PROJECT SUMMARY The overarching theme of the Johns Hopkins Autoimmunity Center of Excellence (ACE) is that distinct immune cell subsets are the major drivers of immunopathogenesis in different autoimmune diseases, and that targeted therapies at a critical juncture of disease trajectory will modify or halt the propagation of disease. The primary clinical project led by Pavan Bhargava, MBBS, MD, proposes to selectively target effector-memory T cells, class- switched memory B cells, and inflammatory microglia in secondary progressive multiple sclerosis (SPMS) by blocking the potassium channel Kv1.3 using dalazatide. Utilizing, cutting-edge immunological, imaging and biomarker assessments, this trial seeks to identify pathogenic immune cells driving disease in SPMS while testing a novel treatment strategy that could be applied to a range of other autoimmune disorders. The alternate clinical project led by Julie Paik, MD, MHS, proposes to target B-cells using a novel, third generation anti-CD 20 agent, ublituximab, early in the course of active, autoantibody positive myositis (excluding inclusion body myositis). The current challenge in the therapeutic landscape of myositis is that B-cell depleting agents are considered third line despite the wealth of literature supporting their efficacy. Therefore, this proposed Phase 2 randomized, double-blind trial of ublituximab in myositis can potentially lead to a paradigm shift in the utilization of B-cell depleting agents as first-add on therapy to background immunosuppression. And lastly, the collaborative project led by Elias Sotrichos, MD, seeks to perform deep phenotyping of single immune cells in the peripheral blood and cerebrospinal fluid in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) to identify subsets that are involved in disease pathogenesis. All three projects highlight the extraordinary cross-discipline synergy that exists at Johns Hopkins through the collaborative resources of the Johns Hopkins Institutional Precision Medicine initiative. The establishment of the Johns Hopkins ACE will further leverage the Multiple Sclerosis and Myositis Precision Medicine Centers of Excellence to achieve the following aims: 1) Enable the implementation and execution of innovative, investigator initiated therapeutic trials, (2) Discover key cellular drivers of autoimmunity through modification of immune function with investigational therapeutic agents, and (3) Increase interdisciplinary collaborations within Johns Hopkins and the broader ACE network to advance the understanding and treatment of autoimmune diseases. These aims will be achieved through the resources of the Administrative coordination group which will be a conduit to integrate all scientific and administrative oversight of the Hopkins ACE. Additionally, the funds management core will provide support to studies throughout the ACE network, while the Biobanking core can handle a varie...