人体1型糖尿病中的关键免疫细胞

1型糖尿病患者胰岛β细胞被破坏与胰岛自身反应性T细胞之间的直接联系从未被证明,对诊断后的疾病进程也所知无几.最近美国科学家的研究第一次对此有了直接的证据.冷冻胰腺样本来自病程在1周到超过50年的45例死亡患者的遗体捐赠,14例非糖尿病患者对照样本,5例有自身抗体的非糖尿病患者样本,2例孕期糖尿病患者样本,以及6例2型糖尿病患者样本.系统检查样本的组织切片是否存在有足够胰岛素的β细胞、CD8阳性的胰岛病变和1型HLA过度表达.最后,对表达HLA-A2的样本的连续切片用四聚体染色法针对6种已知确定的与1型糖尿病有关的胰岛自身抗原进行CD8 T细胞反应性检查.在临床确诊后最长达8年的分组患者胰岛样本中单一和多种CD8 T细胞反应性都检测到了.1型糖尿病特有的1型HLA过度表达和胰岛炎等病理特征存在于一小部分病程很长的患者中.在受影响的器官中.胰岛病变持续存在,表现为不同程度的浸润和β细胞丢失.该研究为人体胰岛自身反应性提供了第一个直接证据并强调了发病历程的异质性和长期性.

Demonstration of islet-autoreactive CD8Tcells in insulitic lesions from recent onset and long-term type 1 diabetes patients

A direct association of islet-autoreactive T cells with β cell destruaction in human pancreatic islets from typel diabetes （T1 D） patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1 D donors with disease durations ranging from 1 wk to 〉 50 yrs, 14 non-diabetic controls, 5 non-diabetics with islet auto-antibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient J3 cells, CD8 （ ＋ ） insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2-expressing individuals were probed for CD8T cell reac- tivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yrs after clinical diagnosis. Patholog- ical features such as HLA class I hyperexpression and insulitis were specific for T1 D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and f3 cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.