Wednesday, April 24, 2024
4/24/2024
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 development of therapeutics that mitigate the progression of this debilitating disease. 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) and IL-1 receptor (IL-1R) family member signaling. Notably, TLRs and IL-1R family members are elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting these receptors contribute to SS. The specific ligands and receptors that mediate activation of Myd88-dependent pathways in pSS have not, as yet, been evaluated in depth. TLR7 is a MyD88-dependent endosomal TLR that is implicated in many autoimmune diseases, although its role in pSS remains largely unknown. Our central hypothesis is that B cell-intrinsic TLR7-dependent signaling networks drive pSS pathogenesis. Our objective is to identify how TLR7 activation of B cells governs pSS disease pathogenesis. We will employ a pSS mouse model (NOD.B10) and a knockout strain of NOD.B10 mice developed in our laboratory that lacks expression of TLR7. These mice provide a unique model system to examine the role of TLR7 in pSS directly. The rationale for this proposal rests on the fact that in lupus, a related autoimmune disease, TLR7 activation of B cells is critical for disease development. Our preliminary data reveal that TLR7 agonism accelerates pSS development and promotes expansion of age-associated B cells (ABCs), a B cell subset implicated in autoimmunity in mice and humans, but one that remains poorly understood in pSS. We will test our hypothesis by completion of two specific aims: (1) Assess TLR7-dependent B cell activation in pSS mice in vitro and (2) Identify specific B cell subsets that mediate pathology in pSS in a TLR7-dependent manner in vivo. This study is innovative because it will uncover new mechanisms related to the role of MyD88-dependent signaling networks in pSS and will identify how TLR7 activation in B cells governs specific disease manifestations. This proposal is significant because it will reveal new mechanisms that govern chronic inflammation in pSS. Insights obtained from the proposed studies will reveal novel pathways and specific cell types that can be targeted to treat pSS and other autoimmune diseases. The fellowship training plan details a comprehensive educational training experience for the PI, including research experience, development of scientific writing and presentation skills, and participation in national meetings. The environment at the University of Buffalo is outstanding, as the Department of Oral Biology has a long history of preparing mentees for successful careers in the oral sciences.
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