The B cell response to both protein and nucleic acid antigens displayed on apoptotic cells are dependent on endosomal pattern recognition receptors

In systemic autoimmune diseases such as systemic lupus erythematosus (SLE), B cell tolerance is lost and there is a production of autoantibodies that drive pathology. The specificities of these antibodies are towards a wide range of autoantigens including proteins such as serum factors including cytokines as well as towards nucleic acids and modified glycolipids. It is known that endosomal pattern recognition receptors are involved in specific responses but if they drive specificity towards a specific group of autoantigens is not known. Here, we used syngeneic apoptotic cells alone to break B cell tolerance and investigated the antibody response in Unc93b1 mutant mice that lack signalling from the TLR3, TLR7 and TLR9 receptors. We found that specific B cell responses known from patients with SLE including antibodies towards Ro-52/60, La, cardiolipin as well as DNA were all significantly lower in the knockout mice. Thus, we found that endosomal TLR receptors were involved in break of tolerance and drive B cell responses for protein, nucleic acid and modified lipid antigens. This pinpoints these receptors as key drivers for the full range of antibody driven pathology in SLE and suggests that targeting of endosomal TLR driven responses will quench all B cell driven autoreactivity.