Intestinal Anti-tissue Transglutaminase2 Autoantibodies: Pathogenic and Clinical Implications for Celiac Disease

Celiac disease (CD) is a systemic disease that primarily affects the small intestine. The presence of anti-tissue transglutaminase 2 (anti-TG2) antibodies in the serum, as well as the presence of autoimmune phenomena, account for the inclusion of CD among autoimmune diseases. Anti-TG2 autoantibodies are produced at intestinal level, where they are deposited even before they appear in circulation. The pathogenic events that lead to their production are still not completely defined, but a central role seems to be played by gliadin-specific T cells. Interestingly, limited somatic mutations have been observed in VH and VL genes in TG2-specific plasma cells, another important aspect being the biased use of a heavy chain encoded by the VH5 gene. Conflicting data have been produced over the years on the effect of anti-TG2 antibodies on TG2 function. Although the presence of anti-TG2 antibodies in serum is considered a hallmark of CD and relevant from a clinical viewpoint, the role of these autoantibodies in the development of the celiac lesion remains to be defined. In the years, different technical approaches have been implemented to detect and measure intestinal CD-associated autoantibody production. Two aspects can make intestinal anti-TG2 antibodies relevant: from a clinical viewpoint: the first is their proposed ability in potential coeliac patients to predict the development of a full-blown enteropathy; the second is their possible role in revealing a condition of reactivity to gluten in patients with no circulating CD-associated autoantibodies. In fact, the detection of CD-specific autoantibodies production in the intestine, in the absence of serum positivity for the same antibodies, could be suggestive of a very early condition of gluten reactivity; alternatively, it could be not specific for CD and merely attributable to intestinal inflammation. In conclusion, the role of mucosal anti-TG2 antibodies in pathogenesis of CD is unknown. Their presence, the modalities of their production, their gluten dependence render them a unique model to study autoimmunity.