Maclaren N, Lan M, Coutant R, Schatz D, Silverstein J, Muir A, Clare-Salzer M, She J X, Malone J, Crockett S, Schwartz S, Quattrin T, DeSilva M, Vander Vegt P, Notkins A, Krischer J
Departments of Pediatrics and Biometry and Genetics, Louisiana State University Medical School at the Research Institute for Children, New Orleans, LA, USA.
J Autoimmun. 1999 Jun;12(4):279-87. doi: 10.1006/jaut.1999.0281.
We report here our prospective study of 15,224 non-diabetic, first-degree relatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined islet cell, insulin, GAD65, insulinoma-associated antigen-2 and 2beta autoantibodies (ICA, IAA, GAD65A, IA-2A and IA-2betaA), on the first available serum samples. The latter three autoantibodies were however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relatives who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of diabetes was however negligible when ICA was found in the absence of the others (5-year risk=5.3%), but increased dramatically whenever two or more autoantibodies were present (5-year risk=28.2% and 66.2%, respectively). The most predictive combination of markers was ICA plus IA-2A and/or IA-2beta A. Loss of first phase insulin release to IVGTT also occurred only in those ICA-positive relatives who had one or more of the other autoantibodies. The data suggests that significant beta-cell damage is seen only when the underlying autoimmunity has spread to multiple antigenic islet cell determinants. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relatives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the prevention of type 1 diabetes could be designed based on testing for these autoantibodies alone, without the need for HLA typing and IVGTT testing.
我们在此报告对15224名免疫介导的（1型）糖尿病（IMD）先证者的非糖尿病一级亲属进行的前瞻性研究，其中135人最终被发现患糖尿病。我们对首次可得的血清样本检测了胰岛细胞、胰岛素、谷氨酸脱羧酶65（GAD65）、胰岛素瘤相关抗原-2和胰岛细胞抗原2β自身抗体（ICA、IAA、GAD65A、IA-2A和IA-2βA）。不过，后三种自身抗体是在有和没有ICA、IAA和/或GAD65A的亲属亚组以及大多数患糖尿病的亲属中检测的。在进展为糖尿病的亲属中，94%在首次筛查时有至少一种这些自身抗体，而ICA被证明是最敏感的单一标志物（敏感性74%）。然而，当ICA单独出现而无其他自身抗体时糖尿病风险可忽略不计（5年风险=5.3%），但当出现两种或更多自身抗体时风险急剧增加（5年风险分别为28.2%和66.2%）。最具预测性的标志物组合是ICA加IA-2A和/或IA-2βA。静脉葡萄糖耐量试验（IVGTT）时第一相胰岛素释放缺失也仅发生在那些有一种或更多其他自身抗体的ICA阳性亲属中。数据表明，只有当潜在的自身免疫扩散到多个抗原性胰岛细胞决定簇时才会出现显著的β细胞损伤。自身抗体组合最常出现在具有最高风险HLA-DR/DQ表型的亲属中。这些数据证明，只有这五种自身抗体中至少两种或更多呈阳性的亲属自身才有显著的糖尿病风险。预防1型糖尿病的干预试验可仅基于检测这些自身抗体来设计，而无需进行HLA分型和IVGTT检测。
