The TLR7 agonist imiquimod mediates immune activation in primary Sjögren’s syndrome

Abstract

Abstract 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 demonstrate 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) to pre-disease NOD.B10 females 3 times a week for 6 weeks (n = 8). Parallel experiments were performed in which age and sex-matched controls received a base cream lacking Imq (n = 9). Saliva was collected following pilocarpine injection before and after treatment. Animals were euthanized, spleens and cervical lymph nodes (cLNs) harvested, and flow cytometry was performed. Imq-treated animals exhibited lymphadenopathy, splenomegaly, and decreased salivary flow. Both cLNs and splenocytes from Imq-treated animals demonstrated an increase in the percentage of activated/memory T cells (CD4+, CD44+, CD62L−) and TLR7 expressing B cells (B220+, CD69+, TLR7+). The percentage of B and CD4+ T cells expressing TLR7 was increased in spleen and cLNs following Imq administration. Aged-associated B cells (ABCs) (B220+, CD23−, CD21−, T-bet+ ) were also expanded in the spleens of Imq-treated mice. In summary, activation of TLR7 mediates adaptive immune activation and promotes expansion of the ABC subset in pSS. Supported by NIH/NIDCR R01DE29472