Comment

Coeliac disease has long been known to reflect an antigen specific immune response to the gliadin component of wheat protein. Although the exact nature of this response has been disputed, most observers consider that CD4+ T cell mediated immunity is the critical event, with production of cytokines and related effector functions being most important.1 ,2 This view is supported by the intense infiltration of the mucosa by activated T cells and by the fact that coeliac disease is strongly associated with certain class II HLA haplotypes, particularly HLA-DQ2.3 ,4 In addition, experimental models which reproduce the characteristic pattern of villus atrophy and crypt hyperplasia are dependent on activated CD4+ T cells and cytokine production.5-8

Nevertheless, it has always been unclear how an antigen specific immune response directed at a component of the diet can stimulate such severe damage to the tissues of the intestine itself. The assumption that the enteropathy is a direct effect of gliadin specific CD4+ T cells is also challenged by the apparently specific association between coeliac pathology and IgA autoantibodies directed at endomysial antigens. These findings have been interpreted as support for an antibody dependent immunopathology.9-11 Recent studies have taken this idea further, by showing that the endomysial autoantibodies are directed at the tissue transglutaminase (tTG) enzyme.12 However, it has been unclear how this unusual pattern of autoreactivity against tissue components can be reconciled with the knowledge that the disease is entirely dependent on exposure to a specific, exogenous antigen. This paradox has now been addressed by a recent paper suggesting that deamidation of gliadin by tTG produces HLA-DQ2 binding peptide epitopes which combine with the tTG enzyme, creating novel antigenic determinants that stimulate an autoantibody response against tTG.

Molberg …