Analysis of MyD88-mediated activation in Sjogren's disease

Project summary Primary Sjögren’s disease (pSD) is a systemic autoimmune disease that primarily affects women. In pSD, exocrine tissue is damaged, resulting in loss of tears and saliva. Additionally, many serious systemic disease manifestations are observed. Once diagnosis is achieved, no pSD-specific curative treatment options are available; rather treatments for pSD are palliative. Thus, there is a critical need to identify underlying disease mechanisms that will facilitate earlier diagnosis of pSD and development of therapeutics that mitigate the progression of this debilitating disease. To discover the underlying mechanisms that govern pSD pathogenesis, our current work focuses on MyD88, a protein that is central to both innate and adaptive immunity. MyD88 is a ubiquitously expressed adaptor molecule employed by all immune cells that is required for signaling by most Toll-like receptors (TLRs) and IL-1 receptor (IL-1R) family members. Our prior and current NIH-funded studies have established that MyD88 is required for pSD manifestations, including loss of salivary flow, autoantibody production, and renal and pulmonary inflammation. This is significant because specific ligands and receptors that activate MyD88-dependent pathways are well-established drug targets for other autoimmune disorders. However, these remain largely unknown in pSD. Our central hypothesis is that MyD88-dependent TLR agonists and IL-1 family members drive pSD pathogenesis. Our objective is to identify specific disease mechanisms employed by MyD88-dependent TLRs and IL-1R family members that govern sex- and tissue-specific pSD manifestations. The rationale for this proposal rests on the fact that activation of MyD88-mediated signaling pathways contributes to many autoimmune diseases. Both salivary tissue and immune cells express receptors that promote inflammation via MyD88. Our studies in pSD mice deficient in MyD88 demonstrate that MyD88 is crucial for pSD pathogenesis; however, the specific cell types, receptors, and signaling pathways that are activated in pSD in a MyD88-dependent manner are incompletely understood. We will test our hypothesis using the following specific aims: (1) Determine how TLR7 activation by distinct ligands in specific tissues alters pSD manifestations, (2) Examine the role of IL-36 family cytokines in pSD pathogenesis, and (3) Evaluate crosstalk between MyD88-dependent TLRs and IL-1 family members in pSD. This study is innovative because it will facilitate discovery of novel inhibitors that can be utilized as therapeutic agents to mitigate chronic MyD88-mediated inflammation in both immune and epithelial cells using cutting-edge technologies and novel mouse models. This proposal is significant because it will reveal new mechanisms that govern chronic inflammation in pSD. Insights obtained from the proposed studies will reveal novel pathways that can be targeted to treat pSD and other autoimmune diseases.