浙江大学学报（医学版）2026，Vol.55Issue(4)：352-363,12.DOI:10.3724/zdxbyxb-2025-0692
ULBP-NKG2D轴在自身免疫病中的研究进展
Research progress of the ULBP-NKG2D axis in autoimmune diseases
摘要
Abstract
The activating receptor natural killer group 2 member D(NKG2D)and its ligands,the UL16-binding protein(ULBP),play pivotal roles in autoimmune diseases,characterized by multidimensional regulatory features.This review employs a three-dimensional framework of"ligand supply-ligand fate-receptor regulation"to analyze the research progress of the ULBP-NKG2D axis in autoimmune diseases,including systemic lupus erythematosus,rheumatoid arthritis,type 1 diabetes,multiple sclerosis,and Crohn disease.In systemic lupus erythematosus,the axis involves both peripheral immune suppression(driven by receptor internalization)and local tissue immune attack,collectively shaping the complex pathology.In rheumatoid arthritis,the core pathological dysre-gulation of the axis is concentrated in the inflammatory synovial microenvironment:membrane-bound ligands derived from synovial fibroblasts directly drive the cytotoxicity of local effector cells,exacerbating joint inflammatory damage,while these ligands may be cleaved by a disintegrin and metalloprotease 10(ADAM10)into soluble forms that enter the circulation and mediate peripheral immunosuppression.In type 1 diabetes,pancreatic β cells directly trigger NKG2D-mediated immune killing by upregulating membrane-bound ULBP proteins.In multiple sclerosis,astrocyte-derived ULBP4,in both membrane-bound and soluble forms,enhances the migration and pro-inflammatory capacity of effector cells.In Crohn disease,endoplasmic reticulum stress induces widespread ULBP expression in intestinal epithelial and endothelial cells,collectively mediating immune cell recruitment and amplifying local inflammation.This review also summarizes the current status of innovative drugs targeting the NKG2D receptor and their clinical translation progress,aiming to provide a reference for unraveling the complex immunopathology and developing precision immunotherapy strategies.关键词
自身免疫病/自然杀伤细胞/自然杀伤细胞家族2成员D/UL16结合蛋白/免疫治疗/综述Key words
Autoimmune disease/Natural killer cells/Natural killer group 2 member D/UL16-binding protein/Immunotherapy/Review分类
医药卫生引用本文复制引用
马佳妮,吴静,金燕樑..ULBP-NKG2D轴在自身免疫病中的研究进展[J].浙江大学学报（医学版）,2026,55(4):352-363,12.基金项目
国家自然科学基金(82171795) （82171795）
浦东新区科技发展基金(PKJ2018-Y44)This study was supported by National Natural Science Foundation of China(82171795)and Science and Technology Development Fund of Shanghai Pudong New Area(PKJ2018-Y44). （PKJ2018-Y44）
