RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus.
RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus.
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DOI：
10.1242/dmm.029835
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发表时间：
2017-11-01
影响因子：
4.3
通讯作者：
Laury-Kleintop LD
中科院分区：
文献类型：
--
作者：
Mandik-Nayak L;DuHadaway JB;Mulgrew J;Pigott E;Manley K;Sedano S;Prendergast GC;Laury-Kleintop LD
在自身免疫性疾病的发展过程中，B细胞的抗体库发生了转换，从而能够产生致病的而不是非致病的自身抗体。然而，关于这一关键步骤是如何发生的，人们知之甚少。在这里，我们提供了遗传和药理学证据，证明泡状小GTP酶RhoB在K/BxN临床前炎性关节炎小鼠模型中特异性地调节致病自身抗体的产生和疾病进展。RhoB的基因缺失消除了致病自身抗体的产生，并消融了模型中的关节炎症。同样，给予一种新的RhoB靶向的单抗足以消除自身抗体的产生和关节炎症。在系统性红斑狼疮(SLE)的MRL/LPR小鼠模型中，另一种与自身抗体产生相关的自身免疫性疾病的临床前模型，给予抗RhoB抗体也降低了血清中抗dsDNA抗体的水平。值得注意的是，RhoB阻断的治疗效果反映了对自身抗原反应的选择性不足，因为RhoB缺陷小鼠和接受抗RhoB免疫球蛋白(Ig)治疗的小鼠在用模型外来抗原免疫后都产生了类似的产生抗体反应。总体而言，我们的结果突出了新发现的RhoB在支持致病自身抗体的特异性产生方面的功能，并为使用抗RhoB Ig作为疾病选择性治疗方法治疗由致病自身抗体引起的自身免疫性疾病提供了临床前的概念证据。编辑选择：小的GTP酶RhoB参与自身免疫反应的发展，特别是通过影响致病性自身抗体的产生。
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. Editors' choice: The small GTPase RhoB participates in the development of an autoimmune response, specifically by influencing the production of pathogenic autoantibodies.
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影响因子：
4.9
作者：
Abreu, Joana R. F.;Dontje, Wendy;Tak, Paul P.
通讯作者：
Tak, Paul P.
影响因子：
10.8
作者：
Kim, Ji-Sun;Choi, Dong-Ki;Kim, Yong-Sung
通讯作者：
Kim, Yong-Sung
影响因子：
6
作者：
Bravo-Nuevo, Arturo;Sugimoto, Hikaru;Benjamin, Laura E.
通讯作者：
Benjamin, Laura E.
影响因子：
5.3
作者：
Choi, Dong-Ki;Bae, Jeomil;Kim, Yong-Sung
通讯作者：
Kim, Yong-Sung
影响因子：
56.9
作者：
Lee, DM;Friend, DS;Brenner, MB
通讯作者：
Brenner, MB