Myd88 activation in immune cells governs distinct disease manifestations in primary Sjögren’s syndrome

Abstract

Abstract Studies in mice and humans identify Myd88 activation as an important driver of autoimmune disease, although the role of this adapter molecule in primary Sjögren’s syndrome (pSS) is poorly understood. In pSS, patients exhibit exocrine gland dysfunction along with serious systemic disease manifestations. Although Myd88-dependent signaling networks are essential for pSS disease pathogenesis, these pathways remain incompletely understood in the context of pSS. The objective of this study was to establish the contribution of Myd88 activation in immune cells to local and systemic pSS manifestations. To this end, we generated a novel conditional knockout pSS mouse model lacking Myd88 in the hematopoietic compartment. We found that ablation of Myd88 in immune cells altered inflammatory mediators in salivary tissue, but did not affect the degree of lymphocytic infiltration in exocrine glands or salivary production. Nephritis was diminished and pulmonary inflammation was increased in mice lacking Myd88 in hematopoietic cells. Finally, we found total IgM titers and autoreactive IgM and IgG were attenuated in pSS mice lacking Myd88 in immune cells. Thus, we demonstrated that Myd88 activation in the hematopoietic compartment is essential for distinct aspects of disease. This study establishes a rationale for design of targeted therapeutics that modulate Myd88 activation in a tissue-specific manner to ameliorate salivary inflammation and systemic disease manifestations characteristic of pSS.