Studies on immunological mechanisms for generation of insulin autoantibodies

胰岛素自身免疫综合征中胰岛素抗体产生的免疫机制尚不清楚。我们的目的是澄清：1)该综合征患者的循环胰岛素是否异常，2)含巯基（SH）基团的药物是否可以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。将酸凝胶色谱法从血浆中提取的游离胰岛素应用于反相高效液相色谱时，所有被研究的该综合征患者均出现胰岛素峰，保留时间与标准人胰岛素相同。此外，在相对较高的乙腈浓度下，持续发现少量的免疫反应性胰岛素。然而，在胰岛素治疗的糖尿病患者和没有胰岛素抗体的高胰岛素患者中也发现了这种疏水胰岛素。因此，似乎不太可能改变内源性产生的胰岛素诱导胰岛素自身抗体的产生。含有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，sh -药物处理的标准人胰岛素在HPLC上的滞留时间和胰岛素与受体的结合活性没有明显改变。到目前为止，已有26例患者进行了HLA型分析。在这些患者中，HLA - A11、bw62 （Bl5）、Cw4和DR4与日本普通人群相比非常普遍。因此，这一结果表明，一些具有遗传易感性的受试者容易发生这种综合征。

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.