Innate Immune Dysregulation in Sjögren’s Syndrome

Abstract

Primary Sjogren’s syndrome (pSS) is an autoimmune disease characterized by immune dysfunction that occurs within exocrine gland tissue and systemically. While adaptive immunity is clearly dysregulated in pSS, the innate immune response also mediates disease pathogenesis in both pSS mouse models and patients. Moreover, studies in mice suggest that activation of innate immunity precedes the adaptive. Many different cell types that contribute to innate immune defense are shown to play pivotal roles in pSS, such as dendritic cells, macrophages, and salivary gland epithelial cells. Moreover, diverse innate immune pathways are implicated in disease, including those activated by both exogenous pathogen-associated molecular patterns and endogenous damage-associated molecular patterns. This chapter will provide an overview of the innate immune pathways that are dysregulated in pSS. Of note, toll-like receptor signaling, inflammasome activation, and stimulator of interferon genes (STING)-mediated cytokine production drive activation of innate immunity in pSS. While the underlying causes of innate immune dysregulation are incompletely understood, genetics, sex hormones, infections, and alterations in both the gut and salivary microbiome likely contribute to disease susceptibility. We will examine the putative causes of innate immune activation and explore established and emerging therapeutics that target innate immunity in pSS.