primary prevention of coeliac disease - Associazione Italiana ...

THE BASIS OF COELIAC DISEASE
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healing . The calcium dependent transglutaminase activity of tTG catalyses selective
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crosslinking or deamidation of protein-bound glutamine residues . In contrast to the
non-enzymatically mediated deamidation that results in a near random deamidation of
the often numerous glutamine residues in gliadin peptides, tTG appears to carry out an
ordered deamidation of some few specific glutamines. In all of the known major DQ2
and DQ8 restricted gluten epitopes recognised by gut T cell of adult patients, there are
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glutamic acid residues modified by tTG which is important for T cell recognition .
Interestingly, the deamidation of glutamine residues that are not targeted by tTG (e.g.
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by acid treatment) can be deleterious for T cell recognition . This suggests that
deamidation in vivo is mediated by tTG. This idea is further supported by the results of
experiments where T cell lines have been established from biopsies challenged with a
minimally deamidated gliadin antigen (chymotrypsin-digested). In all but one of 18
adult patients, the established T cell lines only barely responded to the chymotrypsindigested
gliadins, but efficiently recognized the in vitro tTG-treated variants of the
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same gliadins .
Normally we do not mount immune responses to edible proteins. Moreover,
experimental animal models have demonstrated that oral administration of antigen
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usually results in systemic hyporesponsiveness to the same antigen . This
phenomenon, which is termed oral tolerance, is believed to occur because of active
tolerization towards edible proteins. In keeping with this thinking, oral tolerance to
gluten in CD patients may not have been established properly or is broken. Given the
preferential intestinal T cell response to deamidated gluten fragments in CD patients, it
may be that deamidation is involved in the perturbation of the oral gluten tolerance.
Deamidation increases the binding affinity of gliadin peptides for DQ2 from poor but
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significant binders, to epitopes with reasonable, but by no means exceptional affinity
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. The moderate binding affinity of these epitopes concurs with the finding that they do
not carry optimal anchors in all the anchor positions. Interestingly, T cell clones specific
for the DQ2-g-gliadin-I, DQ2-a-gliadin-I and DQ2-a-gliadin-II epitopes generally fail
to recognise native peptides at higher concentrations that should compensate for their
lower binding affinity for DQ2. Thus, concurrent with the increase in the binding
affinity for DQ2 caused by deamidation of the gliadin peptide, there likely is a change in
the conformation1of the gliadin/DQ2 complexes. Oral tolerance to antigens ingested in
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high doses is usually established by T cell anergy or deletion . It is possible that T cells
specific for native gluten sequences are usually anergised or deleted, and that phlogistic
T cell responses are effectively mounted to novel gluten epitopes being created in an
inflamed environment by the help of tTG.
How many gluten T cell epitopes?
There exist several epitopes in gluten that are recognized by small intestinal T cells
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of CD patients . Recent results of the author's laboratory and the laboratory of Frits
Koning in Leiden indicate that there may be more than ten distinct DQ2 restricted
epitopes. The existence of multiple epitopes raises several interesting questions: are
only some of the epitopes pathogenic and thereby relevant to explain the HLA
association? Are responses towards some of the epitopes generated during the early
phases of disease development, while the responses to others are a result of epitope