TLR7 agonism accelerates disease in a mouse model of primary Sjögren’s syndrome and drives expansion of age-associated B cells. TLR7 agonism accelerates disease in a mouse model of primary Sjögren’s syndrome and drives expansion of age-associated B cells

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that Myd88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which Myd88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, aged-associated B cells (ABCs) were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of the ABC subset in pSS. Overall design: C57BL/10 and NOD.B10H2b/J mice were treated with a sham cream (Con) or a cream containing 5% imiquimod (Imq) for 6 weeks beginning at 6 weeks of age. The cream was administered epicutaneously 3X/week by application to the ear. Animals were euthanized at 13 weeks of age and sera were harvested. Sera were harvested from BL/10 sham-treated ( = 6), BL/10 Imq-treated (n = 6), NOD.B10 sham-treated (n = 9) and NOD.B10 Imq-treated mice (n = 8). PBS was used as negative control for the array. Each gpr file includes the raw signal data for 16 arrays (samples). Independent samples are identified in the .gpr file with the "Block" column ID included on each sample page as a characteristic.