Dr. Mohan's laboratory has focused its efforts on "Genetic Dissection of SLE Pathogenesis". SLE (systemic lupus erythematosus) is a systemic autoimmune disease with a wide spectrum of phenotypes and pathological changes. Equally varied and intriguing are the diverse immunological mechanisms that underlie this disease. Much of what they have learned about this disease has come from studying mouse models of this disease. Importantly, several genetic loci that confer lupus susceptibility in mice have recently been identified. Sle1, Sle2 and Sle3 are three such important loci. They also know that these three loci impact the immune system in very different ways. Sle1 triggers the formation of high titers of anti-nuclear autoantibodies, which do not appear to be intrinsically pathogenic. Sle2 triggers generalized (i.e., not antigen-specific) B-cell hyperactivity, but this is not sufficient to cause any disease. Sle3, in contrast, leads to T-cell activation, increased CD4:CD8 ratios, reduced activation-induced T-cell death, and low titers of antinuclear autoantibodies. As one would predict, when these individual susceptibility loci are bred together, full-blown lupus ensues. Ongoing projects in the laboratory are aimed at elucidating the immunopathological mechanisms through which these loci lead to autoimmunity. Specifically, they are dissecting out the respective contributions of these loci to (a) breaching B-cell and/or T-cell tolerance (using antigen receptor transgenic models), (b) shaping the B-cell and T-cell repertoire at different stages of lymphocyte development and differentiation, and (c) effecting glomerular pathology, via autoantibody-dependent and independent pathways. Additional studies in his laboratory are aimed at defining the molecular pathways that are triggered at each of the above steps leading to disease. Collectively, these studies will help chart out the molecular blueprints for lupus development.
