Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, and National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
PLoS One. 2012;7(9):e45216. doi: 10.1371/journal.pone.0045216. Epub 2012 Sep 21.
Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing β-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-β. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-β (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D.
1 型糖尿病（T1D）是一种自身免疫性疾病，其特征是胰腺中产生胰岛素的β细胞遭到破坏。尽管已经知道几种胰岛细胞自身抗原，但自身抗体靶标的广度和范围尚未得到充分探索。在这里，使用荧光素酶免疫沉淀系统（LIPS）抗体分析技术平行研究胰岛和其他器官特异性自身抗体反应。对最初的 93 名对照者和 50 名 T1D 患者的队列进行检查，结果发现 16%的糖尿病患者存在抗胃壁细胞 ATP 酶自身抗体，这些抗体与 GAD65、IA2 或 IA2-β 自身抗体无关。对包含 18 个潜在自身抗体靶标的第二个队列进行更详细的研究发现，针对胰岛细胞自身抗原的自身抗体反应存在明显的异质性，包括锌转运体 8 的两种多态变体。一部分 T1D 患者针对包括胃壁细胞 ATP 酶（11%）、甲状腺过氧化物酶（14%）和组织转谷氨酰胺酶自身 IgA 抗体（12%）在内的几种器官特异性靶标产生自身抗体。尽管少数 T1D 患者对肺相关蛋白 KCNRG（6%）和 S100-β（8%）有自身抗体，但没有检测到针对几种细胞因子的统计学显著自身抗体。使用热图对整体自身抗体图谱进行分析，揭示了大约数量相同的两个主要亚组，由存在和不存在器官特异性自身抗体的 T1D 患者组成。在器官特异性亚组内，抗胃壁细胞 ATP 酶、抗甲状腺过氧化物酶和抗转谷氨酰胺酶阳性之间几乎没有重叠，并且这些自身抗体与胰岛细胞自身抗体无关。对包含高风险个体的前瞻性纵向样本的第三个队列进行检查，结果表明，在检测到胰岛自身抗体和 1 型糖尿病临床发病之前，几个个体中存在抗胃壁细胞 ATP 酶自身抗体。总之，这些结果表明，源自胰岛和器官特异性靶标的自身抗体图谱可能有助于增强 1 型糖尿病的临床管理。
