B cell-TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in SLE-prone mice

Systemic Lupus Erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of anti-nuclear autoantibodies (ANA). ANA development is recognized as one of the initial stages of disease which often results in systemic inflammation, kidney disease and death. The etiology is complex, but it is clear that innate pathways may play an important role in disease progression. Recent data has highlighted an important role for the TLR family, particularly TLR7 in both human disease and murine models. In the studies presented here, we have presented a low copy conditional TLR7 transgenic (Tg7) mouse strain which does not develop spontaneous autoimmunity. When we combine Tg7 with the Sle1 lupus susceptibility locus, the mice develop severe disease. Using the CD19 Cre -recombinase system, we normalized expression of TLR7 solely within the B cells. Using this method we demonstrated that overexpression of TLR7 within the B cell compartment reduces the marginal zone B cell compartment and increases B and T cell activation but not T follicular helper cell development. Moreover, this enhanced B-cell TLR7 expression permits the specific development of antibodies to RNA/protein complexes and exacerbates SLE disease.