TNF-α, and
transforming growth factor (TGF)-β. 66 These cytokines
induce not only enterocyte injury but also expression of
aberrant HLA class II cell-surface antigens on the
luminal surface of enterocytes, possibly facilitating
additional direct antigen presentation by these cells to
the sensitized lymphocytes (see Fig. 107.2). Only a
minority of persons who express DQ2 actually develop
celiac disease. HLA-DQ2 is expressed by approximately
35% of Europeans and their descendants, but it is rare
in other populations (in sub-Saharan Africa, far eastern
Asia). Thus, much of the genetic predisposition to celiac
disease is conferred by genes other than those
encoding HLA-DQ molecules. The search for other genes
that confer susceptibility to celiac disease has revealed
numerous loci of interest on several different
chromosomes, some of which also are associated with
susceptibility to type 1 diabetes.
Immune Factors
There is substantial evidence implicating both humoral-
and cellmediated immune responses to gliadin and
related prolamins in the pathogenesis of celiac disease.
There is a 2- to 6-fold increase in the numbers of Ig-
producing B cells in the lamina propria of the small
intestine in untreated celiac disease patients.33 In
addition, IgA and IgG serum antibodies to purified
gliadin, all major fractions of gliadin, and DGPs can be
detected in the sera of most patients with untreated
celiac disease.14,73-76 Many healthy persons without
celiac disease have increased levels of IgA or IgG
antigliadin.77 The frequency of elevated IgA or IgG DGP
antibodies in healthy controls, however, is very low,
possibly reflecting the antigenic potency of DGPs and
their more central role in disease pathogenesis.14,74-
76 Many persons with celiac disease have increased
levels of serum antibodies against other food proteins,
such as β-lactoglobulin, casein, and ovalbumin.78 It is
unclear whether this reflects a general aberrant
immune responsiveness to food antigens in patients
with celiac disease or enhanced systemic exposure to
these proteins because of increased small intestinal
permeability. Gluten can be absorbed across the normal
intestinal epithelium, but it is unclear if this results in
immune tolerance in persons who are not genetically
predisposed to develop celiac disease. Patients with
celiac disease develop antibodies to some, but not all,
nongluten wheat proteins.46 The identification of more
specific autoantibody responses has altered our
understanding of the pathogenesis of celiac disease. IgA
antibodies to endomysium, a connective tissue
structure surrounding smooth muscle, are highly
specific for celiac disease.79 It is now known that the
target autoantigen contained within the endomysium is
the enzyme tTG-2.12 Gliadin is a preferred substrate for
this ubiquitous calcium-dependent intracellular
enzyme, and it has been shown that tTG deamidates
key neutral glutamine residues in gliadin and converts
them into negatively charged glutamic acid residues,
which are preferred in positions 4, 6, and 7 of the
nonpeptide antigen-binding groove of the HLA-DQ2
heterodimer, thereby facilitating antigen
presentation.13,14,80 Thus, tTG-mediated modification
of gliadin to generate DGPs plays a pivotal role in
eliciting a stronger proliferative response by gliadin-
specific T cells. With gliadin serving as the glutamine
donor, tTG also can generate additional novel antigenic
epitopes by cross-linking molecules of the extracellular
matrix with gliadin or with tTGgliadin complexes.81 As
evidence of the fundamental role of tTG in celiac
disease pathogenesis, one of the dominant epitopes
responsible for the T-cell response contains a
deamidated glutamine residue (Q65E) of α-gliadin.14
Given the marked infiltration of lymphocytes into the
small intestinal mucosal epithelium and lamina propria
in active disease, it is not surprising that cell-mediated
immune responses also are important in the
pathogenesis of celiac disease. Many findings support
interplay between adaptive immunity, characterized by
a specific and memory T-cell response to gluten
peptides, and innate immunity, involving less specific
mechanisms. Many of the T cells in the small intestinal
mucosa are activated in untreated celiac disease and
release potent proinflammatory mediators such as IFN-
γ, TNF-α, IL-2, IL-6, and TGF-β. 66 Activated T
lymphocytes, most of which are CD4+ cells, are
abundant in the lamina propria of the small intestine.82
In contrast, IELs, which are present in large numbers in
untreated celiac disease, are predominantly CD8+ T
cells.83 There is an influx of primed memory T cells,
marked by high CD45RO expression, in the mucosa of
untreated celiac disease patients.84 In healthy persons,
more than 90% of IELs express the α/β TCR, whereas
expression of the γ/δ TCR by IELs in patients with
untreated celiac disease is increased as much as 6-fold
(to 35%) and is considered a hallmark of the disease.85
These primitive lymphocytes recognize bacterial
nonpeptide antigens and unprocessed stress-related
proteins. They appear to act as mucosal guardians and
might protect the intestinal mucosa from chronic
exposure to dietary gluten in gluten-tolerant persons by
secreting IL-4, which dampens Th1 in favor of Th2
reactivity.86 Their continuous presence in patients on a
GFD might indicate inadvertent gluten ingestion.
Patients with RCD type 2 also have aberrant IELs with
restricted γ/δ TCR gene rearrangements indicating
oligoclonality (see “Refractory Celiac Disease”).87
Studies suggest that IL-15 may play a key role in
bridging the innate and adaptive immune responses in
the pathogenesis of celiac disease.88-91 This
enterocyte- and macrophage-derived proinflammatory
cytokine is increased greatly in the mucosa of patients
with active celiac disease and RCD. Although
mechanisms that lead to its overproduction remain
unknown, IL-15 regulates IEL homeostasis by promoting
migration, preventing apoptosis, and enhancing the
capacity of dendritic cells to function as antigen-
presenting cells.88 In response to gliadin peptides, IL-15
triggers an adaptive CD4+ T-cell response in the lamina
propria and also is capable of inducing direct epithelial
cell injury by inducing IEL secretion of IFN-γ.