Bonifacio E, Lampasona V, Bingley P J
Department of Medicine 1, Istituto Scientifico San Raffaele, Milan, Italy.
J Immunol. 1998 Sep 1;161(5):2648-54.
IA-2 (islet cell Ag 512) and IA-2 beta (phogrin/IAR) are related autoantigens associated with type 1 diabetes. To determine the critical regions for autoantibody binding and which of these autoantigens is the primary target, mutant and chimeric constructs were used to characterize Ab epitope binding in sera from 217 new onset patients with type 1 diabetes and sequential samples from 141 islet cell Ab positive first degree relatives of patients. All 22 relatives and 121 of 129 patients with IA-2/IA-2 beta Abs had reactivity to IA-2-specific epitopes. These epitopes were in the juxtamembrane region (residues 601-682) and the protein tyrosine phosphatase (PTP)-like domain of IA-2. Chimeras showed that IA-2 residues 795-889 were important for IA-2-specific Ab binding in the PTP-like domain, and mutation of IA-2 residues 877 and 911, previously indicated as relevant for phosphatase activity, also reduced Ab binding. In contrast, Ab binding to IA-2 beta was limited to its PTP-like domain, most IA-2 beta Abs recognized epitopes shared with IA-2, and only 20 patients and 2 relatives had Abs to IA-2 beta-specific epitopes. In 4 relatives, IA-2 and/or IA-2 beta Abs developed in follow-up samples. In each of these, Abs to IA-2-specific epitopes were the first detected. In three, spreading to epitopes shared between IA-2 and IA-2 beta in subsequent samples was seen. In the 17 relatives who developed type 1 diabetes, progression to disease was associated with reactivity to multiple IA-2/IA-2 beta epitopes. These data suggest that IA-2 is the primary phosphatase-like autoantigen associated with type 1 diabetes and that studying autoantibody epitope diversity may assist in disease prediction.
IA-2（胰岛细胞抗原512）和IA-2β（phogrin/IAR）是与1型糖尿病相关的自身抗原。为了确定自身抗体结合的关键区域以及这些自身抗原中哪一个是主要靶点，使用突变体和嵌合体构建体来表征217例1型糖尿病新发病患者血清以及141例患者的胰岛细胞抗体阳性一级亲属的连续样本中的抗体表位结合情况。在22名亲属以及129例患有IA-2/IA-2β抗体的患者中的121例中，对IA-2特异性表位具有反应性。这些表位位于IA-2的近膜区域（第601 - 682位氨基酸残基）和蛋白酪氨酸磷酸酶（PTP）样结构域。嵌合体显示，IA-2的第795 - 889位氨基酸残基对于PTP样结构域中IA-2特异性抗体结合很重要，并且先前表明与磷酸酶活性相关的IA-2第877和911位氨基酸残基的突变也降低了抗体结合。相比之下，抗体与IA-2β的结合仅限于其PTP样结构域，大多数IA-2β抗体识别与IA-2共有的表位，只有20例患者和2名亲属具有针对IA-2β特异性表位的抗体。在4名亲属中，随访样本中出现了IA-2和/或IA-2β抗体。在每一例中，首先检测到的是针对IA-2特异性表位的抗体。在三例中，随后的样本中出现了对IA-2和IA-2β共有的表位的反应性扩展。在17例患1型糖尿病的亲属中，疾病进展与对多个IA-2/IA-2β表位的反应性相关。这些数据表明，IA-2是与1型糖尿病相关的主要磷酸酶样自身抗原，并且研究自身抗体表位多样性可能有助于疾病预测。
