Human leukocyte antigen class II transgenic mouse model unmasks the significant extrahepatic pathology in toxic shock syndrome.
Human leukocyte antigen class II transgenic mouse model unmasks the significant extrahepatic pathology in toxic shock syndrome.
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人类白细胞抗原 II 类转基因小鼠模型揭示了中毒性休克综合征中重要的肝外病理学。
DOI：
10.1016/j.ajpath.2011.02.033
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Rajagopalan,Govindarajan
中科院分区：
文献类型：
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作者：
Tilahun,AshenafiY;Marietta,EricV;Wu,Tsung-Teh;Patel,Robin;David,ChellaS;Rajagopalan,Govindarajan
在金黄色葡萄球菌和化脓性链球菌产生的外毒素中，超抗原(SAG)是迄今已知的最有效的T细胞激活剂。SAGS与几种严重疾病有关，包括中毒性休克综合征(TSS)、川崎病和败血症。然而，TSS和其他涉及SAGS的疾病的免疫发病机制仍不完全清楚。通常使用的常规实验室小鼠品系对体内的SAGIN反应不强。因此，必须通过使用ASD-氨基半乳糖(d-GalN)等致敏剂，人为地使它们对TSS敏感，这种致敏剂会使疾病只偏向肝脏，因此不能代表人类的疾病。用表达HLAII类分子的转基因小鼠鉴定SAG诱导的TSS，这些分子对不含d-GalN的TSS非常敏感。HL A-DR3转基因小鼠重现了人类的TSS，并伴有广泛的多器官炎症，影响到肺、肝、肾、心脏和小肠。T淋巴细胞(包括CD_4~+和CD_8~+)、中性粒细胞和巨噬细胞大量浸润。特别是，小肠的病理变化广泛，并伴随着肠细胞吸收功能的显著改变。与TSS致敏模型中的大量肝功能衰竭不同，本研究的结果表明，肠道功能障碍可能是导致TSS患者高发病率和死亡率的关键致病事件。
Among the exotoxins produced byStaphylococcus aureusandStreptococcus pyogenes, the superantigens (SAgs) are the most potent T-cell activators known to date. SAgs are implicated in several serious diseases including toxic shock syndrome (TSS), Kawasaki disease, and sepsis. However, the immunopathogenesis of TSS and other diseases involving SAgs are still not completely understood. The commonly used conventional laboratory mouse strains do not respond robustly to SAgsin vivo. Therefore, they must be artificially rendered susceptible to TSS by using sensitizing agents such asd-galactosamine (d-galN), which skews the disease exclusively to the liver and, hence, is not representative of the disease in humans. SAg-induced TSS was characterized using transgenic mice expressing HLA class II molecules that are extremely susceptible to TSS withoutd-galN. HLA-DR3 transgenic mice recapitulated TSS in humans with extensive multiple-organ inflammation affecting the lung, liver, kidneys, heart, and small intestines. Heavy infiltration with T lymphocytes (both CD4+and CD8+), neutrophils, and macrophages was noted. In particular, the pathologic changes in the small intestines were extensive and accompanied by significantly altered absorptive functions of the enterocytes. In contrast to massive liver failure alone in thed-galN sensitization model of TSS, findings of the present study suggest that gut dysfunction might be a key pathogenic event that leads to high morbidity and mortality in humans with TSS.