|
Department
of Gastroenterology, The Rayne Institute, St Thomas’ Hospital,
London SE1 7EH, UK
Correspondence to: Professor PJ Ciclitira, Department of
Gastroenterology (GKT), The Rayne Institute, St Thomas’ Hospital,
London SE1 7EH, UK. paul.ciclitira@kcl.ac.uk
Telephone: +44 20 7928 9292 Ext. 3063, Fax: +44 20 7620 2597
Received 2001-07-21 Accepted 2001-08-15
Subject headings: coeliac disease; epidemiology; pathogenesi s;
cereal chemistry
Fraser JS, Ciclitira PJ. Pathogenesis of coeliac disease:
implications for treatment. World J Gastroenterol, 2001;7(6):772-776
INTRODUCTION
Coeliac disease (CD) is an enteropathy, characterised by villous
atrophy, which occurs in genetically susceptible individuals. It
affects mainly the proximal sm all intestine, and is caused by an
intolerance to cereal storage proteins found in wheat, barley and
rye. Due to earlier diagnosis, and the recognition of ‘sil ent’
or ‘latent’ forms of the disease, the very severe symptoms that
were seen previously are not very common now[1].
Malabsorption, with steator rhoea and weight loss, occur less
frequently. Anaemia, vitamin deficiencies, complications of
pregnancy and associated autoimmune diseases, such as insulin
dependent diabetes mellitus or thyroid disease are often the clues
which lead to the diagnosis of coeliac disease. Coeliac disease
affects people from all ethnic groups, though it is most common in
people originating in Europe, including people in North America and
Australia. It is rarely seen in people from an Afro-Caribbean
background[2].
In
the past, the prevalence of coeliac disease has been thought to be 1
in 1500 of the population in Western countries, based on the number
of identified cases. However, recent screening studies of blood
donors has shown a far higher prevalence of 1 in 250 in Sweden[3]
and the United States [4]. In Italy, a population
screening study of 17 000 school children between the ages of 6 and
15 revealed a prevalence rate of 1 in 184[5]. This
appears to be uniform throughout most of Europe, with some areas of
higher incidence, such as the west coast of Ireland. It affects
males and females equally.
The
reason for this discrepancy between clinically apparent cases, and
the numbe r of individuals with positive screening results, lies in
the concept of the ‘coeliac iceberg’[2]. The majority
of people with coeliac disease are symptom-free, or have only mild
symptoms, and do not approach a health care professional for a
diagnosis. These individuals have ‘silent’ coeliac disease, if
they have abnormal screening antibodies and an abnormal small bowel
biopsy, but no symptoms. Individuals with abnormal screening
antibody tests, but a normal small bowel biopsy and no symptoms,
have ‘latent’ coeliac disease[6]. Thus, there are
large numbers of people who are undiagnosed, in the ‘coeliac
iceberg’ analogy this would be the vast portion of the iceberg
which is not visible, whereas the diagnosed individuals with
symptoms form the tip of the iceberg (Figure 1).
Figure 1(PDF)
The coeliac iceberg. After A Ferguson[2]
HISTOPATHOLOGY
In the small intestine, the abnormalities are most marked
proximally and decreas e in severity with distal progression through
the small intestine. In severe cases, the lesion may affect the
ileum and even the stomach and rectum[7]. Flattening of
the mucosa can vary from mild, through partial villous atrophy, to a
total absence of villi. Classically, in untreated celiac disease,
there is a flat mucosa with no villi (total villous atrophy), but
more usually there is a reduction in the normal villous height,
resulting in the villous height: crypt depth ratio being reduced
from its normal value of between 3-5∶1.
The thickness of the mucosa is usually increased because of crypt
hyperplasia.
The
surface epithelial cells become pseudostratified compared to their
normal tall columnar shape with resultant fall in enterocyte height.
