High Chlamydia Burden Promotes Tumor Necrosis Factor-Dependent Reactive Arthritis in SKG Mice
High Chlamydia Burden Promotes Tumor Necrosis Factor-Dependent Reactive Arthritis in SKG Mice
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DOI：
10.1002/art.39041
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发表时间：
2015-06-01
影响因子：
13.3
通讯作者：
Thomas, Ranjeny
中科院分区：
文献类型：
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作者：
Baillet, Athan C.;Rehaume, Linda M.;Thomas, Ranjeny
目标。沙眼衣原体是一种性传播的专性细胞内病原体，在生殖器感染后会在一些人中引起炎性反应性关节炎、脊柱炎、牛皮癣样皮炎和结膜炎。易感宿主的这种炎症反应的免疫学基础尚不清楚。由于ZAP-70(W163C)突变的BALB/c(SKG)小鼠全身暴露于微生物葡聚糖后易患脊柱性关节炎，本研究比较了SKG小鼠和BALB/c小鼠对衣原体感染的反应。在生殖器或呼吸道感染鼠疫杆菌后，对结膜炎和关节炎进行临床评估，并对眼、皮肤和关节标本进行组织学分析。在脾细胞中评估衣原体主要外膜蛋白抗原特异性反应。去除FoxP3-DTR BALB/c或SKG小鼠的Treg细胞，聚合酶链式反应定量检测衣原体DNA。在阴道感染活菌5周后，雌性SKG小鼠出现关节炎、脊柱炎和牛皮癣样皮炎，而BALB/c小鼠则没有。在这两个品系的小鼠中都没有发生炎症性肠病。感染后炎性疾病的严重程度与鼠疫杆菌接种量和阴道负荷量有关。接种后第1天开始使用联合抗生素治疗可预防疾病。衣原体抗原存在于巨噬细胞中，并从感染部位扩散到淋巴器官和周围组织。与BALB/c小鼠的T细胞相比，衣原体抗原对SKG小鼠T细胞产生干扰素和白介素17的作用减弱，但肿瘤坏死因子(TNF)的反应被夸大。与之前在葡聚糖引发的关节炎中观察到的不同，没有产生自身抗体。由Treg细胞耗竭引发的加速疾病依赖于肿瘤坏死因子。在敏感的SKG株中，衣原体引起的反应性关节炎是由于缺乏细胞内病原体控制，在抗原传播时产生抗原特异性的肿瘤坏死因子，以及肿瘤坏死因子依赖型炎症性疾病。
Objective. Chlamydia trachomatis is a sexually transmitted obligate intracellular pathogen that causes inflammatory reactive arthritis, spondylitis, psoriasiform dermatitis, and conjunctivitis in some individuals after genital infection. The immunologic basis for this inflammatory response in susceptible hosts is poorly understood. As ZAP-70(W163C)-mutant BALB/c (SKG) mice are susceptible to spondylo-arthritis after systemic exposure to microbial -glucan, we undertook the present study to compare responses to infection with Chlamydia muridarum in SKG mice and BALB/c mice.Methods. After genital or respiratory infection with C muridarum, conjunctivitis and arthritis were assessed clinically, and eye, skin, and joint specimens were analyzed histologically. Chlamydial major outer membrane protein antigen-specific responses were assessed in splenocytes. Treg cells were depleted from FoxP3-DTR BALB/c or SKG mice, and chlamydial DNA was quantified by polymerase chain reaction.Results. Five weeks after vaginal infection with live C muridarum, arthritis, spondylitis, and psoriasiform dermatitis developed in female SKG mice, but not in BALB/c mice. Inflammatory bowel disease did not occur in mice of either strain. The severity of inflammatory disease was correlated with C muridarum inoculum size and vaginal burden postinoculation. Treatment with combination antibiotics starting 1 day postinoculation prevented disease. Chlamydial antigen was present in macrophages and spread from the infection site to lymphoid organs and peripheral tissue. In response to chlamydial antigen, production of interferon- and interleukin-17 was impaired in T cells from SKG mice but tumor necrosis factor (TNF) responses were exaggerated, compared to findings in T cells from BALB/c mice. Unlike previous observations in arthritis triggered by -glucan, no autoantibodies developed. Accelerated disease triggered by depletion of Treg cells was TNF dependent.Conclusion. In the susceptible SKG strain, Chlamydia-induced reactive arthritis develops as a result of deficient intracellular pathogen control, with antigen-specific TNF production upon dissemination of antigen, and TNF-dependent inflammatory disease.