Humanized BAFF transgenic mice develop autoimmune manifestations

Abstract

Abstract The B cell activating factor(BAFF) is a B cell survival factor that supports autoreactive B cells’ survival and prevents their depletion. Excessive BAFF can increase autoreactive B cells, driving autoimmunity. BAFF is commonly overexpressed in Systemic Lupus Erythematosus(SLE) and is strongly involved in the pathogenesis of the disease. Mice with BAFF deficiency results in the lack of mature B cells, whereas mice that overproduce BAFF have high numbers of mature B cells and antibodies, including autoantibodies, and develop an autoimmune disease similar to SLE in humans. BAFF has been shown to be the pivotal target in autoimmune diseases. In this study, we report the generation of two transgenic mouse strains with overexpression of human BAFF (B6-hBAFF, T036791 and T036794), which could be used to study anti-BAFF therapies. Overexpression of human BAFF led to significantly increased IgG, IgA, and IgM levels since 6 weeks of age compared with wild-type mice, which continued to increase gradually as the transgenic mice aged. These mice secreted a high level of anti-DNA autoantibodies, along with an increased ratio of B cells/CD45 +in the spleen and lymph node compared with wild-type mice, indicating overreactive B cells. Proteinuria started at 6 weeks of age with an increase in protein/creatinine ratio. This was accompanied by the infiltration of inflammatory leukocytes in the kidney at 15 weeks of age, suggesting local kidney inflammation. Taken together, the humanized BAFF transgenic mice autoimmune manifestations with enhanced overreactive B cells, providing a valuable tool supporting preclinical efficacy studies of drugs targeting B cells for the development of autoimmune disease therapies.