Oldstone M B
Viral Immunobiology Laboratory, Division of Virology, The Scripps Research Institute,Department of Neuropharmacology, La Jolla, California 92037, USA.
FASEB J. 1998 Oct;12(13):1255-65. doi: 10.1096/fasebj.12.13.1255.
Molecular mimicry has been proposed as a pathogenetic mechanism for autoimmune disease, as well as a probe useful in uncovering its etiologic agents. The hypothesis is based in part on the abundant epidemiological, clinical, and experimental evidence of an association of infectious agents with autoimmune disease and observed cross-reactivity of immune reagents with host 'self' antigens and microbial determinants. For our purpose, molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the molecules' linear amino acid sequences or their conformational fits may be shared, even though their origins are as separate as, for example, a virus and a normal host self determinant. An immune response against the determinant shared by the host and virus can evoke a tissue-specific immune response that is presumably capable of eliciting cell and tissue destruction. The probable mechanism is generation of cytotoxic cross-reactive effector lymphocytes or antibodies that recognize specific determinants on target cells. The induction of cross-reactivity does not require a replicating agent, and immune-mediated injury can occur after the immunogen has been removed a hit-and-run event. Hence, the viral or microbial infection that initiates the autoimmune phenomenon may not be present by the time overt disease develops. By a complementary mechanism, the microbe can induce cellular injury and release self antigens, which generate immune responses that cross-react with additional but genetically distinct self antigens. In both scenarios, analysis of the T cells or antibodies specifically engaged in the autoimmune response and disease provides a fingerprint for uncovering the initiating infectious agent.
分子模拟已被提出作为自身免疫性疾病的发病机制，以及用于揭示其病原体的一种手段。该假说部分基于传染病原体与自身免疫性疾病关联的丰富流行病学、临床和实验证据，以及免疫试剂与宿主“自身”抗原和微生物决定簇之间观察到的交叉反应性。就我们的目的而言，分子模拟被定义为来自不同基因的分子或其蛋白质产物所共有的相似结构。即使它们的起源像病毒和正常宿主自身决定簇那样截然不同，分子的线性氨基酸序列或其构象契合度也可能是共有的。针对宿主和病毒共有的决定簇的免疫反应可引发组织特异性免疫反应，据推测这种反应能够引发细胞和组织破坏。可能的机制是产生识别靶细胞上特定决定簇的细胞毒性交叉反应性效应淋巴细胞或抗体。交叉反应性的诱导不需要复制因子，并且在免疫原被清除（即“打了就跑”事件）后可发生免疫介导的损伤。因此，在明显疾病发生时，引发自身免疫现象的病毒或微生物感染可能已不存在。通过一种互补机制，微生物可诱导细胞损伤并释放自身抗原，这些自身抗原会产生与其他但基因上不同的自身抗原发生交叉反应的免疫反应。在这两种情况下，对特异性参与自身免疫反应和疾病的T细胞或抗体进行分析可为揭示引发感染的病原体提供线索。
