There is a fundamental need to understand how the immune system discriminates self-antigens and regulates potentially harmful autoimmune responses. Increasing evidence from genetics and functional studies indicate that innate immune signaling in response to products caused by cell death is a major etiological factor in autoimmune and chronic inflammatory disease. Our long-term goal is to better understand how immune tolerance to antigens derived from apoptotic cells and other self-antigens is maintained and how this can break down in autoimmune diseases. The objective in this application is to understand how av integrins and components of the autophagy pathway contribute to B cell tolerance. Our central hypothesis is that av- mediated activation of autophagy components regulates TLR signaling in B cells, limiting cell proliferation, differentiation and production of autoantibodies. The rationale for this grant is that the proposed work will define the role of av-mediated autophagy in B cell tolerance, and develop better models for autoimmune disease. Furthermore, this work has the potential to translate into new therapeutic approaches through the use of existing compounds that target av and autophagy. Based on strong preliminary data, our hypothesis will be tested in three specific aims: (1) Determine how av regulates development of autoreactive B cells and lupus- like autoimmunity in mice. av-knockout mice crossed with an autoreactive BCR heavy chain transgenic mouse strain will be used to follow development of autoreactive B cells, and understand how av regulates tolerance and response to self-antigen. (2) Determine how av-mediated regulation of type I-IFNs regulates B cell tolerance. We will test how increased type I IFN production by B cells and plasmacyotid DCs contribute to B cell activation. (3) Test the hypothesis that non-canonical autophagy regulates B cell TLR signaling to promote tolerance. We will analyze the role of Rubicon in autoreactive B cell activation, and evaluate a potential new component of non-canonical autophagy, Atg16l2 Our approach is innovative as it focuses on a novel role for integrins and autophagy components in regulating immune signaling in B cells. The proposed work is significant because it will establish a new paradigm for B cell recognition of potential self-antigens in immune tolerance and provide a mechanism by which this occurs. Ultimately this has the potential to change our understanding of how immune tolerance is maintained and how autoreactive B cells may escape control to promote autoimmunity.
The proposed research is relevant to the mission of the NIH because a better understanding of the mechanisms by which immune responses to self-antigens will contribute to treatment of inflammatory and autoimmune disorders. The proposed work is of particular relevance to systemic lupus erythematosus, and rheumatoid arthritis.
