Investigators have previously shown that the insulin gene (INS) is naturally transcribed in the human thymus and that thymic INS transcription correlates with proinsulin synthesis. Proinsulin shares most immunodominant epitopes with insulin, a major target autoantigen in Type I diabetes. They also found that INS transcription levels in the thymus correlate with allelic variation at the IDDM2 susceptibility locus for Type 1 diabetes, a polymorphic VNTR minisatellite that influences INS steady state transcription. These findings provide a plausible mechanistic explanation for diabetes susceptibility/resistance associated with the IDDM2 locus. In fact, genetically determined differences in proinsulin expression in the thymus may influence the selection of insulin-specific T-lymphocytes and in turn the development of autoimmune responses against insulin. This hypothesis is supported by the association of higher INS mRNA levels with VNTRs conferring dominant protection from diabetes. Moreover, non-obese diabetic (NOD) transgenic mice expressing proinsulin in the thymus do not develop diabetes, suggesting that increased proinsulin levels in the thymus may be sufficient to prevent the disease. Thus, previous work and data from literature suggest the hypothesis that thymic expression of peripheral antigens such as proinsulin may be crucial for the development of self-tolerance. In the mouse thymus, an uncharacterized subset of cells is responsible for the expression of peripheral antigens and reportedly mediates tolerogenic signals essential for the development of tolerance. The investigator hypothesizes that the human thymus may also contain specialized cells expressing peripheral antigens, and proposes to investigate whether cells expressing proinsulin can be demonstrated in the human thymus. Preliminary data indicating that proinsulin-expressing cells can be detected in thymus and peripheral lymphoid organs supports the hypothesis. The plan is to characterize the phenotype of proinsulin-expressing cells, both in the thymus and peripheral lymphoid organs, and to investigate whether proinsulin expression in peripheral lymphoid organs is also under the influence of the INS-VNTR/IDDM2 locus. The characterization of proinsulin expression by specialized immune cells possibly mediating tolerogenic effects may be useful to better understand the pathogenesis of Type 1 diabetes and perhaps develop novel preventive strategies based on autologous, antigen-specific, tolerogenic cells.
