RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus
| Autor: | Laura Mandik-Nayak, James B. DuHadaway, Jennifer Mulgrew, Elizabeth Pigott, Kaylend Manley, Summer Sedano, George C. Prendergast, Lisa D. Laury-Kleintop |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Disease Models & Mechanisms, Vol 10, Iss 11, Pp 1313-1322 (2017) |
| Druh dokumentu: | article |
| ISSN: | 1754-8403 1754-8411 |
| DOI: | 10.1242/dmm.029835 |
| Popis: | 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/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 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. |
| Databáze: | Directory of Open Access Journals |
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