Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes.
Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes.
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DOI：
10.3389/fendo.2020.568446
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发表时间：
2020
影响因子：
5.2
通讯作者：
Eizirik DL
中科院分区：
文献类型：
--
作者：
Colli ML;Szymczak F;Eizirik DL
1型糖尿病（T1 D）是一种慢性疾病，由浸润的免疫细胞选择性破坏产生胰岛素的胰腺β细胞引起。我们目前评估了在早期T1 D的β细胞中观察到的转录组特征，并将其与在体外将人胰岛暴露于炎症或代谢应激后观察到的特征进行比较，目的是鉴定靶β细胞中免疫攻击的“足迹”。我们检测到在疾病的不同时刻存在的细胞因子诱导的β细胞特征之间的相似性，即，干扰素-α（早期疾病）和白细胞介素-1 β加干扰素-γ（晚期阶段）以及来自T1 D患者的β细胞，鉴定在疾病早期和晚期阶段激活的生物过程和信号通路。在β细胞上触发的第一反应中是抗病毒反应、模式识别受体活化、蛋白质修饰和MHC I类抗原呈递的富集。在假定的胰岛炎的后期阶段，该过程由T细胞募集和激活以及β细胞试图通过抗炎途径的激活来保护自己（即，IL 10，IL 4/13）和免疫检查点蛋白（即，PDL 1和HLA-E）。最后，我们使用Connectivity Map（一个大型化合物/药物数据库）挖掘了T1 D患者胰岛中的β细胞特征，并确定了可能逆转胰岛炎对β细胞影响的有趣候选者。
Type 1 diabetes (T1D) is a chronic disease caused by the selective destruction of the insulin-producing pancreatic beta cells by infiltrating immune cells. We presently evaluated the transcriptomic signature observed in beta cells in early T1D and compared it with the signatures observed following in vitro exposure of human islets to inflammatory or metabolic stresses, with the aim of identifying “footprints” of the immune assault in the target beta cells. We detected similarities between the beta cell signatures induced by cytokines present at different moments of the disease, i.e., interferon-α (early disease) and interleukin-1β plus interferon-γ (later stages) and the beta cells from T1D patients, identifying biological process and signaling pathways activated during early and late stages of the disease. Among the first responses triggered on beta cells was an enrichment in antiviral responses, pattern recognition receptors activation, protein modification and MHC class I antigen presentation. During putative later stages of insulitis the processes were dominated by T-cell recruitment and activation and attempts of beta cells to defend themselves through the activation of anti-inflammatory pathways (i.e., IL10, IL4/13) and immune check-point proteins (i.e., PDL1 and HLA-E). Finally, we mined the beta cell signature in islets from T1D patients using the Connectivity Map, a large database of chemical compounds/drugs, and identified interesting candidates to potentially revert the effects of insulitis on beta cells.
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影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
7.7
作者：
Fu W;Farache J;Clardy SM;Hattori K;Mander P;Lee K;Rioja I;Weissleder R;Prinjha RK;Benoist C;Mathis D
通讯作者：
Mathis D
影响因子：
17.1
作者：
Engin F;Yermalovich A;Nguyen T;Hummasti S;Fu W;Eizirik DL;Mathis D;Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
7.5
作者：
Demine, Stephane;Schiavo, Andrea Alex;Eizirik, Decio L.
通讯作者：
Eizirik, Decio L.