T Cell Receptor Variable Regions in Diabetes Bind to Each Other, to Insulin, Glucagon or Insulin Receptor, and to Their Antibodies

Our objective is to elucidate the nature of the autoimmune disregulation in diabetes through the antigen specificity of the T-cell receptor (TCR) sequences generated by patients with type 1 diabetes mellitus (T1DM). Previously we demonstrated that TCR from T1DM patients and NOD mice mimic insulin, glucagon and their receptors. We hypothesize that these TCR will bind to each other (as insulin and glucagon do to their receptors) and also be targets of anti-insulin and anti-glucagon antibodies. The hypervariable regions of multiple TCR from three patients were synthesized and their binding specificities determined using UV spectroscopy. ELISA was used to determine whether these TCR were recognized by anti-insulin and anti-glucagon antibodies. Each patient produced TCR that recognized insulin, glucagon and the insulin receptor (IR). These TCR also recognized each other as complementary (possibly idiotype-antiidiotype) pairs. In addition, each TCR peptide was recognized with nanomolar affinity as an antigen by an antibody against insulin, glucagon, and/or IR. Finally, each of the antibodies against insulin, glucagon and IR formed a complementary antibody (or idiotype-antiidiotype) pair with another antibody involved in the disease, again at nanomolar affinities. Every possible expression of complementarity (or idiotype-antiidiotype cross-reactivity) involving TCRs and antibodies was manifested by each patient. Two interpretations of these observations are offered. One, following Marchelonis, is that TCR-antibody complementarity is a mechanism for down-regulating the autoimmune process to re-establish tolerance to self-antigens. A non-exclusive alternative is that the trigger for autoimmunity is antigenic complementarity, which results in the production of complementary TCR and antibodies that appear to have idiotype-antiidiotype relationships among themselves.