RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus

• Published in: Disease models & mechanisms 2017-11, Vol.10 (11), p.1313-1322
• Main Authors: Mandik-Nayak, Laura, DuHadaway, James B, Mulgrew, Jennifer, Pigott, Elizabeth, Manley, Kaylend, Sedano, Summer, Prendergast, George C, Laury-Kleintop, Lisa D
• Format: Article
• Language: English
• Subjects: Age; Antigens; Autoantibodies; Autoimmune diseases; Cartilage; Cytokines; Disease; Fibroblasts; Inflammation; K/BxN; Lupus; MRL/lpr; Rheumatoid arthritis; Rho GTPases; Systemic lupus erythematosus
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.029835

During the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells so that the production of pathogenic rather than non-pathogenic autoantibodies is enabled. However, there is limited knowledge concerning how this pivotal step occurs. Here, we present genetic and pharmacological evidence of a positive modifier function for the vesicular small GTPase RhoB in specifically mediating the generation of pathogenic autoantibodies and disease progression in the K/BxN preclinical mouse model of inflammatory arthritis. Genetic deletion of RhoB abolished the production of pathogenic autoantibodies and ablated joint inflammation in the model. Similarly, administration of a novel RhoB-targeted monoclonal antibody was sufficient to ablate autoantibody production and joint inflammation. In the MRL/ mouse model of systemic lupus erythematosus (SLE), another established preclinical model of autoimmune disease associated with autoantibody production, administration of the anti-RhoB antibody also reduced serum levels of anti-dsDNA antibodies. Notably, the therapeutic effects of RhoB blockade reflected a selective deficiency in response to self-antigens, insofar as RhoB-deficient mice and mice treated with anti-RhoB immunoglobulin (Ig) both mounted comparable productive antibody responses after immunization with a model foreign antigen. Overall, our results highlight a newly identified function for RhoB in supporting the specific production of pathogenic autoantibodies, and offer a preclinical proof of concept for use of anti-RhoB Ig as a disease-selective therapy to treat autoimmune disorders driven by pathogenic autoantibodies.