Department of Pathology & Laboratory Medicine, University of Calgary, Faculty of Medicine, Calgary, AB, Canada.
Crit Rev Clin Lab Sci. 2010 Mar-Apr;47(2):51-71. doi: 10.3109/10408361003787171.
Type 1 diabetes mellitus (TID) is an autoimmune genetic disease with unidentified environmental agents affecting its pathogenesis. Susceptibility is determined by the interaction of MHC and non-MHC genes in the thymus, primarily by the IDDM1 locus, which is extremely polymorphic and thus generates multitudes of predisposing and protective haplotypes for binding self-peptides. By presenting these peptide antigens to immature T-cells for activation and selection, most autoreactive cells will be deleted, but inefficient presentation and subsequent deficiencies of non-MHC genes allow some cells to escape to the periphery and to be eliminated by anergy or regulatory T-cells. T-cell dysregulation to a Th1 response with secretion of inflammatory cytokines promotes a self-perpetuating autoimmune cascade leading to overt disease unless blocked by suppressive cytokines from Th2-type cells. Since autoantibodies reflect target-cell destruction, early insulin autoantibodies may be transient due to benign insulitis induced by insulin or proinsulin. Multiple autoantibodies denote epitope spreading to cryptic autoantigens, likely involving posttranslational variants. Thus, the resulting T1D development requires coordinated abnormal variations, and this requirement limits its occurrence to a small minority of susceptible individuals.
1 型糖尿病（TID）是一种自身免疫性遗传疾病，其发病机制受未明环境因素影响。易感性由胸腺中的 MHC 和非 MHC 基因相互作用决定，主要由 IDDM1 基因座决定，该基因座高度多态性，因此产生了大量与自身肽结合的易感性和保护性单倍型。通过将这些肽抗原呈递给不成熟的 T 细胞以进行激活和选择，大多数自身反应性细胞将被删除，但非 MHC 基因的低效呈递和随后的缺陷允许一些细胞逃到外周，并通过失能或调节性 T 细胞被消除。T 细胞向 Th1 反应的失调，导致炎症细胞因子的分泌，促进了自我维持的自身免疫级联反应，导致显性疾病的发生，除非被 Th2 型细胞的抑制性细胞因子所阻断。由于自身抗体反映了靶细胞的破坏，早期胰岛素自身抗体可能由于胰岛素或胰岛素原诱导的良性胰岛炎而短暂存在。多种自身抗体表示抗原决定簇扩展到隐匿自身抗原，可能涉及翻译后变异体。因此，T1D 的发展需要协调的异常变化，这种需求将其发生限制在少数易感个体中。
