Requirements of NK cells and proinflammatory cytokines in T cell-dependent neonatal autoimmune ovarian disease triggered by immune complex
Requirements of NK cells and proinflammatory cytokines in T cell-dependent neonatal autoimmune ovarian disease triggered by immune complex
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DOI：
10.4049/jimmunol.173.2.1051
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发表时间：
2004-07-15
影响因子：
4.4
通讯作者：
Tung, KSK
中科院分区：
文献类型：
--
作者：
Setiady, YY;Pramoonjago, P;Tung, KSK
最近描述了一种新生儿自身免疫性疾病模型，其中针对鼠透明带 3 的表位特异性自身抗体会在新生小鼠而非成年小鼠中诱导严重卵巢疾病（新生儿 AOD）。自身抗体与内源性卵巢透明带3形成免疫复合物，并触发致病性CD4(+) T细胞反应。新生儿主要易感性的基础尚未明确。在这项研究中，对新生儿 AOD 中的先天免疫（包括新生儿 NK 细胞）进行了调查。新生儿脾脏含有易于检测的 NK1.1(+)TCRVbeta(-) 细胞，但不含 NK1.1(+)TCRVbeta(+) 细胞。 NK1.1(+)TCRVbeta(-)细胞的Ab耗竭抑制了新生儿AOD的发育。此外，在新生儿 AOD 过继转移中，当供体或受体 NK 细胞耗尽时，受体疾病得到改善。因此，NK 细胞在疾病的诱导期和效应期均发挥作用。 IFN-γ是由新生儿NK细胞在体内产生的，它在新生儿AOD中可能很重要。事实上，患有新生儿 AOD 的卵巢表达高水平的 IFN-γ 和 TNF-α，这与疾病的严重程度相关，并且该疾病被 IFN-γ 或 TNF-α Ab 抑制。重要的是，重组 IFN-γ 会加剧疾病，并且用 IFN-γ Ab 治疗 T 细胞供体也显着减少了新生儿 AOD 的过继转移。最后，FcgammaRIII 缺陷小鼠的新生儿 AOD 得到改善，而 FcgammaRIIB 缺陷小鼠的新生儿 AOD 得到增强。我们得出的结论是，新生儿 NK 细胞在新生儿自身免疫性疾病发病机制的多个阶段促进致病性 T 细胞反应。先天系统的其他介质也在新生儿 AOD 中发挥作用，包括促炎细胞因子和 FcgammaRIII 信号传导。
A model of neonatal autoimmune disease has been described recently in which an epitope-specific autoantibody to murine zona pellucida 3 induces severe ovarian disease in neonatal, but not adult, mice (neonatal AOD). The autoantibody forms immune complex with endogenous ovarian zona pellucida 3, and a pathogenic CD4(+) T cell response is triggered. The basis for the predominant neonatal susceptibility has not been clarified. In this study innate immunity, including neonatal NK cells, in neonatal AOD was investigated. Neonatal spleen contained readily detectable NK1.1(+)TCRVbeta(-), but not NK1.1(+)TCRVbeta(+), cells. Ab depletion of NK1.1(+)TCRVbeta(-) cells inhibited neonatal AOD development. Moreover, in adoptive transfer of neonatal AOD, recipient disease was ameliorated when either donor or recipient NK cells were depleted. Thus, NK cells operate in both induction and effector phases of the disease. IFN-gamma was produced by neonatal NK cells in vivo, and it may be important in neonatal AOD. Indeed, ovaries with neonatal AOD expressed high levels of IFN-gamma and TNF-alpha which correlated with disease severity, and the disease was inhibited by IFN-gamma or TNF-alpha Ab. Importantly, disease was enhanced by recombinant IFN-gamma, and treatment of T cell donors with IFN-gamma Ab also significantly reduced adoptive transfer of neonatal AOD. Finally, neonatal AOD was ameliorated in mice deficient in FcgammaRIII and was enhanced in FcgammaRIIB-deficient mice. We conclude that neonatal NK cells promote pathogenic T cell response at multiple stages during neonatal autoimmune disease pathogenesis. Also operative in neonatal AOD are other mediators of the innate system, including proinflammatory cytokines and FcgammaRIII signaling.