Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G Harrison
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引用次数: 0
摘要
翻译后修饰可增强自身蛋白的免疫原性。在包括高血压、系统性红斑狼疮和心力衰竭在内的多种疾病中,脂质过氧化会形成异蓝藻素(IsoLGs),并与蛋白质赖氨酸残基共价键合。在这里,我们发现小鼠 I 类主要组织相容性复合体(MHC-I)变体 H-2Db 能独特地呈现异LG修饰的肽,并开发了一种计算管道,用于识别 MHC-I 容纳此类肽的结构特征。我们从肾脏蛋白(包括葡萄糖钠转运体 2、粘连蛋白 16、含 Kelch 结构域的蛋白 7A 和溶质运载家族 23)中鉴定出了可被高血压小鼠组织中的 CD8+ T 细胞识别、体外诱导 T 细胞增殖并在收养性转移后引发高血压的异LG修饰肽。最后,我们发现 I 类人类白细胞抗原中的异LG诱导抗原限制模式与鼠类类似物相似。因此,我们采用了计算与实验相结合的方法来确定高血压可能的抗原肽。
Posttranslationally modified self-peptides promote hypertension in mouse models.
Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain-containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.
期刊介绍:
The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science.
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The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.