ERAP2 是一种参与抗原加工和呈递的氨肽酶，并含有与炎症性肠病 (IBD) 等多种炎症性疾病相关的遗传变异。小鼠中缺乏 ERAP2 基因同源物阻碍了功能研究，大多数人类研究都集中在造血来源的细胞上。本研究以 IBD 生物库为有利位置，探讨了 ERAP2 的遗传变异如何影响人源性上皮类器官在促炎刺激下的基因表达。针对两个单核苷酸多态性 (SNP) (rs2910686/rs2248374) 对 IBD 患者队列进行了基因分型。与 ERAP2 表达水平相关，我们检查了结肠基因表达与基因型之间的相关性，特别是旨在建立与 ERAP2 表达水平的关系。建立了具有已知 ERAP2 基因型的人源结肠类器官（colonoids），并用于探索 ERAP2 缺陷（n = 4）和 ERAP2 丰富（n = 4）供体在促炎症反应时全基因组基因表达的差异。考虑到rs2910686基因型，ERAP2基因表达在IBD患者发炎结肠中上调。集落在 IFNɣ 刺激下上调 ERAP2，并且 ERAP2 表达能力取决于 rs2910686 基因型。结肠样基因分型证实，独立于经常研究的 SNP rs2248374 的机制可导致 ERAP2 缺陷。在促炎刺激下，ERAP2 丰富和缺乏的结肠样细胞中共有 586 个涉及各种分子机制的基因存在差异表达，包括编码具有以下分子功能的蛋白质的基因：催化活性（AOC1、CPE、ANPEP 和 MEP1A）、调节活性（TNFSF9） 、MDK、GDF15、ILR6A、LGALS3 和 FLNA）、跨膜转运蛋白活性（SLC40A1 和 SLC5A1）以及细胞外基质结构成分（FGL2、HMCN2 和 MUC17）。 ERAP2 在发炎的 IBD 结肠粘膜中表达上调，且表达熟练度高与rs2910686的基因型相关。虽然 SNP rs2248374 通常用于确定 ERAP2 表达能力，但我们的数据证实，独立于该 SNP 的机制可能导致 ERAP2 缺陷。我们的数据表明，上皮 ERAP2 的存在会影响结肠中的炎症反应，表明 ERAP2 在 MHC I 类抗原处理之外具有多效性作用。© 2024。作者。

ERAP2 is an aminopeptidase involved in antigen processing and presentation, and harbor genetic variants linked to several inflammatory diseases such as Inflammatory Bowel Disease (IBD). The lack of an ERAP2 gene homologue in mice has hampered functional studies, and most human studies have focused on cells of hematopoietic origin. Using an IBD biobank as vantage point, this study explores how genetic variation in ERAP2 affects gene expression in human-derived epithelial organoids upon proinflammatory stimulation.An IBD patient cohort was genotyped with regards to two single nucleotide polymorphisms (SNP) (rs2910686/rs2248374) associated with ERAP2 expression levels, and we examined the correlation between colon gene expression and genotype, specifically aiming to establish a relationship with ERAP2 expression proficiency. Human-derived colon organoids (colonoids) with known ERAP2 genotype were established and used to explore differences in whole genome gene expression between ERAP2-deficient (n = 4) and -proficient (n = 4) donors upon pro-inflammatory encounter.When taking rs2910686 genotype into account, ERAP2 gene expression is upregulated in the inflamed colon of IBD patients. Colonoids upregulate ERAP2 upon IFNɣ stimulation, and ERAP2 expression proficiency is dependent on rs2910686 genotype. Colonoid genotyping confirms that mechanisms independent of the frequently studied SNP rs2248374 can cause ERAP2-deficiency. A total of 586 genes involved in various molecular mechanisms are differentially expressed between ERAP2 proficient- and deficient colonoids upon proinflammatory stimulation, including genes encoding proteins with the following molecular function: catalytic activity (AOC1, CPE, ANPEP and MEP1A), regulator activity (TNFSF9, MDK, GDF15, ILR6A, LGALS3 and FLNA), transmembrane transporter activity (SLC40A1 and SLC5A1), and extracellular matrix structural constituents (FGL2, HMCN2, and MUC17).ERAP2 is upregulated in the inflamed IBD colon mucosa, and expression proficiency is highly correlated with genotype of rs2910686. While the SNP rs2248374 is commonly used to determine ERAP2 expressional proficiency, our data confirms that mechanisms independent of this SNP can lead to ERAP2 deficiency. Our data demonstrates that epithelial ERAP2 presence affects the inflammatory response in colonoids, suggesting a pleiotropic role of ERAP2 beyond MHC class I antigen processing.© 2024. The Author(s).