Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.
Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.
J Clin Immunol. 2024 May 23;44(6):133. doi: 10.1007/s10875-024-01726-5.
A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease.
DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3).
The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls.
This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.
相当一部分普通可变免疫缺陷（CVID）患者存在十二指肠炎症，伴有上皮内淋巴细胞（IEL）增多，其病因不明。这些患者的组织学表现类似于乳糜泻，导致在治疗方面存在混淆（无麸质饮食）。我们旨在阐明表观遗传 DNA 甲基化在 CVID 患者十二指肠炎症发病机制中的作用，并将其与真正的乳糜泻区分开来。
从十二指肠活检的速冻组织中提取 DNA，并分析 CVID 患者中 IEL 增加（CVID_IEL；n=5）与无 IEL（CVID_N；n=3）、乳糜泻（n=3）和健康对照（n=3）之间全基因组表观遗传 DNA 甲基化的差异。
CpG 位点 5-甲基胞嘧啶的 DNA 甲基化数据将 CVID 和乳糜泻与健康对照组区分开来。在 CVID 和乳糜泻中鉴定到启动子基因的差异甲基化，这些基因可能是 CVID 和乳糜泻的潜在新的介质。CVID_IEL 和乳糜泻之间与甲基化相关的基因重叠有限。与健康对照组相比，在 CVID_IEL 和乳糜泻中，在转录起始位点（TSS）附近的 100 多个基因中检测到高频差异甲基化 CpG 位点。与健康对照组相比，CVID_IEL 中涉及 TNF/细胞因子产生调节的基因的差异甲基化更为丰富。
这是第一项揭示表观遗传 DNA 甲基化在 CVID 患者十二指肠炎症发病机制中的作用的研究，将 CVID_IEL 与乳糜泻区分开来。我们在 CVID_IEL 和乳糜泻中鉴定到了基因启动子内以及 TSS 附近高频差异甲基化 CpG 区域内的潜在生物标志物和治疗靶点。
