Fas (Apo-1, CD95), has been implicated in the regulation of normal and auto-specific immune responses. The role of Fas in autoimmunity is dual: it is involved in the limitation of T cell proliferation in the course of an immune response and it participates in the death of cells targeted by T cells in organ-specific autoimmune responses. Studying mice with conditional deletion of Fas from several cell types we found that mice lacking Fas from antigen presenting cells (ARC) developed systemic autoimmunity. We formulated a hypothesis that a loss of Fas receptor by APC leads to their prolonged survival, extendedpresentation of antigens to T cells, and, thus, contributes to autoimmunity observed in Fas-deficient animals and humans. We are also pursuing a hypothesis that Fas expression by target cells (insulin-producing (I cells) is critical for spontaneous development of an organ-specific autoimmune disease (type 1 diabetes). Using several already developed animal models, we will pursue the following Specific Aims:
Specific Aim 1. Determine the contribution of Fas expression by antigen-presenting T cells to normal and auto-specific immune responses. a. We will study the dynamics of Fas-sensitivity of APC and its role in the immune responses. We will also test a hypothesis that Fas-mediated elimination of APC can influence the development of chronic infections. b. We will determine how Fas-mediated death of antigen-presenting cells regulates the development of organ-specific autoimmunity (T1D).
Specific Aim 2. Determine the degree of Fas involvement in Bcell destruction during development of autoimmune diabetes. a. We will determine whether fi-cell-specific deletion of Fas affects the development of spontaneous diabetes in NOD model of T1D; b. We will determine the input of other cytotoxic mechanisms into Fas-dependent and Fas-independent apoptosis of &cells. Our studies will open new venues to regulation of immune responses through controlling the lifespan of APC and to prevention of development of autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Bourcier, Katarzyna
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University of Chicago
Schools of Medicine
United States
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Varanasi, Vineeth; Khan, Aly Azeem; Chervonsky, Alexander V (2014) Loss of the death receptor CD95 (Fas) expression by dendritic cells protects from a chronic viral infection. Proc Natl Acad Sci U S A 111:8559-64
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