T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin
T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin
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DOI：
10.1073/pnas.95.7.3833
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发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Sonderstrup, G
中科院分区：
文献类型：
--
作者：
Congia, M;Patel, S;Sonderstrup, G
大约一半的新近诊断为胰岛素依赖型糖尿病（IDDM）的白种人具有胰岛素自身抗体，并且这些人中的大多数表达HLA-DR 4基因型[齐格勒，R.，阿尔珀角一、Awdeh，Z. L.，Castano，L.，Brink，S，J.，Soeldner，J.S.，杰克逊，R，A，& Eisenbarth，G，S，（1991）Diabetes 40，709-714]，然而，难以证明在IDDM患者中对人胰岛素的T细胞增殖应答[Durinovic-Bello，I.，Hummel，M. &齐格勒，A. G，（1996）Diabetes 45，795-800]。我们免疫了表达易感HLA-DR的转基因小鼠，（alpha 1*0101，beta 1*0401）（下文称为DRB 1 *0401）和人CD 4分子与人前胰岛素原（PPI）、胰岛素原（PI）和胰岛素以及衍生的大组T细胞杂交瘤的杂交，以确定这些蛋白质的免疫原性表位，这些结果表明，激素原PI或PPI携带DRB 1 *0401转基因小鼠中的主要免疫原性T细胞表位。PPI/PI免疫显性表位LALEGSLQK定位于C-肽/A-链连接处，该T细胞表位PPI/PI LALEGSLQK是不寻常的，因为通常在胰岛素分子的成熟过程中其被蛋白水解破坏。此外，该T细胞表位由人DRB 1 *0401阳性Epstein-Barr病毒转化的B细胞加工和呈递，并且它还可以刺激来自HLA-DR 4阳性的1型糖尿病患者的外周血的T细胞，这些发现可能部分解释了为什么1型糖尿病的易感性与HLA-DR 4相关。阳性个体以及为什么在IDDM患者中很少检测到对成熟胰岛素蛋白的T细胞应答。
Approximately one-half of Caucasians with newly diagnosed insulin-dependent diabetes mellitus (IDDM) have autoantibodies to insulin, and the majority of those express the HLA-DR4 genotype [Ziegler, R., Alper, C. A., Awdeh, Z. L., Castano, L,, Brink, S, J,, Soeldner, J. S,, Jackson, R, A, & Eisenbarth, G, S, (1991) Diabetes 40, 709-714], However, it has been difficult to demonstrate T cell proliferative responses to human insulin in IDDM patients [Durinovic-Bello, I., Hummel, M. & Ziegler, A. G, (1996) Diabetes 45, 795-800]. We have immunized transgenic mice expressing the susceptible HLA-DR (alpha 1*0101, beta 1*0401) (hereafter called DRB1*0401) and human CD4 molecules on a murine major histocompatibility complex class II null background, with human preproinsulin (PPI), proinsulin (PI), and insulin and derived large panels of T cell hybridomas to determine the immunogenic epitopes of these proteins, These results show that the prohormones PI or PPI carry the major immunogenic T cell epitope in the DRB1*0401 transgenic mice. The PPI/PI immunodominant epitope LALEGSLQK was localized at the C-peptide/A-chain junction, This T cell epitope PPI/PI LALEGSLQK is unusual because, normally, it is proteolytically destroyed during the maturation of the insulin molecule, Additionally, this T cell epitope is both processed and presented by human DRB1*0401-positive Epstein-Barr virus transformed B cells, and it can also stimulate T cells from the peripheral blood of HLA-DR4-positive patients with type 1 diabetes, These findings may partly explain why susceptibility to type 1 diabetes is associated with HLA-DR4-positive individuals and why T cell responses to the mature insulin protein are rarely detected in IDDM patients.