Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?
Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?
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DOI：
10.1038/s41574-023-00826-3
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发表时间：
2023-04-18
影响因子：
40.5
通讯作者：
Mallone，Roberto
中科院分区：
文献类型：
--
作者：
Eizirik，Decio L.;Szymczak，Florian;Mallone，Roberto
1型糖尿病（T1 D）的一个令人困惑的特征是免疫系统破坏胰腺β细胞，但不破坏邻近的α细胞，即使β细胞和α细胞都功能失调。然而，只有β细胞的功能障碍才会发展到死亡。最近的研究结果表明这两种细胞类型之间存在重要差异。首先，BCL 2L 1（一种关键的抗凋亡基因）在α细胞中的表达高于β细胞。第二，内质网应激相关基因的表达存在差异，β细胞中促凋亡CHOP的表达水平高于α细胞，α细胞中HSPA 5（编码保护性伴侣BiP）的表达水平高于β细胞。第三，病毒识别和先天免疫应答基因在α细胞中的表达高于β细胞，有助于增强α细胞对柯萨奇病毒感染的抵抗力。第四，免疫抑制性HLA-E分子在α细胞中的表达高于β细胞。值得注意的是，α细胞的免疫原性低于β细胞，并且侵入T1 D中胰岛的CD 8 +T细胞对前胰岛素原有反应，但对胰高血糖素无反应。我们认为，这一发现是α细胞耐受病毒感染和ER应激的能力增强的结果，这使它们能够更好地在早期应激源中存活，这些应激源可能导致细胞死亡，从而扩大抗原呈递给免疫系统。此外，与前胰岛素原相比，前胰高血糖素原前体在肠内分泌细胞中的加工可能有利于对这种潜在自身抗原的免疫耐受。
A perplexing feature of type 1 diabetes (T1D) is that the immune system destroys pancreatic β-cells but not neighbouring α-cells, even though both β-cells and α-cells are dysfunctional. Dysfunction, however, progresses to death only for β-cells. Recent findings indicate important differences between these two cell types. First, expression ofBCL2L1, a key antiapoptotic gene, is higher in α-cells than in β-cells. Second, endoplasmic reticulum (ER) stress-related genes are differentially expressed, with higher expression levels of pro-apoptoticCHOPin β-cells than in α-cells and higher expression levels ofHSPA5(which encodes the protective chaperone BiP) in α-cells than in β-cells. Third, expression of viral recognition and innate immune response genes is higher in α-cells than in β-cells, contributing to the enhanced resistance of α-cells to coxsackievirus infection. Fourth, expression of the immune-inhibitory HLA-E molecule is higher in α-cells than in β-cells. Of note, α-cells are less immunogenic than β-cells, and the CD8+T cells invading the islets in T1D are reactive to pre-proinsulin but not to glucagon. We suggest that this finding is a result of the enhanced capacity of the α-cell to endure viral infections and ER stress, which enables them to better survive early stressors that can cause cell death and consequently amplify antigen presentation to the immune system. Moreover, the processing of the pre-proglucagon precursor in enteroendocrine cells might favour immune tolerance towards this potential self-antigen compared to pre-proinsulin.