The Molecular Mimicry Mechanism In The Generation Of Auto-antibodies To Thyrotropin Receptor Induced By Yersinia Enterocolitica

Graves'disease (GD) is the main type of autoimmune thyroid disease (AITD). It afflicts up to 30 per 100,000 of the population, especially young women. Thyroid-specific autoantibodies are frequently found in the serum of GD patients, while over 90% of patients with GD have anti-thyrotropin receptor (TSHR) autoantibodies (TRAb). Some TRAb are thyroid-timulating antibodies (TSAb) that can bind to the TSHR and stimulate the thyroid to produce excessive thyroid hormone resulting in hyperthyroidism. TSAbs are considered to be the primary cause of thyroid dysfunction and also the most important autoantibody and immunological hallmark in GD. Although a lot of information is known regarding the characteristics of TRAb in patient serum and on GD pathology, the mechanism of loss of immune tolerance to TSHR and how TRAbs are induced are not fully understood. Many studies have suggested that susceptibility is determined by genetic factors (e.g., HLA-DR alleles and CTLA-4 polymorphisms), which play important roles in the pathogenesis of GD, similar to other autoimmune diseases. Nevertheless, many evidences suggest that genetics cannot totally account for susceptibility to GD, and genes are not the only factor in the disturbance of autoimmune tolerance to TSHR and the induction of autoantibodies resulting in GD. Non-genetic and environmental factors including infection, irradiation, iodine, smoking and stress may have secondary causative roles that are likely very important. Yersinia enterocolitica (YE) is a common intestinal infection with symptoms of diarrhea, myocarditis, reactive arthritis and erythema nodosum. Yersinia enterocolitica (YE) infection played an important causative role in the pathogenesis of Graves'disease (GD) through molecular mimicry. However, the specific YE proteins and epitopes recognized by anti-thyrotropin receptor (TSHR) autoantibodies (TRAb) have not been fully clarified, resulting in conflicting results from clinical research. Our aim was to explore the roles of YE in the pathogenesis of GD and identify the YE proteins and epitopes that are similar to the TSHR and are recognized by TRAb. Assays of YEAb, TRAb, TGAb and TMAb as well as cross-absorption and two-way immunodiffusion were performed in 120 patients with GD. Utilizing mass spectrometry and the bioinformatics tools of protein structure modeling and epitope prediction, we identified the YE protein and its epitope, which was recognized by TRAb and was similar to TSHR. Our clinical study showed that YE infection was significantly related to the production of TRAb and the relapse of GD. We demonstrated for the first time that the YE protein ompF shared cross-immunogenicity with a leucine rich domain of TSHR. The epitope recognized by anti-hTSHR antibody is located within the ompF region of amino acids 190-197. Our results showed that YE ompF is involved in the production of TRAb and the pathogenesis of GD through molecular mimicry. These findings are potentially important for understanding the role molecular mimicry plays in the disturbance of immune tolerance and the induction of autoimmunity to the TSHR.