The relationship between humoral and cellular immunity to IA-2 in IDDM
The relationship between humoral and cellular immunity to IA-2 in IDDM
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DOI：
10.2337/diabetes.47.4.566
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发表时间：
1998-04-01
期刊：
影响因子：
7.7
通讯作者：
Atkinson, MA
中科院分区：
文献类型：
--
作者：
Ellis, TM;Schatz, DA;Atkinson, MA
神经内分泌蛋白胰岛素瘤相关蛋白2（IA-2），酪氨酸磷酸酶家族的成员，自身抗体已被观察到的个人或在增加的风险为胰岛素依赖型糖尿病。由于这种疾病被认为是由T细胞介导的自身免疫破坏产生胰岛素的胰腺β细胞，我们分析了体液和细胞免疫反应，这种自身抗原，以进一步确定其在IDDM的发病机制中的作用。用IA-2的整个42-kDa内部结构域（氨基酸603-979）、一系列对照抗原（谷胱甘肽-S-转移酶、破伤风环、白色念珠菌、腮腺炎、牛血清白蛋白）和有丝分裂原（植物血凝素）体外刺激来自新诊断的IDDM或处于不同疾病风险水平的个体的外周血单核细胞（PBMC）。初诊IDDM患者PBMC对IA-2的增殖频率和平均刺激指数明显高于对照组（14/33 [42%]; 10 μ g/ml时为3.8 +/- 4.5）和自身抗体阳性亲属患IDDM的风险增加（6/9 [66%]; 3.9 +/- 3.2）与自身抗体阴性亲属（1/15 [7%]; 1.8 +/- 1.0）或健康对照受试者（1/12 [8%]; 1.5 +/- 1.0）相比。对所有其他抗原的细胞免疫反应性频率在每个受试者组之间非常相似。58%的新诊断的IDDM患者的血清检测仅IA-2自身抗体阳性。尽管研究表明对胰岛细胞相关自身抗原的体液和细胞免疫反应性之间存在负相关，但对于IA-2，未观察到这种关系（r（s）= 0.18，P = 0.39）。这些研究支持了胰岛素依赖型糖尿病中IA-2的自身抗原性质，并建议将细胞免疫应答作为该疾病的辅助标志物。
Autoantibodies to the neuroendocrine protein insulinoma-associated protein 2 (IA-2), a member of the tyrosine phosphatase family, have been observed in individuals with or at increased risk for IDDM. Because this disease is thought to result from a T-cell-mediated autoimmune destruction of the insulin-producing pancreatic beta-cells, we analyzed humoral and cellular immune reactivity to this autoantigen to further define its role in the pathogenesis of IDDM. Peripheral blood mononuclear cells (PBMC) from individuals with newly diagnosed IDDM or at varying levels of risk for the disease were stimulated in vitro with the entire 42-kDa internal domain of IA-2 (amino acids 603-979), a series of control antigens (glutathionine-S-transferase, tetanus toroid, Candida albicans, mumps, bovine serum albumin), and a mitogen (phytohemagglutinin). The frequency and mean stimulation index of PBMC proliferation against IA-2 was significantly higher in newly diagnosed IDDM subjects (14 of 33 [42%]; 3.8 +/- 4.5 at 10 mu g/ml) and autoantibody-positive relatives at increased risk for IDDM (6 of 9 [66%]; 3.9 +/- 3.2) compared with autoantibody-negative relatives (1 of 15 [7%]; 1.8 +/- 1.0) or healthy control subjects (1 of 12 [8%]; 1.5 +/- 1.0). The frequencies of cellular immune reactivities to all other antigens were remarkably similar between each subject group. Sera from 58% of the newly diagnosed IDDM patients tested mere IA-2 autoantibody positive. Despite investigations suggesting an inverse association between humoral and cellular immune reactivities against islet-cell-associated autoantigens, no such relationship was observed (r(s) = 0.18, P = 0.39) with respect to IA-2. These studies support the autoantigenic nature of IA-2 in IDDM and suggest the inclusion of cellular immune responses as an adjunct marker for the disease.