Crypt mitotic activity is no longer confined to the base and,
although the histological appearance is usually normal, crypt
abscesses have been described. Cell migration from the crypt base to
the villous tip is reduced in untreated coeliac disease to 12-24
hours compared with the normal 3-5 days.
There
is a chronic inflammatory cell infiltrate in the mucosa of the small
intes tine in untreated coeliac disease with a rise in the number of
plasma cells in the lamina propria. There is an increase in the
ratio of intra-epithelial lymphocytes to surface enterocytes in
active disease. Most of the intra-epithelial lymphocytes express the
common leucocyte antigen CD3, 70% express the suppressor/cytotoxic
leucocyte antigen CD8, 5% express the helper/inducer CD4 phenocyte,
whereas 20% of the cells are CD3+ve, CD4-ve and CD8-ve. Most of
these cells express the more primitive γ/δ rather than the
more usual α/β T-cell receptor. This results in a
significant increase in the number of γ/δ T-cell receptor
+ve lymphocytes in the surface epithelium of the small intestin e,
both in treated and untreated coeliac disease[7].
CEREAL CHEMISTRY
Cereal storage proteins fall into four groups, the minor
albumins, the globulins, the ethanol-insoluble glutenins, and the
ethanol-soluble fraction termed prolamins. Initial separation of
wheat proteins depends on their relative solubility charac teristics.
Gliadins are soluble in 40%-90% ethanol and high molecular weight
glutenins are insoluble in neutral aqueous solution, saline or
ethanol, although low molecular weight glutenins are ethanol
soluble. The gliadins may be subdivided according to their relative
electrophoretic mobility into α, β, γ and ω
subfractions or according to their N-terminal amino acid sequence
into α, γ or ω subfractions, the previously described
β-subfraction being reclassified as a type of α gliadin[8].
The molecular weight of these proteins rises from 32K to 58K daltons
through α to ω gliadins. Prolamins, the alcohol-soluble
fraction of storage proteins are responsible for triggering the
disease[9]. Wheat, barley and rye, being closely related,
all contain prolamins (known respectively as gliadins, hordeins and
secalins) with a high composition of glutamine and proline, whereas
the prolamins of oats and more distantly related cereals, contain
less glutamine and proline and more alanine and leucine[10].
The glutamine-rich peptide sequences appear to be responsible for
the toxicity of wheat, barley and rye in coeliac disease.
Immune
activation occurs after ingestion of these cereals, when these
peptides a re presented, in conjunction with MHC class Ⅱ
molecules, to activate CD4+ T helper lymphocytes, causing release of
Th1 and Th2 cytokines, which encourag e
expansion of autoreactive B cell clones, and mucosal destruction.
Much recent research has provided an insight into the mechanisms of
pathogenesis by which this occurs.
Once
the diagnosis of coeliac disease has been made, the patient needs to
be est ablished on a gluten free diet. All foods which contain wheat
or wheat flour, as well as barley and rye must be avoided. There are
a number of foods which contain hidden gluten, including soy sauce,
mustard, mayonnaise and beer, which contains the barley prolamin,
hordein. Gluten-free flour, bread, biscuits, pasta and snacks are
available from a variety of companies.
An
average Western diet contains 13g of gluten, a
“Codex-Alimentarius” gluten free diet contains ＜0.3%
gluten from grains, and is sufficiently gluten free for the majority
of coeliac patients, however, some patients continu e to have
symptoms, and improve only when gluten is completely removed from
the diet. This was shown in a study by Faulkner-Hogg[11],
where 15 out of 22 patients with symptoms on a Codex-Alimentarius
gluten free diet improved after removal of all detectable gluten.
In
the past, it was assumed that the small bowel mucosa returns to
normal after introduction of a gluten-free diet, however, despite
improvement of symptoms, persistent small bowel mucosal
abnormalities may occur, and are not necessarily an indication of
poor dietary compliance[12].
