primary prevention of coeliac disease - Associazione Italiana ...

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RECENT ADVANCES ON GLUTEN TOXICITY
involved in the pathogenesis of coeliac disease is higher than previously thought further
reduces the technical feasibility of targeted inactivation of gliadins (and glutenins)
genes.
The most recent results of the Sollid's group are on the same line of Koning. Even in
adults, DQ2-restricted mucosal T-cells recognize an additional a-gliadin epitope and
several new g-gliadin peptides, confirming also that deamidation is not an absolute
prerequisite for T-cell activation. Interestingly the new and the previously identified
peptides are not randomly scattered accross gliadin molecules but cluster in regions of
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the proteins with a high content of proline residues .
In apparent contrast with these recent studies indicating a wide array of a,/g-gliadin
and glutenin peptides playing a complementary role in coeliac disease activation, a
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recent study identified a 33-mer peptide having several characteristics suggesting it is
the primary initiator of the inflammatory response in this condition. First of all, the 33-
mer peptide appeared to be stable toward digestion by gastric, pancreatic and brushborder
proteases. Secondly, it reacted with tTG with substantially greater selectivity
than known natural substrates of the enzime. Finally, it turned out to be a potent inducer
of gut-derived coeliac T-cell lines and its homologs were absent in cereal that are not
toxic for coeliac patients. Besides these important features, the aminoacid sequence of
the peptide included the residues 57-89 of a-gliadin, largely overlapping with the 57-68
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and the 62-75 Arentz-Hansen and the Anderson 57-73 peptides. In addition it should
be noted that the 33-mer peptide is particularly rich in proline residues (n=13) and that
its exposure to a bacterial prolyl-endopeptidase catalyzes the breakdown of the peptide
diminishing its toxic effect. Should the 33-mer peptide be the dominant epitope in
coeliac disease, this would offer a possible strategy for oral peptidase supplement
therapy for the treatment of this condition.
The apparent discrepancy between multiple and a single toxic peptide in the
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pathogenesis of coeliac disease has been addressed in a recent editorial . It has been
hypothesized a multi-step sequence in which, in an early phase, T-cell response is
directed to a wide array of native gluten (glutenin plus gliadin) epitopes as a
consequence of an epitope spreading due to the ubiquitous presence of the same highly
repetitive sequence. In a more advanced phase the immune response becomes polarized
to an immunodominant peptide (the 33-mer ?) as a consequence of an epitope focusing
catalized by tTG increasingly released from the tissue lesions.
It should be underlined that this view does not preclude a selective immunotherapy.
Several lines of evidence suggest that the primary problem is understanding the
hierarchy of epitope spreading in coeliac disease, since in other animal and disease
models it has been shown that immunodominant T-cell epitopes behave as potent
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tolerogens when ingested by alternative routes and that this process may induce
tolerance to the whole antigenic molecule in a mechanism of intramolecular epitope
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suppression . Alternative strategies may be represented by DNA vaccines based on the
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construction of plasmids containing multiple epitopes and by the use of antigen
presenting cells engineered to present both the dominant gluten peptide and the FAS
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ligand molecule to target and kill FAS positive antigen-specific coeliac T-cells .
Toxic peptides must reach the sub-epithelial environment to exert their pathogenic
role. At the Paris meeting new data have been presented on the interaction between