Mathematical analysis of clinical data reveals a homunculus of bacterial mimotopes protecting from autoimmunity via oral tolerance in human.

Oral tolerance (OT) means systemic immunological unresponsiveness to harmless antigens present in the gastrointestinal tract. We presumed that tolerance to these antigens may also protect self-proteins that show immunological similarity to the intestinal normal flora. To investigate the existence and in vivo relevance of such a tolerogenic molecular mimicry, we focused our attention to Autoimmune Polyendocrine Syndrome type 1 (APS1) and Hemolysis, Elevated Liver Enzymes, Low Platelet count (HELLP) syndrome. APS1 is a human form of Autoimmune Regulator (AIRE) dysfunction with severely impaired central immunotolerance to a specific set of autoantigens, allowing investigation of tolerogenic mimicry by itself, without a disturbing background. HELLP syndrome is a mediocre manifestation of thrombotic microangiopathy, complicating pregnancy, with platelet-fibrin deposits in small blood vessels and transient development of autoantibodies. Impaired microcirculation in the liver is well described, while intestinal ischemia is possible but has not yet been studied. As the harmless nature of an antigen is essential for OT, ischemia-induced bacterial microinvasion represses this process. In case that oral tolerance to a bacterial homunculus is an existing way of self-protection and has an in vivo relevance when central tolerance is intact, significant intestinal ischemia--if present--is expected to promote autoimmunity in HELLP syndrome. We used an experimentally validated, highly reliable mathematical algorithm to predict the extent of immunological similarity between a certain autoantigen and intestinal bacteria. We found a strong negative correlation between the similarity of autoantigens to intestinal bacteria and the production of specific autoantibodies in APS1 (R=-0.70, P=0.002), while a positive correlation was observed in patients with predominantly the severe/moderately severe form of HELLP syndrome according to Mississippi classification (R=0.94, P=0.005). Autoantigen length inversely correlated with the production of autoantibodies in APS1 (R=-0.68, P=0.004). As a longer chain with more epitopes associates with an increased possibility of mimicry to any proteome, molecular mimicry in general--regarding at least major tissue-specific autoantigens--seems to be rather protective. Our calculations support the hypothesis that OT to an intestinal "bacterial homunculus" is an in vivo relevant mechanism of self-protection in humans, furthermore, HELLP syndrome presumably associates with significant intestinal ischemia and leak, resulting in transient autoimmunity via loss of OT.