Oats
are a member of the avena tribe of the gramineae, or grass family,
of plant s, whereas wheat, barley and rye belong to the triticeae
tribe, both tribes belo nging to the pooideae sub-family. Thus
avenin, the prolamin of oats, is genetically less like gliadin than
secalin and hordein (Figure 2).
Figure 2(PDF)
The taxonomic relationships of cereals. After P Shewr y, A Tatham
and D Kasarda[10]
The
toxicity of oats to patients with coeliac disease has been a
controversial issue, as early studies have shown conflicting
results. Harmful effects were observed by some workers[9,13],
but not by others[14,15], and some investigators found
variable results[16,17]. However, a recent Finnish study[18]on
newly diagnosed patients, as well as coeliac patien ts in remission
on a gluten-free diet, have shown that moderate amounts (up to 60
g/day) of oats are not detrimental, as witnessed by no significant
differences in gliadin and reticulin antibodies, as well as numbers
of intra-epithelial lymphocytes before and after introduction of
oats into the diet. Sequence homologies, and weak immunological
cross reactivity, have been found between avenin and the prolamins
of wheat, barley and rye[10,19,20]. Additionally, only 5%
to 15% of the total protein in oats is avenin, whereas 40% to 50% of
the total protein in wheat, barley and rye are made up of their
respective prolamins[21]. Thus, there is a smaller amount
of avenin per gram if oat seed, and there are fewer toxic epitopes
per gram of avenin. This suggests that a small amount of oats can be
consumed by patients with coeliac disease, as long as the oats are
not contaminated by wheat flour. In many mills however, the same
equipment is used to grind wheat, as that used to grind oats,
causing enough contamination to have a detrimental effect on the
health of sensitive coeliac patients.
THE IMMUNODOMINANT PEPTIDE
The precise structure of the gluten proteins that exacerbate
coeliac disease rem ains unknown, although there have been
considerable recent advances in this area . Peptides from the fully
sequenced α-gliadin, A-gliadin, have been used in a number of
studies to try to identify the toxic epitope, which induces
intestinal inflammation. A peptide corresponding to amino acids 31
to 49 of A gliadin was found to cause significant histological
changes in small
bowel biopsy specimens after in vivo challenge by intraduodenal
infusion [22]. Anderson et al used 51 overlapping
synthetic 15-amino acid peptides, spanning the complete sequence of
the A-gliadin. They assessed optimal peripheral blood mononuclear
cell (PBMC) secretion of the Th1 cytokine gamma
interferon (IFN-γ) in response to incubation with each of the
peptides and demonstrated a transient, disease-specific, DQ2
restricted, CD4 T-cell response to a single dominant epitope. This
peptide corresponded to amino acids 57-73 of A-gliadin, which had
been partially deamidated by tissue transglutaminse at position 65
(Q65E)[23].
Arentz-Hansen
et al produced eleven different recombinant antigens from α-gliadin,
to demonstrate that the intestinal T cell response to α-gliadin
in adult coeliac disease patients is focused on two immunodominant,
DQ2 restricted peptides that overlap by a seven residue fragment.
Gluten-specific T cell lines from small intestinal biopsies of 16
different patients all responded to one or both of the deamidated
peptides, indicating that these epitopes are highly relevant to
disease pathology. The peptides correspond to amino acids 62-75 (α2)
and 57-68 (α9) with Q65E[24].
The
identification of these peptide sequences, which act as potent T
cell epitop es, may lead to the development of antigen specific
therapy for coeliac disease. Once a target has been defined for
immunomodulation, it may be possible to create non-toxic cereal
based wheat, by removal or modification of the antigeni c sequence
in gliadin proteins.
TISSUE TRANSGLUTAMINASE
Tissue transglutaminase (tTG) is a ubiquitous cytoplasmic
enzyme, which is found mainly in respiratory and gut epithelial
cells. It is important in prevention of tissue damage, by catalysing
protein cross-linkage, causing formation of isopeptide bonds between
glutamine and lysine residues. tTG also deaminates glutamine
residues to glutamic acid.
