TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE

Loss of tolerance in systemic lupus erythematosus (SLE) leads to the generation of auto-antibodies, which accumulate in end-organs where they induce disease. Here we show that immunoglobulin (Ig) G2a and 2b autoantibodies are the pathogenic isotypes by recruiting Fc gamma RIV expressing macrophages. Class switching, but not development, of IgM anti-self B cells to these pathogenic subclasses requires the innate immune receptor Toll-like receptor (TLR)9 and MyD88 signaling. In their absence, switching of autoreactive B cells to the IgG2a and 2b subclasses is blocked, resulting in reduced pathology and mortality. In contrast, switching of anti-self B cells to IgG1 is not perturbed and generation of nonautoreactive IgG2a and 2b antibodies is not impaired in TLR9-deficient mice. Thus, the TLR9 pathway is a potential target for therapeutic intervention in SLE.