Targeting RhoB as a novel approach for the treatment of Rheumatoid Arthritis (THER6P.856)

Abstract

Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by high titers of autoantibodies and increased levels of proinflammatory cytokines leading to chronic inflammation of the distal joints. Current biologic therapies, such as the B cell depleting antibody rituximab, have uncovered the important role that autoreactive B cells play in the disease process. Unfortunately, neither immunosuppressive nor biologic therapies specifically target autoreactive B cells. Here, we present data identifying a novel molecular target and newly developed therapeutic that may specifically target these cells. The small GTPase RhoB is a stress response protein that mediates tyrosine kinase receptor stimulated proliferation and migration. While much of the work on RhoB has focused on its function in cancer, we suggest a new role for this GTPase in autoimmune disease. Using the K/BxN model of RA, we show that treatment with an anti-RhoB antibody lowers autoantibody production and attenuates joint swelling. Mice genetically deficient in RhoB exhibit reduced arthritis, providing genetic confirmation of RhoB’s role in mediating autoimmunity. Interestingly, both RhoB deficient mice and mice treated with anti-RhoB Ig mounted productive antibody responses to immunization with model antigens, suggesting that RhoB may have a specific role in the autoreactive B cell. Our data suggest that RhoB antibody therapy could be a new effective therapeutic to treat antibody-mediated autoimmune diseases.