La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, 92037, CA, USA.
La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, 92037, CA, USA; Global Chief Medical Officer, Novo Nordisk, Denmark.
J Autoimmun. 2021 May;119:102628. doi: 10.1016/j.jaut.2021.102628. Epub 2021 Mar 9.
Human leukocyte antigens of class-I (HLA-I) molecules are hyper-expressed in insulin-containing islets (ICI) of type 1 diabetic (T1D) donors. This study investigated the HLA-I expression in autoantibody positive (AAB+) donors and defined its intra-islet and intracellular localization as well as proximity to infiltrating CD8 T cells with high-resolution confocal microscopy. We found HLA-I hyper-expression had already occurred prior to clinical diagnosis of T1D in islets of AAB+ donors. Interestingly, throughout all stages of disease, HLA-I was mostly expressed by alpha cells. Hyper-expression in AAB+ and T1D donors was associated with intra-cellular accumulation in the Golgi. Proximity analysis showed a moderate but significant correlation between HLA-I and infiltrating CD8 T cells only in ICI of T1D donors, but not in AAB+ donors. These observations not only demonstrate a very early, islet-intrinsic immune-independent increase of HLA-I during diabetes pathogenesis, but also point towards a role for alpha cells in T1D.
人类白细胞抗原 I 类（HLA-I）分子在 1 型糖尿病（T1D）供者的含胰岛素胰岛（ICI）中过表达。本研究调查了自身抗体阳性（AAB+）供者中 HLA-I 的表达情况，并通过高分辨率共聚焦显微镜定义了其在胰岛内和细胞内的定位以及与浸润性 CD8 T 细胞的接近程度。我们发现，在 AAB+供者的胰岛中，HLA-I 的过表达早在 T1D 的临床诊断之前就已经发生。有趣的是，在疾病的所有阶段，HLA-I 主要由 alpha 细胞表达。AAB+和 T1D 供者中的过表达与高尔基体中的细胞内积累有关。临近分析显示，仅在 T1D 供者的 ICI 中，HLA-I 与浸润性 CD8 T 细胞之间存在中度但显著的相关性，而在 AAB+供者中则没有。这些观察结果不仅表明在糖尿病发病机制中，HLA-I 在胰岛内发生了非常早期的、免疫独立的增加，而且还表明 alpha 细胞在 T1D 中发挥作用。
