SLE is a chronic and debilitating autoimmune disease afflicting more than 1.5 million Americans and requires lifelong immunosuppressive therapies that have potentially life-threatening and damaging side effects. The loss of immunological tolerance is fundamental to this disease and B cells are a central player in its etiology, which is underscored by the efficacy of a B cell depletion therapy. Because not all patients benefit from this treatment, and the elimination of B cells can compromise a patient's defenses against pathogens, therapies that target only autoreactive B cells would be of great benefit to patients. Therefore, there is a critical need to identify molecular mechanisms of immune tolerance because without it, the development of a targeted therapeutic approach is unlikely to occur. Our preliminary data shows that NLRC3, a member of the nucleotide-binding, leucine repeat-containing (NLR) family of """"""""danger"""""""" sensors, regulates toll like receptor (TLR)-mediated activation of autoreactive B cells. This is a novel finding, as a function of NLR family proteins i B cells is unknown. The long-term goal of our work is to understand the molecular mechanisms of B cell tolerance with the eventual goal of developing targeted therapies for the treatment of autoimmune diseases. The objective of this proposal is to determine the mechanism by which NLRC3 blocks the activation of autoreactive B cells and to determine whether its expression affects autoreactive B cell responses in health and disease. Our central hypothesis is that NLRC3 inhibits TLR- mediated autoreactive B cell activation to prevent autoimmune disease. The rationale is that once we determine the mechanism of action of NLRC3, then new therapies that target this mechanism could be developed to prevent autoreactive B cell activation. We propose two specific aims. 1) To determine the mechanism of NLRC3-mediated inhibition of TLR activation in B cells, and 2) to determine whether NLRC3 regulates normal and pathogenic B cell responses to self-antigens.
For Aim 1, we will use we will use primary autoreactive B cells that are NLRC3-sufficient and -deficient to identify the TLR signaling intermediates that are regulated by NLRC3.
For Aim 2, we will determine the ability of self-antigen to activate NLRC3-deficient B cells from normal and autoimmune prone mice, and determine whether autoimmune disease prone mice develop accelerated more severe disease in the absence of NLRC3. We expect to find that NLRC3 blocks TLR- mediated B cell activation through its ability to prevent NF-kB and IRF-5 translocation to the nucleus. In addition, we expect to find that NLRC3 prevents autoreactive B cell activation and attenuates the onset and severity of disease in autoimmune mice. This work is innovative in our opinion because NLR protein involvement in B cell tolerance constitutes a completely new regulatory mechanism. Our results will have an important positive impact because they could lead to the eventual development of new therapies designed to specifically target the mechanisms of tolerance loss.
The proposed research is relevant to public health because determining the mechanism of B cell tolerance is ultimately expected to increase understanding of the underlying mechanisms leading to the loss of tolerance in systemic lupus erythematosus. This would have a positive impact because it could lead to the development of new therapies for this and other autoimmune diseases. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental and translational knowledge that will help reduce the burdens of human disease.
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