Analysis of B cell activation by endogenous mediators of inflammation in Sjogrens syndrome

Project Summary Sjögren's syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss of tears and saliva. Primary SS (pSS) affects salivary and lacrimal tissue and results in many serious systemic disease manifestations. Once diagnosis is achieved, no SS-specific curative treatment options are available; rather treatments for SS are palliative. Thus, there is a critical need to identify etiologic events that will facilitate earlier diagnosis of SS and mitigate or abrogate the progression of this debilitating disease. Even though the immune system drives SS, few mechanistic studies of the seminal factors responsible for SS are reported. Studies in our laboratory revealed that Myeloid Differentiation Factor Primary Response Protein 88 (MyD88) is essential for pSS development. MyD88 is an adaptor molecule that is expressed ubiquitously and is required for most Toll-like receptor (TLR) signaling. Notably, TLRs are elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting TLR signaling contributes to SS pathogenesis. TLRs can be activated by both pathogen and host-derived ligands. Damage-associated molecular patterns (DAMPs) are endogenous mediators of inflammation. Upon tissue damage, DAMPs are released in soluble form where they activate TLRs. Thus, DAMPs can serve as potent and unremitting sources of chronic inflammation. B cells express TLRs and mediate pathology in SS. However, little is known about the seminal factors that drive persistent B cell activation in this disease. Our central hypotheses are that (i) TLR2 and TLR4 signaling induced by DAMPs via MyD88 drives B cell activation and (ii) DAMPs and DAMP-related autoantibodies are elevated in pSS patients. Our objectives are to evaluate the means by which DAMPs activate B cell-intrinsic MyD88-dependent pathways in pSS and to determine whether blockade of TLR2 and TLR4 signaling may be efficacious in this disease. We will examine B cells from pSS murine models and patients. We will also assess DAMP levels and DAMP-specific autoantibodies in pSS patient sera. The rationale for this proposal is that DAMPs can serve as a continuous source of chronic inflammation through activation of TLR2 and TLR4 via MyD88. DAMPs are important in the progression of several autoimmune diseases but have not been studied in depth in SS. We will test our hypotheses by completion of two specific aims: (1) To examine the role of DAMP-mediated B cell intrinsic TLR2 and TLR4 activation via MyD88 in pSS mouse models (2) To assess DAMP-mediated B cell dysregulation in pSS patients. This study is innovative because it will identify a novel source of chronic B cell stimulation in SS that may be targeted therapeutically. This work will provide new knowledge related to the role of DAMPs in pSS and other autoimmune disease that are characterized by DAMP-mediated inflammation, such as systemic lupus erythematosus and rheumatoid arthritis. This proposal is significant because it will reveal novel mechanisms that govern persistent B cell activation in pSS. Therapeutics that target B cell activation by DAMPs may diminish autoantibody production and reduce the risk of B cell lymphoma, thereby improving the management of pSS patients.