Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients

J Clin Immunol. 2024 May 23;44(6):133. doi: 10.1007/s10875-024-01726-5.


Purpose: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

Keywords: 5-methylcytosine; CVID; Celiac disease; CpG regions; Duodenum; Epigenetic; Gastrointestinal tract; Genome-wide DNA methylation; Primary immunodeficiency; TNF.

MeSH terms

  • 5-Methylcytosine / metabolism
  • Adult
  • Celiac Disease* / genetics
  • Common Variable Immunodeficiency* / genetics
  • CpG Islands* / genetics
  • DNA Methylation*
  • Duodenum* / metabolism
  • Duodenum* / pathology
  • Epigenesis, Genetic*
  • Female
  • Genome-Wide Association Study
  • Humans
  • Intraepithelial Lymphocytes / immunology
  • Male
  • Middle Aged
  • Promoter Regions, Genetic / genetics
  • Young Adult


  • 5-Methylcytosine