Studies on immunological mechanisms for generation of insulin autoantibodies

自身免疫性胰岛素综合征中胰岛素抗体产生的免疫机制尚不清楚。我们打算澄清：1）该综合征患者的循环胰岛素是否异常，2）含巯基（SH）基团的药物是否能改变胰岛素及其细胞受体的结构，3）某些HLA类型是否与该综合征患者有关。当从血浆中提取的游离胰岛素酸凝胶色谱法应用于反相HPLC，出现了一个主要的胰岛素峰与标准的人胰岛素在所有研究的患者与这种综合征相同的保留时间。此外，在相对较高的乙腈浓度下始终发现少量免疫反应性胰岛素。然而，这种疏水性胰岛素也见于胰岛素治疗的糖尿病患者和没有胰岛素抗体的高胰岛素血症患者。因此，在该综合征中，内源性胰岛素的改变不可能诱导胰岛素自身抗体的产生，含SH基团的药物的使用可能与该综合征的发病机制有关。然而，标准人胰岛素经SH-药物处理后，其HPLC保留时间及其与受体的结合活性无明显改变。在这些患者中，HLA-A11、Bw 62（B15）、Cw 4和DR 4的流行率均高于日本的一般人群。因此，这一结果表明，一些受试者与遗传决定的易感性是容易发展这种综合征。

The immune mechanism for generation of insulin antibodies in the insulin autoinunune syndrome is unclear. We intended to clarify : 1) whether the circulating insulin in the patients with this syndrome is abnormal, 2) whether sulfhydryl (SH) group - containing drugs can alter the structure of insulin and its cell receptors, and 3) whether certain HLA-types relate to these patients with the syndrome. When free insulin extracted from plasma by acid gel chromatography was applied to reverse phase HPLC, a major insulin peak emerged with the same retention time as standard human insulin in all studied patients with this syndrome. In addition, a minor immunoreactive insulin was consistently found at relatively high acetonitrile concentrations. However, this hydrophobic insulin was also found in insulin-treated diabetic patients and in hyperinsulinemic patients who did not have insulin antibodies. Therefore, it seems unlikely that an altered endogenously produced insulin induced the generation of autoantibodies to insulin in this syndrome.The usage of drugs containing SH-group may be potentially implicated in the pathogenesis of the syndrome. However, the retention time on HPLC of standard human insulin treated with SH-drugs and the binding activity of such insulin to its receptor were not altered significantly.Until now, 26 patients with this syndrome were analyzed for HLA types. In these patients, each HLA - A11, Bw 62 (Bl5), Cw4 and DR4 was highly prevalent compared with that in the general population in Japan. Therefore, this result suggests that some subjects with genetically determined susceptibility are prone to the development of this syndrome.