Szalai Alexander J, Hu Xianzhen, Adams Jillian E, Barnum Scott R
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Mol Immunol. 2007 May;44(12):3132-6. doi: 10.1016/j.molimm.2007.02.002. Epub 2007 Mar 13.
Complement per se has been shown to play an important role in demyelinating disease but controversy remains regarding the role of C3 in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In this study, we used C3(-/-) mice to confirm previous findings that C3 is required for full development of EAE. Furthermore, C3(+/-) mice (with serum C3 levels 50% that of wild-type mice) developed EAE with a severity intermediate between wild-type and C3(-/-) mice. Importantly transfer of wild-type encephalitogenic T cells to C3(-/-) mice resulted in attenuated EAE. C3(-/-) mice with EAE had fewer CD4(+) and CD8(+) T cells in the CNS and 50% fewer of these cells produced IFN-gamma compared to wild-type mice. When treated with anti-CD3 antibody, CD4(+) T cells from wild-type and C3(-/-) mice had similar activation profiles as judged by IFN-gamma production and CD25 and CD69 expression, indicating there is no gross or intrinsic defect in T cells from C3(-/-) mice. T cells from primed C3(-/-) mice proliferated comparably to that of control T cells on re-stimulation with MOG peptide. Our results confirm a requirement for C3 for maximal development of EAE and suggest that receptors for C3-derived activation fragments might be a viable therapeutic target for prevention and treatment demyelinating disease.
补体本身已被证明在脱髓鞘疾病中起重要作用，但关于C3在实验性自身免疫性脑脊髓炎（EAE，多发性硬化症的动物模型）的发生和发展中的作用仍存在争议。在本研究中，我们使用C3基因敲除小鼠来证实先前的发现，即C3是EAE充分发展所必需的。此外，C3杂合子小鼠（血清C3水平为野生型小鼠的50%）发生的EAE严重程度介于野生型和C3基因敲除小鼠之间。重要的是，将野生型致脑炎性T细胞转移到C3基因敲除小鼠中会导致EAE减轻。与野生型小鼠相比，患有EAE的C3基因敲除小鼠中枢神经系统中的CD4⁺和CD8⁺ T细胞较少，且这些细胞产生干扰素-γ的数量减少50%。当用抗CD3抗体处理时，根据干扰素-γ产生以及CD25和CD69表达判断，野生型和C3基因敲除小鼠的CD4⁺ T细胞具有相似的激活谱，表明C3基因敲除小鼠的T细胞没有明显的或内在的缺陷。用髓鞘少突胶质细胞糖蛋白（MOG）肽再次刺激时，来自致敏C3基因敲除小鼠的T细胞增殖与对照T细胞相当。我们的结果证实了C3是EAE最大程度发展所必需的，并表明C3衍生的激活片段的受体可能是预防和治疗脱髓鞘疾病的可行治疗靶点。
