Coeliac disease: it takes three to tango!

Coeliac disease: it takes three to tango! Coeliac disease (CD), the most common food sensitive enteropathy in humans, is caused by permanent intolerance for dietary gluten. 1 2 Typical symptoms include chronic diarrhoea, abdominal distension, and failure to thrive. These symptoms are the result of a lesion in the upper small bowel characterised by (sub)total villous atrophy , hypertrophic crypts, an increased number of inter-epithelial lymphocytes, and a chronic inflammatory response of the lamina propria lymphocytes. IgA antibod-ies against endomysium are specific indicators of CD. 3 4 Yet CD is considered to be primarily a T cell mediated disease because the majority of patients express the HLA-DQ2 [DQ(1*0501, 1*02)], and/or −DQ8 [DQ(1*03, 1*0302)] molecules 5 6 ; gluten specific HLA-DQ restricted T cells are present at the site of the lesion in the gut 7 and withdrawal of gluten stops the disease process. 2 The identity of potentially disease inducing, gluten derived T cell stimulatory peptides, however, was unknown until recently. Here we briefly discuss recent work which sheds light on the requirements for an optimal interaction between gluten, HLA-DQ, and T cells, requirements which explain the association of CD with HLA-DQ2/8. Specificity of the humoral immune response CD patients generally have high serum levels of antigliadin antibodies. A more specific indicator for the disease, however, is the presence of antiendomysium antibodies. 3 4 Recently, these antibodies have been found to be specific for the enzyme tissue transglutaminase (tTG). 8 tTG is a ubiquitous protein that belongs to a family of structurally and functionally related calcium dependent enzymes. These enzymes cross link proteins by catalysing the formation of isopeptide bonds between carboxamide groups of glutamine residues and amino groups of lysine residues. 9 10 An important function of tTG is thought to be cross linking of extracellular matrix proteins which stabi-lises damaged tissue 10 11 but other activities have also been identified. 12–14 Identification of tTG as an autoantigen 8 has fuelled novel concepts about the pathogenesis of CD. Schuppan and colleagues 15 have suggested that anti-tTG antibodies could play a direct role in the pathogenesis of CD as tTG is required for activation of transforming growth factor (TGF-). 14 It was proposed that the observed lack of diVerentiation of villous epithelium in CD patients could be a result of an excess of locally produced anti-tTG antibodies as this would block tTG and thus activation of TGF-required for epithelial diVerentiation. …