Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK.
Diabetes Research Institute, University of Miami - Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL, 33136, USA.
Curr Diab Rep. 2019 Dec 9;19(12):159. doi: 10.1007/s11892-019-1245-z.
Hyperexpression of classical HLA class I (HLA-I) molecules in insulin-containing islets has become a widely accepted hallmark of type 1 diabetes pathology. In comparison, relatively little is known about the expression, function and role of non-classical subtypes of HLA-I. This review focuses on the current understanding of the non-classical HLA-I subtypes: HLA-E, HLA-F and HLA-G, within and outside the field of type 1 diabetes, and considers the possible impacts of these molecules on disease etiology.
Evidence is growing to suggest that non-classical HLA-I proteins are upregulated, both at the RNA and protein levels in the pancreas of individuals with recent-onset type 1 diabetes. Moreover, associations between non-classical HLA-I genotypes and age at onset of type 1 diabetes have been reported in some studies. As with classical HLA-I, it is likely that hyperexpression of non-classical HLA-I is driven by the release of diffusible interferons by stressed β cells (potentially driven by viral infection) and exacerbated by release of cytokines from infiltrating immune cells. Non-classical HLA-I proteins predominantly (but not exclusively) transduce negative signals to immune cells infiltrating at the site of injury/inflammation. We propose a model in which the islet endocrine cells, through expression of non-classical HLA-I are fighting back against the infiltrating immune cells. By inhibiting the activity and function on NK, B and select T cells, the non-classical HLA-I, proteins will reduce the non-specific bystander effects of inflammation, while at the same time still allowing the targeted destruction of β cells by specific islet-reactive CD8+ T cells.
胰岛中经典 HLA-I 分子的过度表达已成为 1 型糖尿病病理的广泛公认标志。相比之下，人们对非经典亚型 HLA-I 的表达、功能和作用知之甚少。本综述重点介绍了非经典 HLA-I 亚型 HLA-E、HLA-F 和 HLA-G 在 1 型糖尿病领域内外的最新研究进展，并探讨了这些分子对疾病病因学的可能影响。
越来越多的证据表明，在近期发生 1 型糖尿病患者的胰腺中，非经典 HLA-I 蛋白在 RNA 和蛋白质水平上均上调。此外，在一些研究中报道了非经典 HLA-I 基因型与 1 型糖尿病发病年龄之间的关联。与经典 HLA-I 一样，非经典 HLA-I 的过度表达可能是由应激β细胞释放可扩散干扰素（可能由病毒感染驱动）引起的，并且浸润免疫细胞释放细胞因子会使其恶化。非经典 HLA-I 蛋白主要（但不是唯一）向浸润损伤/炎症部位的免疫细胞传递负信号。我们提出了一个模型，即胰岛内分泌细胞通过表达非经典 HLA-I 来对抗浸润免疫细胞。通过抑制 NK、B 和选择性 T 细胞的活性和功能，非经典 HLA-I 蛋白将减少炎症的非特异性旁观者效应，同时仍然允许特异性胰岛反应性 CD8+T 细胞靶向破坏β细胞。
