Islet amyloid disrupts MHC Class II antigen presentation and protects NOD mice from autoimmune diabetes.

Heather C Denroche, Victoria Ng, Jane Velghe, Imelda Suen, Liam Stanley, Dominika Nackiewicz, Mitsu Komba, Sam Chen, Galina Soukhatcheva, Lei Dai, C Bruce Verchere
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Abstract

Islet amyloid contributes to beta cell failure in type 2 diabetes through several mechanisms, one being the potent induction of local islet inflammation through activating inflammatory pathways in islet macrophages. We performed an unbiased phenotypic investigation of islet macrophages in the early stage of islet amyloid formation using single cell RNA sequencing of resident islet macrophages in mice with and without the amyloidogenic form of human islet amyloid polypeptide (hIAPP). This revealed that MHC Class II antigen presentation genes were strongly down-regulated in islet macrophages during islet amyloid formation. As islet amyloid has recently been reported in pancreases of people with type 1 diabetes, we sought to investigate the impact of islet amyloid in the NOD mouse model of type 1 diabetes. Both overexpression and physiological expression of hIAPP delayed diabetes in NOD mice relative to littermate controls, corresponding with decreased markers of antigen presentation and activation, as well as decreased immune cell infiltration in islets. Adoptive transfer studies showed that systemic autoimmune function remained intact and beta cells from hIAPP transgenic mice did not evade immune recognition by diabetogenic T cells, collectively indicating the protection from diabetes was mediated by localized disruption of antigen presentation in the pancreas. Consistent with this, incubation of dendritic cells with IAPP aggregates decreased MHC Class II surface expression and diminished antigen-specific T cell activation in vitro, through a phagocytosis-dependent mechanism. Collectively our data show that despite the well-established pro-inflammatory response of macrophages to IAPP aggregates, the uptake of IAPP aggregates during early amyloid formation also disrupts MHC Class II antigen presentation and slows beta cell autoimmunity.
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胰岛淀粉样蛋白可破坏 MHC II 类抗原呈递,保护 NOD 小鼠免受自身免疫性糖尿病的侵害。
胰岛淀粉样蛋白通过多种机制导致2型糖尿病患者的β细胞衰竭,其中一种机制是通过激活胰岛巨噬细胞的炎症通路强力诱导局部胰岛炎症。我们利用单细胞 RNA 测序技术,对胰岛巨噬细胞在胰岛淀粉样蛋白形成早期阶段的表型进行了无偏见的研究。结果发现,在胰岛淀粉样蛋白形成过程中,胰岛巨噬细胞中的 MHC II 类抗原呈递基因被强烈下调。由于最近有报道称 1 型糖尿病患者的胰腺中存在胰岛淀粉样蛋白,我们试图研究胰岛淀粉样蛋白对 1 型糖尿病 NOD 小鼠模型的影响。与同卵对照组相比,hIAPP 的过表达和生理性表达都能延缓 NOD 小鼠的糖尿病,这与抗原呈递和激活标记物的减少以及胰岛免疫细胞浸润的减少有关。接受性转移研究表明,全身自身免疫功能保持完好,来自 hIAPP 转基因小鼠的 beta 细胞并没有逃避致糖尿病 T 细胞的免疫识别,这共同表明糖尿病保护是由胰腺中抗原呈递的局部破坏介导的。与此相一致的是,用 IAPP 聚集物培养树突状细胞会降低 MHC II 类表面表达,并通过吞噬依赖机制降低体外抗原特异性 T 细胞的活化。总之,我们的数据表明,尽管巨噬细胞对 IAPP 聚集物的促炎反应已得到证实,但在早期淀粉样蛋白形成过程中对 IAPP 聚集物的摄取也会破坏 MHC II 类抗原呈递并减缓β细胞自身免疫。
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