Sex Differences And Rheumatoid ArthritisMain Category: Arthritis NewsArticle Date: 03 Jan 2007 - 11:00 PSTCharacterized by chronic synovial tissue inflammation, increasing erosions of cartilage and bone, and eventual destruction of joints, rheumatoid arthritis (RA) is a complex and confounding autoimmune disease. It is associated with a variety of genetic and environmental factors and known to strike women about three times as frequently as men. A major obstacle to investigating this clear sex bias has been the lack of a laboratory rat or mouse that mimics human RA. Until now. Researchers at the Mayo Clinic have produced a new breed of transgenic mice with autoimmune responses similar to human RA patients and increased incidence of the disease in females. Featured in the January 2007 issue of Arthritis & Rheumatism, this humanized mouse model may be valuable for not only studying sex differences in RA, but also for understanding why women are particularly vulnerable to autoimmunity and for developing future therapeutic strategies. For this novel experiment, mice were genetically modified with a well-established RA susceptibility, the allele HLA-DRB1*0401. This gene variant is linked to anti-cyclic citrullinated peptide (anti-CCP) autoantibodies, which precede the onset of RA. Collagen-induced arthritis (CIA) in the mice was initiated by injection of type II collagen. These transgenic mice were then tested for incidence and severity of arthritic symptoms, as well as assessed for vulnerability to the disease by sex. Of the transgenic mice that developed arthritis, all produced rheumatoid factors and anti-CCP autoantibodies strikingly similar to humans. These included auto antibodies to type II collagen (CII), increased expression of class II molecules T cells, and production of proinflammatory cytokines. In addition, female mice developed arthritis at a higher rate than the male mice, by a ratio greater than 3 to 1, and exhibited all the disease hallmarks at higher levels. Commenting on this study's implications for further understanding and future treatment of RA, Maurizio Cutolo, M.D., a researcher with the Department of Rheumatology, the University of Genoa, Italy, considers its potential to shed light on the role of estrogen and androgen in the disease. "Sex hormone balance is a crucial factor in the regulation of immune and inflammatory responses," Dr. Cutolo notes. "Modulation of this balance should represent part of advanced biologic treatments for RA. Sharing the sex hormone effects of the human disease, the new humanized mouse may provide a better model with which to study the pathogenesis and treatment of arthritis." >本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领性别差异与类风湿性关节炎类风湿性关节炎（RA）是一种复杂的自身免疫性疾病，以慢性滑液性组织炎、软骨和骨进行性受损，最终导致关节破坏为特征. 本病的发生与一系列遗传和环境因素相关；已知的男女发病的性别比例是3：1. 对此“性别差异”的研究还存在实验技术上的困难，因为迄今为止还没有开发出来能完全模仿人类RA的大鼠或小鼠模型.梅奥诊所的研究者们开发出了一种新的转基因小鼠品种，该小鼠可产生类似人类RA患者的自身免疫反应，并且发病的性别比例也与人类相似. 2007年1月期的关节炎和风湿病杂志特别在显著位置刊登该文，这一“人化”的小鼠模型可能不仅对研究人类RA的性别差异十分珍贵，而且还有助于理解为何妇女对于自身免疫疾病特别易感，还有助于未来治疗策略的研发.这一全新的尝试是把一个已稳定建立的具有RA易感性的等位基因HLA-DRB1*040引入小鼠体内使其发生突变. 这一基因突变体与抗环瓜氨酸肽（anti-CPP）抗体有关，其往往出现于RA的发病之前. 小鼠胶原诱发的关节炎（CIA）是由注射二型胶原引起的. 这些转基因小鼠随后接受了关节炎症状发生率和严重程度的测试，以及性别发病率的测试. 在那些形成关节炎的转基因小鼠中，无一例外的像人类患者一样均产生类风湿因子和anti-CPP抗体. 包括针对二型胶原（CII）的自身抗体，还有二型T淋巴细胞表达的升高以及致炎细胞因子的产生. 另外，雌性小鼠形成关节炎的比例要远大于雄性，其比例甚至大于3:1, 而且所有的疾病指标都处于较高的水平. 该研究对于进一步的理解RA和未来的有效治疗方案的研发有重要意义；对此意大利热那亚大学风湿病学研究人员Maurizio Cutolo博士发表了自己的评论，他认为该研究对于理解性激素在该病发生中的作用打开了一扇窗户. “在调节免疫和炎症反应中性激素是一个很关键的因素”，Cutolo博士强调，“对这一平衡的调节可能代表了RA的高级生物学治疗的一部分. 通过这一人化小鼠提供有关性激素对疾病影响的信息，从而可为关节炎的病理学和治疗的研究提供一个很好的模型”