T oll‐like receptor 8 deletion accelerates autoimmunity in a mouse model of lupus through a T oll‐like receptor 7‐dependent mechanism

Summary Systemic lupus erythematosus is an autoimmune disorder characterized by increased levels of lymphocyte activation, antigen presentation by dendritic cells, and the formation of autoantibodies. This leads to immune complex‐mediated glomerulonephritis. Toll‐like receptor 7 ( T 7) and TLR 9 localize to the endosomal compartment and play important roles in the generation of autoantibodies against nuclear components, as they recognize RNA and DNA , respectively. In contrast, very little is known about endogenous TLR 8 activation in mice. We therefore tested whether TLR 8 could affect autoimmune responses in a murine model of lupus. We introduced a Tlr8 null mutation into C57 BL /6 mice congenic for the Nba2 ( NZB autoimmunity 2) locus and bearing the Yaa (Y‐linked autoimmune acceleration) mutation containing a tlr8 duplicated gene, and monitored disease development, autoantibody production, and glomerulonephritis‐associated mortality. Cellular responses were investigated in female Nba2. TLR 8 −/− mice bearing no copy of tlr8 . The TLR 8 deficiency accelerated disease progression and mortality, increased the number of circulating antibodies and activated monocytes, and heightened cellular responses to TLR 7 ligation. TLR 8‐deficient antigen‐presenting cells exhibited increased levels of MHC class II expression. The ability of dendritic cells to present antigens to allogeneic T cells after TLR 7 ligation was also improved by TLR 8 deficiency. TLR 8 deletion accelerated autoimmunity in lupus‐prone mice in response to TLR 7 activation. Antigen‐presenting cell function seemed to play a key role in mediating the effects of TLR 8 deficiency.