Sammendrag
Celiac disease is an intestinal disorder that develops as a result of
interplay between genetic and environmental factors. HLA genes along
with non-HLA genes predispose to the disease. Linkage studies have
failed to identify chromosomal regions other than the HLA region which
have major effects, indicating the existence of multiple non-HLA
predisposing genes with modest effects. Association studies have shown
that CTLA4 or a closely located gene is one of these genes. The primary
HLA association in the majority of celiac disease patients is with DQ2
(DQA1*05/DQB1*02) and in the minority of patients with DQ8
(DQA1*0301/DQB1*0302). Gluten reactive CD4+ T cells can be isolated
from small intestinal biopsies of celiac patients but not from
controls. DQ2 or DQ8, but not other HLA molecules carried by patients,
present peptides to these T cells. A number of distinct T cell gluten
epitopes exist, most of them posttranslationally modified by
deamidation. DQ2 and DQ8 bind the epitopes such that the glutamic acid
residues created by deamidation are accommodated in pockets that have a
preference for negatively charged side chains. There is evidence that
deamidation in vivo is mediated by the enzyme tissue transglutaminase
(tTG). Overall, the results point to control of the immune response to
gluten by intestinal T cells restricted by the DQ2 or DQ8 molecules.
This is likely to be a critical checkpoint for the development of
celiac disease and could explain the dominant genetic role of HLA in
this disorder. The products of the other predisposing genes may
participate in pathway(s) that lead(s) to lesion formation. The minor
genetic effects of the non-HLA genes could indicate a lack of critical
checkpoints along these pathways, or that there are several pathways
leading to the lesion formation.
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