Project Summary Sjgren?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. Autoimmunity is characterized by loss of tolerance to self, and autoantibodies are indicative of this failure to eliminate self-reactive B cells. While IgG autoantibodies clearly mediate pathology, our understanding of the role of IgM in the context of SS disease is surprisingly limited. Currently, treatments for SS are only palliative; there are no therapies that target disease etiology. Our central hypothesis is that self-reactive IgM is concentrated in specific innate-like B cell subsets and this IgM attenuates SS pathogenesis. Our objectives are to establish the source of IgM+ salivary B cells and to determine whether specific IgM+ B cell subsets are enriched for autoreactivity. Moreover, we will assess expression of a receptor that regulates IgM levels (Fc?R) and determine if IgM is primarily pathogenic or protective in SS. We will examine autoreactive IgM+ B cells from a pSS murine model. We will also transfer serum IgM from pSS mice to SS animals lacking B cells and assess SS-like salivary gland disease manifestations. The rationale for this proposal is that IgM is protective in many autoimmune diseases. Several studies show IgM+ B cells are dysregulated in SS and self-reactive IgM is identified in pSS mouse models and patients. Currently, B cell depletion therapies are being tested in SS patients and many such therapies reduce IgM levels significantly. While this is a promising new treatment, the consequences of IgM reduction long-term in this disease are not well understood. We will test our hypothesis by completion of two specific aims: (1) To evaluate the source and specificity of autoreactive IgM using a pSS mouse model. (2) To examine the regulation and function of IgM in pSS. This study is innovative because it will examine a class of antibody (IgM) that has not been studied in depth in SS. The specificity of IgM and whether it is primarily pathogenic or protective is unclear at present. The importance of IgM in health and disease is well established, and IgM+ B cells likely have a profound impact on immune regulation and pathophysiology in patients with autoimmunity, given the recent discovery of human IgM+ B1, memory, and plasma cells. This work will provide new knowledge related to the regulation and role of IgM in SS, and other autoimmune disease that are characterized by IgM dysregulation, such as systemic lupus erythematosus and rheumatoid arthritis. The proposal is significant because pSS patients with systemic disease manifestations tend to have elevated IgM levels. However, it is unclear at present which B cell subsets produce this IgM, and whether IgM autoantibodies in SS are pathogenic or arise as part of a compensatory protective mechanism. Thus, it is important to identify the B cells subsets responsible for autoreactive IgM production in SS patients and to determine whether IgM is protective in the context of SS disease. Therapeutics that maintain or even expand IgM-secreting B cells may ameliorate disease, and may represent a novel approach for management of SS patients.