Native
gluten proteins have very few negatively charged residues, as they
contai n approximately 40% glutamine and 20% proline, however,
several of these glutami nes are converted to glutamic acid in the
presence of tTG. Deamidation of glutam ine residues to glutamic acid
was found to strongly enhance T cell reactivity, d ue to the
formation of negatively charged amino acids needed for efficient
bindi ng to DQ molecules, thus inducing maximal T cell proliferation[25].
Virtually
all patients with CD have been found to express either HLA-DQ2 or
-DQ8 class Ⅱ
molecules. HLA class Ⅱ
molecules are responsible for binding exogenous protein antigens and
presenting them to CD4+ T cells. These molecules have a
characteristic binding groove, which differ in size, shape and
position between class Ⅱ
alleles, and which can be used to predict the sequence of pep tides
needed to fit into it. Both DQ2 and DQ8 require negatively charged
amino acids at certain positions for effective binding. Gluten
specific HLA-DQ2 and -DQ8 restricted T cell clones can be isolated
from small intestinal biopsy samp les of patients with CD, and have
been used to characterise gluten derived peptides capable of
stimulating T cells[26].
Arentz-Hansen
proposes that conditions may exist in the gut where T cell epitop es
are both created and trapped locally by tTG, prohibiting their
presentation by tolerogenic APCs in the gut. Alternatively, tTG may
prevent these epitopes from spreading systemically as soluble
antigen, a factor thought to be important in oral tolerance. Thus,
it may be possible to administer soluble deamidated gliadin peptide
to patients with coeliac disease, to induce tolerance to gliadin[24].
IMMUNOGENETICS
The precise mode of inheritance of coeliac disease is unknown,
although l0%-15% of first degree relatives of probands are similarly
affected[27,28]. There is 70%-100% concordance in
affected monozygotic twins and 30%-50% concordance in human
leukocyte antigen[29] (HLA)-identical siblings. Efforts
to understand the mechanisms and genetics of polygenic human
diseases have focused on the identification of DNA or protein
products and protein molecules that segregate in both populations
and families.
The
most significant observation was the increased frequency of specific
serolog ically defined lymphoid cell surface proteins, termed HLA
class Ⅱ
molecules, in people with coeliac disease. These are glycosylated
transmembrane heterodimer s comprising both α and β-chains,
the genes for which are organised into three related subregions DR,
DP and DQ. The genes are encoded within the HLA-class Ⅱ
region of the major histocompatibility complex on the short arm of
chromosome 6. The association of particular HLA-DR and DQ types with
coeliac disease is well established[30]. Associations
with the HLA-DP region and the TNF-α genes have been reported
but are thought to be secondary to linkage disequilibrium with HLA-DR
and DQ haplotypes[31,32]. The genes most strongly
associated with coeliac disease are DQAl *0501, DQB1 *0201[33,34].
98% of northern Europeans with coeliac disease have these alleles in
cis (DQ2) whereas in Southern Europe a third of the population with
the condition express the same class Ⅱ
molecule from these alleles in trans (DR5,7)[30]. Italian
and Argentinian coeliac disease populations are also reported to
have a increased frequency of the DR5,7 haplotype[35]. In
Israel there is also an association with the haplotype HLA-DR4, DQ8[36].
This genotyp e encodes a class Ⅱ
molecule with considerable similarity in the peptide bind ing groove
configuration to that produced by the DQ2 genes, supporting a
central role for the class Ⅱ
molecule in an immune mediated model of coeliac disease.
