TLR7 activation of age-associated B cells mediates disease in a mouse model of primary Sjögren's disease.

Primary Sjögren's disease (pSD, also referred to as Sjögren's syndrome) is an autoimmune disease that primarily occurs in women. In addition to exocrine gland dysfunction, pSD patients exhibit B cell hyperactivity. B cell-intrinsic TLR7 activation is integral to the pathogenesis of SLE, a disease that shares similarities with pSD. The role of TLR7-mediated B cell activation in pSD, however, remains poorly understood. We hypothesized that age-associated B cells (ABCs) were expanded in pSD and that TLR7-stimulated ABC subsets exhibited pathogenic features characteristic of disease. Our data revealed that ABC expansion and TLR7 expression were enhanced in a pSD mouse model in a Myd88-dependent manner. Splenocytes from pSD mice showed enhanced sensitivity to TLR7 agonism as compared to those derived from controls. Sort-purified marginal zone (MZ) B cells and ABCs from pSD mice showed enhanced inflammatory cytokine secretion and were enriched for anti-nuclear autoantibodies following TLR7 agonism. Finally, IgG from pSD patient sera showed elevated anti-nuclear autoantibodies, many of which were secreted preferentially by TLR7-stimulated murine MZ B cells and ABCs. Thus, these data indicate pSD B cells are hyper-responsive to TLR7 agonism and TLR7-activated B cells contribute to pSD through cytokine and autoantibody production. Thus, therapeutics that target TLR7 signaling cascades in B cells may have utility in pSD patients.