Segurado O G, Arnaiz-Villena A, Wank R, Schendel D J
Institute of Immunology, University of Munich, Germany.
Autoimmunity. 1993;15(1):85-9. doi: 10.3109/08916939309004844.
Several lines of evidence suggest that major histocompatibility complex (MHC)-linked susceptibility to insulin-dependent diabetes mellitus (IDDM) is not restricted to the presence or absence of any single gene product. The existence of population-specific haplotypes associated with IDDM supports the concept that distinct combinations of MHC alleles interact synergistically to induce disease when other environmental and genetic factors are present. MHC-controlled peptide transport and binding to MHC molecules as well as the levels of MHC class I and class II expression in the thymus and pancreatic beta cells may also play significant roles in the outbreak of IDDM. These intrinsic factors shape the T-cell receptor (TCR) repertoire during T-cell ontogeny in the thymus and later influence the efficiency of potentially autoreactive T cells in the periphery. Several extrinsic factors, such as viruses or dietary proteins, may be directly involved in the TCR/MHC interaction at the cell surface; furthermore viruses can alter the regulatory mechanisms of peptide/MHC interaction and expression. We propose that these intrinsic and extrinsic factors need not be mutually exclusive and might even be interdependent: a given virus may act deleteriously only when certain autoreactive T cells and combinations of MHC alleles are present in the individual. IDDM would develop if pathogenic T-cells are activated and an appropriate target MHC/peptide is expressed in pancreatic beta cells. Future knowledge of the host-virus relationships influenced by the MHC genes, the function of their encoded proteins and the polymorphic gene structure of well-established susceptibility MHC haplotypes will help delineate an overall picture of this issue.
多条证据表明，主要组织相容性复合体（MHC）与胰岛素依赖型糖尿病（IDDM）的易感性关联并不局限于任何单一基因产物的存在与否。与IDDM相关的群体特异性单倍型的存在支持了这样一种概念，即当存在其他环境和遗传因素时，MHC等位基因的不同组合会协同相互作用以诱发疾病。MHC控制的肽转运以及与MHC分子的结合，以及胸腺和胰腺β细胞中MHC I类和II类分子的表达水平，在IDDM的发病过程中也可能起重要作用。这些内在因素在胸腺中T细胞个体发育过程中塑造了T细胞受体（TCR）库，随后影响外周潜在自身反应性T细胞的效率。一些外在因素，如病毒或饮食蛋白，可能直接参与细胞表面的TCR/MHC相互作用；此外，病毒可以改变肽/MHC相互作用和表达的调节机制。我们提出，这些内在和外在因素不一定相互排斥，甚至可能相互依赖：特定病毒可能只有在个体中存在某些自身反应性T细胞和MHC等位基因组合时才会产生有害作用。如果致病性T细胞被激活，并且胰腺β细胞中表达了合适的靶MHC/肽，IDDM就会发生。未来对受MHC基因影响的宿主-病毒关系、其编码蛋白的功能以及已确定的易感性MHC单倍型的多态基因结构的了解，将有助于勾勒出这个问题的全貌。
