Department of Anesthesiology, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Mol Immunol. 2010 Feb;47(5):972-81. doi: 10.1016/j.molimm.2009.11.022. Epub 2009 Dec 9.
Recent work reveals that the innate immune system is able to recognize self-targets and initiate an inflammatory response similar to that of pathogens. One novel example of this innate autoimmunity is ischemia/reperfusion (I/R) injury, in which reperfusion of the ischemic tissues elicits an acute inflammatory response activated by natural IgM (nIgM) binding to ischemia-specific self-antigens, which are non-muscle myosin heavy chains type II (NMHC-II) subtype A and C. Subsequently, the complement lectin pathway is activated and eventually tissue injury occurs. Although earlier studies in the intestinal model showed that the classical complement pathway did not initiate I/R injury, C1q deposition was still observed in the local injured tissues by imaging analysis. Moreover, the involvement of the alternative complement pathway became unclear due to conflicting reports using different knockout mice. To explore the immediate downstream pathway following nIgM-ischemic antigen interaction, we isolated the nIgM-ischemic antigen immunocomplexes from the local tissue of animals treated in the intestinal I/R injury model, and examined the presence of initial molecules of three complement pathways. Our results showed that mannan-binding lectin (MBL), the early molecule of the lectin pathway, was present in the nIgM-ischemic Ag immunocomplex. In addition, C1q, the initial molecule of the classical pathway was also detected on the immunocomplex. However, Factor B, the early molecule in the alternative pathway, was not detected in the immunocomplex. To further examine the role of the alternative pathway in I/R injury, we utilized Factor B knockout mice in the intestinal model. Our results showed that Factor B knockout mice were not protected from local tissue injury, and their complement system was activated in the local tissues by nIgM during I/R. These results indicated that the lectin complement pathway operates immediately downstream of the nIgM-ischemic antigen interaction during intestinal I/R. Furthermore, the classical complement pathway also appears to interact with the of nIgM-ischemic antigen immunocomplex. Finally, the alternative complement pathway is not involved in I/R injury induction in the current intestinal model.
近期研究揭示，固有免疫系统能够识别自身靶标并引发类似于病原体的炎症反应。固有自身免疫的一个新范例是缺血/再灌注（I/R）损伤，其中缺血组织的再灌注引发由天然 IgM（nIgM）与缺血特异性自身抗原结合激活的急性炎症反应，这些自身抗原是非肌肉肌球蛋白重链 II 型（NMHC-II）亚型 A 和 C。随后，补体凝集素途径被激活，最终导致组织损伤。尽管肠道模型中的早期研究表明经典补体途径不会引发 I/R 损伤，但通过成像分析仍观察到局部损伤组织中 C1q 沉积。此外，由于使用不同基因敲除小鼠的相互矛盾的报告，替代补体途径的参与变得不清楚。为了探索 nIgM-缺血抗原相互作用后的直接下游途径，我们从接受肠道 I/R 损伤模型治疗的动物的局部组织中分离了 nIgM-缺血抗原免疫复合物，并检查了三种补体途径的初始分子的存在。我们的结果表明，甘露聚糖结合凝集素（MBL），即凝集素途径的早期分子，存在于 nIgM-缺血 Ag 免疫复合物中。此外，还在免疫复合物上检测到经典途径的初始分子 C1q。然而，替代途径的早期分子因子 B 并未在免疫复合物中检测到。为了进一步研究替代途径在 I/R 损伤中的作用，我们在肠道模型中利用了因子 B 基因敲除小鼠。我们的结果表明，因子 B 基因敲除小鼠不能防止局部组织损伤，并且它们的补体系统在 I/R 期间通过 nIgM 在局部组织中被激活。这些结果表明，在肠道 I/R 期间，凝集素补体途径在 nIgM-缺血抗原相互作用的下游立即发挥作用。此外，经典补体途径似乎也与 nIgM-缺血抗原免疫复合物相互作用。最后，在当前的肠道模型中，替代补体途径不参与 I/R 损伤的诱导。
