Project-002

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The overarching objective of the Emory Autoimmunity Center of Excellence (ACE) U19 is to decipher the molecular programs responsible for the aberrant effector immune responses that lead to autoimmune disease. Specifically, based on the work performed by the Emory ACE during the current funding cycle, we postulate that epigenetic regulation of effector B cell differentiation and function is a critical pathogenic component of Systemic Lupus Erythematosus (SLE). Further, we contend that disease-related epigenetic imprinting is first established at early stages of B cell development and then maintained throughout the differentiation of naïve cells into their effector progeny upon activation by antigens and co- stimulatory pathways. Finally, we propose that SLE will also be characterized by abnormal regulation of other critical effector immune responses, namely CD8 T cells and in particular, the stem-like population responsible for the maintenance of antigen-specific responses in chronic viral infections and anti-tumor responses in patients treated with checkpoint inhibitors. The fundamental goals of the Emory ACE are: 1) to understand B cells and CD8 T cells dysregulation in human SLE; and 2) to assemble a scientific and technological platform that engages other ACE U19 and UM1 Centers to perform similar studies in other immune cells and autoimmune disorders. The specific aims of the Emory ACE U19 are: Aim 1: To establish an Administrative Core (I. Sanz, Core Director) for the successful operation of the ACE U19 Scientific Program and its interaction with the ACE Network; Aim 2: To develop a highly integrated Emory ACE U19 Scientific Program comprised of the following components: Principal Project (Sanz, PI): Mechanisms of B cell dysregulation in human SLE; Collaborative Project (Boss, PI): Epigenetic regulation of autoimmune responses; Pilot Project (Ahmed, PI): Characterization of stem-like CD8 T cells in SLE. The expected results will unravel disease pathogenesis; segment patients; design personalized therapies; and develop biomarkers of disease onset, evolution, and outcome. Our efforts will naturally dovetail with the mission of the UM1 ACEs centers and contribute greatly to the charter mission of the ACE network.