Keith Rebecca C, Sokolove Jeremy, Edelman Benjamin L, Lahey Lauren, Redente Elizabeth F, Holers V Michael, Sakaguchi Shimon, Robinson William H, Riches David W H
National Jewish Health, Denver, CO 80206, USA.
Arthritis Rheum. 2013 Jun;65(6):1487-93. doi: 10.1002/art.37943.
Rheumatoid arthritis (RA) is a sexually dimorphic inflammatory autoimmune disease with both articular and extraarticular disease manifestations, including RA-associated interstitial lung disease. Low levels of testosterone have been linked to disease severity in men with RA, and supplemental testosterone has been shown to improve RA symptoms in both postmenopausal women and men with low levels of testosterone. The mechanisms by which sex and sex steroids affect the immune system and autoimmunity are poorly understood. The purpose of this study was to examine the protective effects of testicular-derived sex hormones on the development of joint and lung disease in an autoimmune mouse model.
Arthritis prevalence and severity were assessed in orchiectomized, sham-orchiectomized, and intact male SKG mice as well as in female SKG mice over a 12-week period after intraperitoneal injection of zymosan. Lung tissues were evaluated by quantifying cellular accumulation in bronchoalveolar lavage fluid, collagen levels, and histologic changes. An antigen microarray was used to evaluate autoantibody generation under each experimental condition.
Female SKG mice developed arthritis and lung disease at increased prevalence and severity as compared to intact male mice. The absence of testosterone after orchiectomy led to increased arthritis, lung disease, and autoantibody generation in orchiectomized male mice as compared to intact male mice.
SKG mice represent an authentic sexually dimorphic mouse model of both the joint and lung disease seen in humans with RA. Testosterone protects against the development of joint and lung disease in male SKG mice.
类风湿关节炎（RA）是一种具有性别差异的炎症性自身免疫性疾病，有关节和关节外疾病表现，包括类风湿关节炎相关的间质性肺疾病。睾酮水平低与男性类风湿关节炎患者的疾病严重程度相关，补充睾酮已被证明可改善绝经后女性和睾酮水平低的男性的类风湿关节炎症状。性别和性类固醇影响免疫系统和自身免疫的机制尚不清楚。本研究的目的是在自身免疫小鼠模型中研究睾丸源性性激素对关节和肺部疾病发展的保护作用。
在腹腔注射酵母聚糖后的12周内，评估去势、假去势和完整雄性SKG小鼠以及雌性SKG小鼠的关节炎患病率和严重程度。通过定量支气管肺泡灌洗液中的细胞积聚、胶原蛋白水平和组织学变化来评估肺组织。使用抗原微阵列评估每种实验条件下自身抗体的产生。
与完整雄性小鼠相比，雌性SKG小鼠患关节炎和肺部疾病的患病率和严重程度增加。与完整雄性小鼠相比，去势后睾酮缺乏导致去势雄性小鼠的关节炎、肺部疾病和自身抗体产生增加。
SKG小鼠代表了人类类风湿关节炎中所见关节和肺部疾病的真实性别差异小鼠模型。睾酮可预防雄性SKG小鼠关节和肺部疾病的发展。
