Ito Y, Nieda M, Uchigata Y, Nishimura M, Tokunaga K, Kuwata S, Obata F, Tadokoro K, Hirata Y, Omori Y
Department of Transfusion Medicine and Immunohematology, University of Tokyo, Japan.
J Immunol. 1993 Nov 15;151(10):5770-6.
Our recent study indicated that all the insulin autoimmune syndrome (IAS) patients had specific HLA class II alleles, the DRB10406, DQA10301, and DQB10302, which allowed T cells to proliferate when autologous APC were exposed to human insulin. The study implied that gene products of DRB10406, DQA10301, and/or DQB10302 may be involved in the presentation of human insulin to T cells. We therefore examined T cell response of healthy donors with different HLA phenotypes to human insulin using an autologous MLR system. The T cells from not only IAS patients but also healthy donors were able to proliferate after exposure of human insulin to autologous APC with DRB10406, DQA10301, and DQB10302 products. The class II molecules are considered to be involved in the recognition of human insulin by T cells. The proliferative response of T cells was completely blocked by anti-HLA-DR mAb and not by anti-HLA-DQ mAb or other mAb. Furthermore, human insulin-specific CD4-positive T cell clones were established from blast cells in autologous MLR of PBMC from two healthy donors with DRB10406 in the presence of human insulin. Using DRB10406-transfected L cells as APC, we confirmed that these T cells clones recognize human insulin in the context of gene products of DRB10406. These results provide the first evidence that HLA-DRB10406 products act as the dominant restriction element for the presentation of human insulin to T cells, and suggest that this particular class II gene, HLA-DRB10406, contributes to the development of IAS.
我们最近的研究表明，所有胰岛素自身免疫综合征（IAS）患者都有特定的人类白细胞抗原（HLA）Ⅱ类等位基因，即DRB10406、DQA10301和DQB10302，当自体抗原呈递细胞（APC）暴露于人类胰岛素时，这些等位基因会使T细胞增殖。该研究暗示，DRB10406、DQA10301和/或DQB10302的基因产物可能参与了人类胰岛素向T细胞的呈递过程。因此，我们使用自体混合淋巴细胞反应（MLR）系统，检测了具有不同HLA表型的健康供体对人类胰岛素的T细胞反应。不仅IAS患者的T细胞，而且健康供体的T细胞在人类胰岛素暴露于具有DRB10406、DQA10301和DQB10302产物的自体APC后都能够增殖。Ⅱ类分子被认为参与了T细胞对人类胰岛素的识别。T细胞的增殖反应被抗HLA-DR单克隆抗体完全阻断，而不被抗HLA-DQ单克隆抗体或其他单克隆抗体阻断。此外，在存在人类胰岛素的情况下，从两名具有DRB10406的健康供体的外周血单个核细胞（PBMC）的自体MLR中的母细胞中建立了人类胰岛素特异性CD4阳性T细胞克隆。使用转染了DRB10406的L细胞作为APC，我们证实这些T细胞克隆在DRB10406的基因产物背景下识别人类胰岛素。这些结果提供了首个证据，表明HLA-DRB10406产物作为人类胰岛素向T细胞呈递的主要限制元件，并表明这个特定的Ⅱ类基因HLA-DRB10406促成了IAS的发生。
