RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus
Abstract
During the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells favoring the production of pathogenic versus non-pathogenic autoantibodies. 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 model of inflammatory arthritis. Genetic deletion of RhoB abolished the production of pathogenic autoantibodies and ablated joint inflammation in the model. In like manner, administration of a novel RhoB-targeted monoclonal antibody was sufficient to ablate autoantibody production and joint inflammation. In the MRL/lpr 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 Ig both mounted comparable productive antibody responses after immunization with a model foreign antigen. Overall, our results highlight a novel 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2017
- Source ID
- 10.1242/dmm.029835
Entities
People
- Elizabeth Pigott
- George C. Prendergast
- James B DuHadaway
- Jennifer Mulgrew
- Kaylend Manley
- Laura Mandik-nayak
- Lisa D Laury-Kleintop
- Summer Sedano
Organizations
- Lankenau Institute for Medical Research
- Office of Extramural Research
- Thomas Jefferson University
- United States Department of Defense