Bach J F, Koutouzov S, van Endert P M
INSERM U 25, Hôpital Necker, Paris, France.
Immunol Rev. 1998 Aug;164:139-55. doi: 10.1111/j.1600-065x.1998.tb01216.x.
Using three reference disease models--insulin-dependent diabetes mellitus (IDDM) as a prototype of T-cell mediated organ-specific autoimmune disease, myasthenia gravis (MG) as a prototype of autoantibody-mediated organ-specific autoimmune disease and systemic lupus erythematosus (SLE) as a prototype of non-organ-specific autoimmune disease--we have reached several conclusions: 1) All three diseases are associated with the presence of multiple autoantibodies and/or autoreactive T cells that recognize a large number of antigenic molecules. The apparent predominant role of certain antibodies in some diseases could relate to their functional properties such as acetylcholine receptor (AChR) blockade for anti-AChR autoantibodies in MG or anti-dsDNA in SLE. 2) Major target antigens are clustered in the target cell affected by organ-specific autoimmune diseases: beta cells in IDDM, striated-muscle cells in MG, or apoptotic cells in the case of SLE. 3) Antibodies and T cells recognize multiple epitopes in these molecules. 4) The most evident explanation for the observed clustering and diversity is autoantigen spreading. Spreading probably involves T cells secreting proinflammatory cytokines but also possibly antibodies as in the case of nucleosome autoantibodies in SLE. 5) The counterpart of antigen spreading is bystander suppression in which regulatory cytokines deviate the immune response towards a protective response. 6) The mechanisms underlying the initiation of the autoimmune response and antigen spreading are still undetermined. They could imply a direct abnormality of the target cell in the case of organ-specific autoimmune diseases (e.g. infection with a virus showing a selective tropism for the target cell in organ-specific autoimmune diseases, or loss of physiological regulation of major histocompatibility complex molecule expression) or could be consequence of a ubiquitous cell abnormality such as increased apoptosis in SLE. The respective roles of genetic and environmental factors in these triggering events remain to be determined.
我们使用三种参考疾病模型——胰岛素依赖型糖尿病（IDDM）作为T细胞介导的器官特异性自身免疫性疾病的原型、重症肌无力（MG）作为自身抗体介导的器官特异性自身免疫性疾病的原型以及系统性红斑狼疮（SLE）作为非器官特异性自身免疫性疾病的原型——得出了以下几个结论：1）这三种疾病均与多种自身抗体和/或自身反应性T细胞的存在相关，这些抗体和T细胞可识别大量抗原分子。某些抗体在某些疾病中看似起主要作用，可能与其功能特性有关，如MG中抗乙酰胆碱受体（AChR）自身抗体对AChR的阻断作用，或SLE中抗双链DNA抗体的作用。2）主要靶抗原聚集在受器官特异性自身免疫性疾病影响的靶细胞中：IDDM中的β细胞、MG中的横纹肌细胞，或SLE中的凋亡细胞。3）抗体和T细胞识别这些分子中的多个表位。4）对观察到的聚集和多样性最明显的解释是自身抗原扩散。扩散可能涉及分泌促炎细胞因子的T细胞，但也可能涉及抗体，如SLE中的核小体自身抗体。5）与抗原扩散相对应的是旁观者抑制，其中调节性细胞因子使免疫反应转向保护性反应。6）自身免疫反应启动和抗原扩散的潜在机制仍未确定。在器官特异性自身免疫性疾病中，它们可能意味着靶细胞的直接异常（例如，感染对器官特异性自身免疫性疾病中的靶细胞具有选择性嗜性的病毒，或主要组织相容性复合体分子表达的生理调节丧失），或者可能是普遍存在的细胞异常的结果，如SLE中细胞凋亡增加。遗传和环境因素在这些触发事件中的各自作用仍有待确定。
