BCR/TLR7 coligation uniquely drives plasma cell differentiation of autoreactive B cells (171.34)

Abstract

Abstract Endosomal Toll-like receptors (TLRs) play an important role in the manifestation of systemic autoimmune diseases such as SLE. In vitro, DNA-/RNA-associated autoantigens have been reported to activate B cells, pDCs, and other APCs, through TLR9/TLR7-dependent pathways. However, in vivo, TLR9 appears to negatively regulate TLR7-dependent responses. Hence, TLR9-/- autoimmune prone mice develop more severe disease and increased autoantibody titers against RNA associated proteins, while TLR7-/- and TLR7/9-/- autoimmune-prone mice develop less severe disease. AM14 BCR side-directed transgenic B cells recognize IgG2a-bound immune complexes (ICs) and initially proliferate in response to both DNA and RNA autoantigens. However, the TLR9-dependent DNA responses eventually promote a form of programmed cell death that can only be rescued by B cell survival factors such as BLyS. By contrast, the TLR7-dependent RNA responses promote differentiation to the plasma cell lineage. The RNA-driven phenotype is characterized by increased levels of plasma cell associated proteins such as IRF-4 and CD138 and antibody secretion. Even in the presence of BLyS, DNA containing ICs did not promote plasma cell development. Our results identify B cell intrinsic mechanisms whereby TLR9 activation restrains B cell responses and TLR7 activation induces a unique signal for plasma cell development.