Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice
Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice
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DOI：
10.1016/j.jaut.2009.12.007
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发表时间：
2010-08-01
影响因子：
12.8
通讯作者：
Taneja, Veena
中科院分区：
文献类型：
--
作者：
Behrens, Marshall;Trejo, Theodore;Taneja, Veena
HLA II类等位基因DRB 1 *0401与人类风湿性关节炎以及小鼠胶原诱导的关节炎的易感性相关。在人类和DR 4转基因小鼠中，主要是雌性发生关节炎;然而，性别偏见的机制仍不清楚。我们研究了DR 4与关节炎性别偏倚相关的分子基础。在这里，我们表明，DR 4雄性和雌性小鼠的差异抗原特异性免疫机制导致雌性小鼠的易感性增加。与男性相比，女性的B细胞过度活跃，并强烈呈递DR限制性肽。抗原特异性反应显示雌性产生B细胞调节细胞因子如IL-13，而雄性产生IFN γ。雄性转基因小鼠具有更高数量的T和B调节细胞。雄性小鼠外源性供应17 β雌二醇导致DR 4的表达增强和对DR 4限制性肽的抗原特异性反应。另一方面，阉割增加了关节炎的发病率。我们认为，性别偏见在关节炎涉及B细胞和抗原的HLA-DR 4导致激活的自身反应性细胞和自身抗体的生产在女性，而男性的调节B细胞保护他们免受发病机制。表达RA易感单倍型的转基因小鼠模拟人类RA，可能对研究患者中观察到的性别差异有价值。(C)2009爱思唯尔有限公司保留所有权利。
HLA class II allele DRB1*0401 is associated with predisposition to Rheumatoid Arthritis in humans as well as collagen-induced arthritis in mice. Predominantly females develop arthritis in humans and DR4 transgenic mice; however the mechanism of sex-bias is still unknown. We have investigated the molecular basis by which DR4 is associated with sex-bias of arthritis. Here we show that differential antigen-specific immune mechanisms in DR4 male and female mice lead to increased susceptibility in female mice. B cells are hyperactive and present DR-restricted peptides robustly in females compared to males. Antigen-specific response showed that females produced B cell modulating cytokines like IL-13 while males produced IFN gamma. Male transgenic mice have higher number of T and B regulatory cells. An exogenous supply of 17 beta estradiol in male mice led to enhanced expression of DR4 and antigen-specific response to DR4-restricted peptides. On the other hand, castration increased the incidence of arthritis. We propose that sex-bias in arthritis involves B cells and presentation of antigen by HLA-DR4 leading to activation of autoreactive cells and autoantibodies production in females, while regulatory B cells in males protect them from pathogenesis. The transgenic mice expressing RA susceptible haplotype simulate human RA and may be valuable to study gender differences observed in patients. (C) 2009 Elsevier Ltd. All rights reserved.