Knip Mikael
Hospital for Children and Adolescents, University of Helsinki, Finland.
Horm Res. 2002;57 Suppl 1:6-11. doi: 10.1159/000053305.
The clinical presentation of type 1 diabetes is preceded by an asymptomatic latent period characterized by the presence of diabetes-associated autoantibodies in the peripheral circulation, reflecting beta-cell damage. This prediabetic period may last for months and years. Several studies observing genetically susceptible subjects from birth have shown that insulin autoantibodies (IAA) are the first or among the first autoantibodies to appear in young children, implying that insulin may be the primary autoantigen in most cases of childhood type 1 diabetes. About 12-16% of siblings of children with type 1 diabetes have been observed to test positive for at least one diabetes-associated autoantibody, whereas the risk of diabetes among siblings has been estimated to be 6-8%. In parallel, close to 4% of Finnish schoolchildren tested positive for at least one diabetes-associated autoantibody; the lifetime risk of type 1 diabetes in the Finnish population has been estimated to be close to 1%. These observations suggest that only 25-50% of those with signs of beta-cell autoimmunity eventually progress to clinical type 1 diabetes. Accordingly there is a considerable proportion of children in whom beta-cell autoimmunity remains subclinical or is aborted. Positivity for only one diabetes-associated autoantibody may actually represent innocent beta-cell autoimmunity, while positivity for two or more autoantibodies seems to mark a point of no return. The autoimmune response is very dynamic in the early phase of prediabetes, with spreading from one antigen to another and from one epitope to another within a given antigen. In addition both isotype spreading and switching can be observed in early prediabetes. This indicates that the early prediabetic process may be a suitable target for immunomodulation aimed at delaying or preventing progression to clinical diabetes.
1型糖尿病的临床表现之前有一个无症状的潜伏期，其特征是外周循环中存在与糖尿病相关的自身抗体，这反映了β细胞的损伤。这个糖尿病前期可能持续数月甚至数年。几项对从出生就进行基因易感性观察的研究表明，胰岛素自身抗体（IAA）是幼儿中最早出现或最早出现的自身抗体之一，这意味着在大多数儿童1型糖尿病病例中，胰岛素可能是主要的自身抗原。据观察，1型糖尿病患儿的兄弟姐妹中约12-16%至少有一种与糖尿病相关的自身抗体检测呈阳性，而兄弟姐妹中患糖尿病的风险估计为6-8%。与此同时，近4%的芬兰学龄儿童至少有一种与糖尿病相关的自身抗体检测呈阳性；芬兰人群中1型糖尿病的终生风险估计接近1%。这些观察结果表明，只有25-50%有β细胞自身免疫迹象的人最终会发展为临床1型糖尿病。因此，有相当一部分儿童的β细胞自身免疫仍处于亚临床状态或自行终止。仅一种与糖尿病相关的自身抗体呈阳性实际上可能代表无害的β细胞自身免疫，而两种或更多自身抗体呈阳性似乎标志着不可逆转的点。在糖尿病前期的早期阶段，自身免疫反应非常活跃，会从一种抗原扩散到另一种抗原，以及在给定抗原内从一个表位扩散到另一个表位。此外，在糖尿病前期早期还可以观察到同种型扩散和转换。这表明糖尿病前期早期过程可能是旨在延迟或预防进展为临床糖尿病的免疫调节的合适靶点。
