Just like rheumatoid arthritis (RA), coeliac disease (CD) is an HLA-associated disease. In the case of CD the association is extraordinarily strong: close to 100% of patients are either HLA-DQ2 and/or HLA-DQ8 positive. CD is caused by pro-inflammatory T cell responses to gluten, proteins present in the cereals wheat, barley and rye. The resulting chronic inflammation in the upper small intestine leads to a variety of symptoms like stomach ache, malabsorption of nutrients, failure to grow and diarrhoea. Removal of gluten from the diet constitutes an effective treatment modality. Several amplification loops likely play a crucial role in the initiation and propagation of the gluten-specific T cell response. It has been established that native gluten peptides bind poorly to the disease predisposing HLA-DQ2 and HLA-DQ8 molecules while gluten peptides in which one or more glutamine residues are modified into glutamic acid bind with very high affinity. Such posttranslational modification of gluten is mediated by the enzyme tissue transglutaminase (TG2), which is released upon tissue damage. Thus, a critical step in CD pathogenesis is the occurrence of tissue damage, potentially as the result of an environmental insult, and the associated modification of gluten proteins generating an immunogenic repertoire of gluten-derived peptides. The IFNγ produced by the gluten-specific T cells can locally enhance HLA-DQ expression, facilitating the presentation of modified gluten peptides. A strongly biased, high affinity public T cell receptor (TCR) repertoire specific for immunodominant gluten peptides is observed in patients with CD, indicative of the stringent selection and expansion of T cells expressing such TCR. Structural studies have revealed the molecular basis for the interaction between such TCR and HLA-DQ-gluten. Next to T cells, antibodies specific for modified gluten are typically found in patients as well, providing yet another amplification loop as such antibodies can significantly enhance the uptake of modified gluten peptides and mediate effective B to T cell antigen presentation.
There are striking similarities with RA. Next to the HLA-association, indicative for an involvement of T cells in the autoimmune process in RA as well, antibodies to enzymatically modified autoantigens (ACPA) are present in a subgroup of patients with RA. Strikingly, there is a very strong correlation between smoking and ACPA positive RA, pointing to a link between this environmental insult and the generation of ACPA. Finally, similar to in CD, ACPA could play a role in B to T cell presentation in RA and provide an amplification loop. Thus, the accumulated knowledge on CD pathogenesis is likely relevant to other HLA-associated immune diseases, including RA, and strongly suggests that a presently ill understood T cell response underlies the initiation of RA.
Disclosure of Interest None declared
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