Schloot N C, Roep B O, Wegmann D R, Yu L, Wang T B, Eisenbarth G S
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, USA.
Diabetologia. 1997 Mar;40(3):332-8. doi: 10.1007/s001250050683.
GAD65 is one of the major autoantigens associated with insulin-dependent diabetes mellitus (IDDM). The two peptides p17 and p18 of GAD65 that share sequence similarity with coxsackie virus (amino acid sequence identity: PEVKEK) appeared to be the major determinants of GAD65 recognized preferably by T cells from new-onset IDDM patients and their first degree relatives. In contrast, in our study unrelated control subjects frequently recognized the two GAD peptides (55%, 16/29), similar to first degree relatives (41%, 12/29) and IDDM patients post-onset (68%, 15/22). However, recent-onset IDDM patients, responded less frequently (25%, 4/16) compared with IDDM patients post-onset (p < 0.03) or unrelated control subjects (borderline significant) confirming previous observations in humans and NOD mice that T-cell reactivity to GADp17/p18 at diabetes onset is decreased. Moreover, this study demonstrated a positive correlation of T-cell proliferation to GAD p17 (amino acid 247-266) and p18 (amino acid 260-279) with simultaneous responses to both peptides in 13% of all subjects tested (n = 97) (p < 0.001). T-cell proliferation to GAD p17 was higher than to p18 in recent-onset diabetic patients, first degree relatives and unrelated control subjects (p < 0.02, p < 0.004, p < 0.002, respectively). However, in post-onset IDDM patients, the two peptides were recognized equally well. Our results show that T-cell reactivity to GAD65, peptides homologous with coxsackie protein is very frequently observed, but not primarily associated with IDDM. The temporary decline of T-cell proliferation is not associated with the beta-cell destruction process, but with clinical manifestation. The positive correlation of reactivity to the two peptides in the viral motif implicates that PEVKEK is an immunogenic epitope.
谷氨酸脱羧酶65（GAD65）是与胰岛素依赖型糖尿病（IDDM）相关的主要自身抗原之一。GAD65的两种肽p17和p18与柯萨奇病毒具有序列相似性（氨基酸序列一致性：PEVKEK），它们似乎是新发病的IDDM患者及其一级亲属的T细胞优先识别的GAD65的主要决定因素。相比之下，在我们的研究中，非相关对照受试者经常识别这两种GAD肽（55%，16/29），这与一级亲属（41%，12/29）和发病后的IDDM患者（68%，15/22）相似。然而，与发病后的IDDM患者（p < 0.03）或非相关对照受试者（临界显著）相比，新发病的IDDM患者的反应频率较低（25%，4/16），这证实了之前在人类和非肥胖糖尿病（NOD）小鼠中的观察结果，即糖尿病发病时T细胞对GADp17/p18的反应性降低。此外，本研究表明，在所有测试的受试者（n = 97）中，有13%的受试者T细胞对GAD p17（氨基酸247 - 266）和p18（氨基酸260 - 279）的增殖与对两种肽的同时反应呈正相关（p < 0.001）。在新发病的糖尿病患者、一级亲属和非相关对照受试者中，T细胞对GAD p17的增殖高于对p18的增殖（分别为p < 0.02、p < 0.004、p < 0.002）。然而，在发病后的IDDM患者中，这两种肽的识别情况相同。我们的结果表明，T细胞对与柯萨奇蛋白同源的GAD65肽的反应性很常见，但与IDDM无主要关联。T细胞增殖的暂时下降与β细胞破坏过程无关，而是与临床表现有关。对病毒基序中两种肽的反应性呈正相关意味着PEVKEK是一个免疫原性表位。
