Interferon Gamma-Dependent Intestinal Pathology Contributes to the Lethality in Bacterial Superantigen-Induced Toxic Shock Syndrome

Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon-γ (IFN-γ), followed by multiple organ dysfunction and often death. As IFN-γ possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-γ or targeted disruption of IFN-γ gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-γ+/+ mice became sick and succumbed to TSS, HLA-DR3.IFN-γ−/− mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-γ−/− transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA-DR3.IFN-γ−/− transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vβ8+ CD4+ and CD8+ T cells was even more pronounced in HLA-DR3.IFN-γ−/− transgenic mice when compared to HLA-DR3.IFN-γ+/+ mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-γ+/+ and HLA-DR3.IFN-γ−/− transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-γ+/+ transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-γ−/− transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-γ+/+ but not HLA-DR3.IFN-γ−/− mice during TSS. Overall, IFN-γ seemed to play a lethal role in the immunopathogenesis of TSS by inflicting fatal small bowel pathology. Our study thus identifies the important role for IFN-γ in TSS.

由金黄色葡萄球菌（Staphylococcus aureus）与化脓性链球菌（Streptococcus pyogenes）的超抗原外毒素（superantigen exotoxins）引发的中毒性休克综合征（Toxic shock syndrome, TSS），以强烈的T细胞活化（T cell activation）、多种细胞因子（cytokines）——包括干扰素-γ（interferon-γ, IFN-γ）——的全身水平显著升高为特征，后续可进展为多器官功能障碍，常导致死亡。鉴于干扰素-γ兼具促炎与抗炎特性，本研究明确了其在中毒性休克综合征发病机制中的作用。通过抗体介导的体内IFN-γ中和或靶向敲除IFN-γ基因，可使HLA-DR3转基因小鼠（HLA-DR3 transgenic mice）显著抵御致死性中毒性休克综合征。全身给予高剂量葡萄球菌肠毒素B（SEB）攻击后，HLA-DR3.IFN-γ+/+小鼠会患病并死于中毒性休克综合征，而HLA-DR3.IFN-γ−/−小鼠则保持健康，且可显著抵御SEB诱导的致死效应。SEB诱导的全身性细胞因子风暴（cytokine storm）在HLA-DR3.IFN-γ−/−转基因小鼠中显著减弱。该类小鼠血清中多种细胞因子（IL-4、IL-10、IL-12p40及IL-17）与趋化因子（chemokines）（KC、RANTES、嗜酸性粒细胞趋化蛋白（eotaxin）及单核细胞趋化蛋白-1（MCP-1））的浓度均显著降低。然而，SEB诱导的脾脏T细胞增殖未受影响；与HLA-DR3.IFN-γ+/+小鼠相比，HLA-DR3.IFN-γ−/−转基因小鼠中SEB反应性TCR Vβ8+ CD4+及CD8+ T细胞的增殖甚至更为显著。对多个重要器官开展系统性组织病理学检查后发现，中毒性休克综合征发生期间，HLA-DR3.IFN-γ+/+与HLA-DR3.IFN-γ−/−转基因小鼠的肺脏及肝脏均出现程度相当的严重炎症改变。值得注意的是，该时期HLA-DR3.IFN-γ+/+转基因小鼠的小肠可见显著病理改变，而HLA-DR3.IFN-γ−/−转基因小鼠的小肠组织结构得以完整保留。与上述组织病理学变化一致，中毒性休克综合征发生期间，HLA-DR3.IFN-γ+/+小鼠的肠道大分子通透性显著升高，而HLA-DR3.IFN-γ−/−小鼠未出现该变化。综上，干扰素-γ似乎通过引发致命性小肠病变，在中毒性休克综合征的免疫发病机制中发挥致死性作用。本研究因此明确了干扰素-γ在中毒性休克综合征中的关键作用。