Twenty-five
percent of people in the general population of Northern Europe have
HLA-DQ2. It has been shown in epidemiological studies that only 30%
of the genetic susceptibility to coeliac disease lies in the HLA
region[37], the remaining 70% being elsewhere in the
human genome. Two genome-wide linkage studies to identify these
remaining susceptibility alleles have been undertaken using sibling
pair analysis and have produced conflicting results. The first group
from Ireland performed an autosomal screen using 40 affected sibling
pairs, and identified five areas of interest at the following
locations: 6p23, 7q31.3, 11p11, 15q26 and 22cen[38]. The
second group from Italy using 110 sibling pairs, failed to confirm
linkage in the areas identified in the previous study, but proposed
to further areas of interest, at 5qter, and in a subgroup of
patients at 11qter[39].
Our
group, employing analysis of multi-generation families, identified
two new potential susceptibility loci at 10q23.1 and 16q23.3, and
found evidence of linkage on chromosome 7, close to the γ
T-cell receptor gene and on chromosome 2,near the CTLA4 gene[40].
The
CTLA4/CD28 region, on chromosome 2q33, has been independently
implicated in an association study from France[41] and a
linkage study from Finlan d[42]. These genes control T
cell proliferation, and play a part in othe r autoimmune dieases,
such as type Ⅰ
insulin dependent diabetes mellitus and Graves’ disease.
IMMUNE RESPONSE
It has been suggested that in coeliac disease there is a primary
abnormal immune response of the small intestine to gluten proteins
that produces an allergic phenomenon. There is considerable evidence
to support this hypothesis, although the observed aberrant immune
response may be secondary to an unrecognised alternative
aetiopathology. There is a dense infiltration of the small
intestinal lamina propria with lympho cytes and plasma cells in
patients with untreated coeliac disease. There is also an increased
ratio of intra-epithelial lymphocytes to surface enterocytes with
the majority of these cells expressing the suppresser/cytotoxic
phenotype and having the appearance of immunoblasts[43],
and there is a strong assoc iation with the histocompatibility
antigen HLA-DQ2 which is also associated with other auto-immune
disorders. High titres of antibodies to gliadin occur in coeliac
disease as well as antibod ies to reticulin and endomysium, which
also implies an immune mediated mechanism [44]. The role
of these antibodies in the disease pathogenesis is unknown. However,
it has recently been shown that the antigen for anti-endomysial
antibodies is the enzyme tissue transglutaminase, which is present
in the small intestine and causes selective partial deamidation of
gluten molecules.
There
are an increased number of cells that express the cytokines IL-2,
interferon-γ (IFN-γ) tumour necrosis factor-α (TNF-α)
and tumour necrosis factor-β (TNF-β), IL-10, IL-1β
and transforming growth factor-β (TGF-β). The expression
of both Th1 (IFN-γ and IL-2) and Th2 (IL-4 and IL-10)
associated cytokine transcripts in the same biopsies indicate the
activation of Th0 cells. The expression of IL-2 and IL-4 mRNA was
not observed in the peripheral blood samples of patients with
inactive coeliac disease, implying that they are associated with
disease activity[45]. This also supports the
immune-mediated hypothesis. The isolation of gluten-sensitive
T-cells both from both the peripheral blood and small intestinal
biopsies from coeliac patients[34,46], the HLA-DQ2
restriction of the majority of these cells and their production of
pro-inflammatory cytokines when stimulated with wheat gliadin[47],
provide further evidence that these represent an hyperimmune
sensitivity to certain cereal peptides.
“Gliadin
(or gluten) shock”, is a rare condition which affects treated
coeliac patients. In this condition a gluten challenge is followed
by collapse with vomiting and tachycardia. The condition responds to
treatment with corticosteroi ds.
In
patients who do not respond to a strict gluten free diet, or who
relapse on a gluten free diet, steroids can be used, such as
prednisolone 20mg/day, with a reducing course over the next 6 weeks.
Azathioprine can also be used as a steroid-sparing agent[48].
Cyclosporine does not appear to be useful[49], indeed,
some patients’ symptoms increase, and budesonide, despite reducing
the risk of osteoporosis, is not useful, as it is formulated to be
slowly released in the terminal ileum, usually beyond the coeliac
small bowel lesion, and is absorbed only in very small amounts.
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