Extrapancreatic Autoantibody Profiles in Type I Diabetes

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（Type I diabetes, T1D）是一类以胰腺内产胰岛素β细胞遭到破坏为特征的自身免疫性疾病。尽管目前已明确多种胰岛细胞自身抗原，但自身抗体靶标的整体范围与谱型尚未得到完全探索。本研究采用荧光素酶免疫沉淀系统（LIPS）抗体谱分析技术，同步开展胰岛及其他器官特异性自身抗体应答的平行研究。对由93名对照受试者与50名T1D患者组成的初始队列进行检测后发现，16%的糖尿病患者体内存在抗胃ATPase自身抗体，且该抗体与针对GAD65、IA2或IA2-β的自身抗体无显著相关性。针对包含18种潜在自身抗体靶标的第二队列开展更细致的分析，结果揭示了胰岛细胞自身抗体应答的显著异质性，其中涵盖ZnT8的两种多态性变体。部分T1D患者可检测到针对多种器官特异性靶标的自身抗体，包括抗胃ATPase（11%）、甲状腺过氧化物酶（14%）以及针对组织型转谷氨酰胺酶的抗IgA自身抗体（12%）。尽管少数T1D患者体内可检测到针对肺相关蛋白KCNRG（6%）与S100-β（8%）的自身抗体，但未在多种细胞因子中检测到具有统计学意义的自身抗体。通过热图对整体自身抗体谱进行分析，可将受试者划分为两大数量相近的亚组，分别为携带器官特异性自身抗体的T1D患者与未携带该类抗体的T1D患者。在器官特异性自身抗体亚组中，抗胃ATPase、抗甲状腺过氧化物酶与抗组织型转谷氨酰胺酶的血清阳性率重叠度极低，且此类自身抗体与胰岛细胞自身抗体无相关性。对由高危个体前瞻性收集的纵向样本组成的第三队列进行检测后发现，抗胃ATPase自身抗体可在检测到胰岛自身抗体之前、甚至临床确诊T1D之前，就已在部分个体中出现。综上，上述结果表明，基于胰岛与器官特异性靶标的自身抗体谱或可用于优化1型糖尿病的临床管理。