Opposing Impact of B Cell–Intrinsic TLR7 and TLR9 Signals on Autoantibody Repertoire and Systemic Inflammation

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by autoantibodies targeting nucleic acid-associated antigens. The endosomal toll-like receptors TLR7 and TLR9 are critical for generation of Abs targeting RNA- or DNA-associated antigens, respectively. In murine lupus models, deletion of TLR7 limits autoimmune inflammation, while deletion of TLR9 exacerbates disease. Whether B cell or myeloid TLR7/TLR9 signaling is responsible for these effects has not been fully addressed. Here, we utilize a chimeric strategy to evaluate the effect of B cell-intrinsic deletion of TLR7 vs. TLR9 in parallel lupus models. We demonstrate that B cell-intrinsic TLR7 deletion prevents RNA-associated Ab formation, decreases production of class-switched Abs targeting non-nuclear antigens and limits systemic autoimmunity. In contrast, B cell-intrinsic TLR9 deletion results in decreased DNA-reactive Ab, but increased Abs targeting a broad range of systemic autoantigens. Further, we demonstrate that B-intrinsic TLR9 deletion results in increased systemic inflammation and immune-complex (IC) glomerulonephritis despite intact TLR signaling within the myeloid compartment. These data stress the critical importance of dysregulated B cell-intrinsic TLR signaling in the pathogenesis of SLE.

A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens

“…For example, it may help explain why TLR9-deficient autoimmune strains develop more severe disease than do their TLR9-sufficient counterparts (15,16,(18)(19)(20). Consistent with this notion, autoimmune disease is similarly exacerbated when TLR9 deficiency is limited to B cells (72). Nevertheless, in addition to its negative regulatory role, TLR9 is also required for B cell activation, ASC differentiation, and the production of isotype-switched, DNA-reactive autoantibodies in autoimmune-prone mice (15,32).…”

Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation

“…The specific need for TLR7, but not TLR9, in AM14 GC differentiation mirrors reports in other systems (39)(40)(41). The connection between TLR7 and GC cells is interesting because B cells with RNA-related specificities appear more T cell dependent.…”

Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

“…The ability for TACI signaling to upregulate TLR7 expression shown in our study is significant since TLR7 signaling has emerged as a critical pathogenic pathway in SLE, in contrast to TLR9, which may actually play a regulatory or protective role in these circumstances [29]. The different roles of TLR7 and TLR9 in autoimmunity have been demonstrated in studies using B6.NBa2 mice, in which TLR9-deficiency increased autoantibody levels, yet TLR7 À/À TLR9 À/À double deficiency negated autoantibody production in this spontaneous mouse model of SLE [30].…”