Tlr9 governs Tlr7-mediated disease in a mouse model of primary Sjogren’s disease in a sex-biased manner 3918

Abstract Description Primary Sjogren’s disease (pSD) is a systemic autoimmune disease. The etiology is poorly understood, and no curative therapies exist. Previously, we found Myd88 was required for pSD, and Tlr7 drove disease in females. As Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would worsen disease in a Tlr7-dependent manner. We generated pSD mice that lacked either Tlr9 (NOD.B10Tlr9-/-) or both Tlr7 and Tlr9 (NOD.B10Tlr-DKO) systemically. We harvested tissues for histologic analysis and assessed disease-relevant immune populations. We examined total and autoreactive antibody levels in sera. Our data revealed that NOD.B10Tlr9-/- females had enhanced Tlr7-dependent nephritis and dacryoadenitis. Moreover, splenic Tlr7+ B cells, germinal center and age-associated B cells, and CD4+ and CD8+ activated/memory T cells were increased in NOD.B10Tlr9-/- female mice, while this expansion was absent in NOD.B10Tlr-DKO females. Finally, total IgM levels were elevated in NOD.B10Tlr9-/- females as compared to the parental strain and autoreactive IgM and IgG were also enriched in NOD.B10Tlr9-/- females. NOD.B10Tlr-DKO females and males showed reduced IgM and IgG titers as compared to the NOD.B10 strain, and also had negligible IgM and IgG autoreactivity. Overall, our study revealed that ablation of Tlr9 drives pSD in females, and Tlr9 deletion has negligible effects in males. Overall, Tlr9 regulates Tlr7-dependent sex-biased tissue-specific inflammation and immune activation in pSD. Funding Sources NIH/NIDCR R01DE- 29472; T32DE023526; NIH/NIDCR F31- DE032884 Topic Categories Basic Autoimmunity (BA)