Identifying genetic determinants of T cell-dependent autoimmunity using forward genetics

Abstract: Rheumatoid arthritis (RA) affects 0.5-1% of the population and is an important health and socioeconomic problem. RA has a high degree of heritability. Thus, extensive efforts have been made to better understand the genetic variability contributing to disease susceptibility. However, dissecting the genetic component of RA in humans has been difficult due to heterogeneity in the human population, multiple testing issues, and lack of accessibility to relevant tissues for proof-of-concept studies. Genetic studies in mouse model systems circumvent these problems, enhancing the possibility to identify disease regulating genetic variants. Here, we use a forward genetics approach in mice to identify and characterize genetic determinants of RA and related autoimmune diseases. First, we have mapped quantitative trait loci (QTL) regulating experimental arthritis using linkage analysis, and then isolated these QTL in congenic strains for in depth functional characterization. Using this approach, we make several important observations. In the first study, we find that promoter polymorphisms regulating expression of the vitamin D receptor affect T cell activation and T cell-driven collagen-induced arthritis. These findings are particularly interesting considering the long-standing association between serum vitamin D and several autoimmune diseases. In the second study, we discover a spontaneous insertion of a long terminal repeat which leads to a deficiency in the SH3GL1 gene (Endophilin A2), protecting mice in several arthritis models. We are first to identify the immunomodulatory properties of SH3GL1, which may prove to be a valuable therapeutic target. In the third study, we identify a polymorphic estrogen receptor binding site that regulates susceptibility to experimental arthritis and other autoimmune models by interfering with estrogen regulation of the T cell marker CD2. These results suggest an important role for CD2 and estrogen in shaping the sexually dimorphic immune response. Collectively, our findings make a significant contribution towards the understanding of RA genetics while demonstrating the value of animal models.

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