T-cell and monocyte DNA methylation and Wnt dysregulation in common variable immunodeficiency: an exploratory study
- 1Research Institute of Internal Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital , ,
- 2Department of Microbiology, Oslo University Hospital , ,
- 3Institute of Clinical Medicine, University of Oslo , ,
Abstract
Background: Many patients with common variable immunodeficiency (CVID) develop inflammatory/autoimmune complications associated with T-cell and monocyte dysregulation which may involve epigenetic modifications.
Objective: To characterize genome-wide CpG methylation in CD3 ⁺ T-cells and CD14 ⁺ monocytes in CVID and relate epigenetic alterations to gene expression and circulating proteins.
Methods: Whole-genome bisulphite sequencing was performed on purified CD3 ⁺ T-cells and CD14 ⁺ monocytes from three CVID patients with inflammatory complications and three healthy controls per cell type. Differentially methylated cytosines were identified and analysed by pathway over-representation. Selected pathway-related proteins were measured in plasma from 60 CVID patients and 30 controls and evaluated in three public CVID transcriptomic datasets.
Results: In this small discovery cohort, CVID was associated with widespread, cell type-specific methylation differences in T-cells and monocytes. T-cells showed a predominance of hypomethylated cytosines and regions, whereas monocytes displayed a more mixed pattern with roughly balanced hypo- and hypermethylation at individual sites. In T-cells, pathway analysis identified Wnt signalling, T-cell differentiation and actin organisation among the top differentially methylated processes. As Wnt signalling is underexplored in CVID and key Wnt modulators are measurable in plasma, we measured Wnt-related proteins in a larger CVID cohort and controls. In plasma, the Wnt antagonists DKK1 and DKK3 were reduced and Wnt agonist RSPO3 increased in CVID. Analyses of three public CVID transcriptomic datasets showed differential expression of Wnt-related genes. Monocyte pathway signals, mainly related to cell adhesion and actin organisation, were more heterogeneous and should be regarded as exploratory given the very small discovery cohort and the inclusion of a patient with a TNFAIP3 variant.
Conclusion: In this explorative study we found that CVID is associated with extensive, cell type-specific epigenetic remodelling, particularly in T cells. Wnt signalling emerges as a recurrently altered pathway across DNA methylation, circulating proteins and gene expression, supporting Wnt-related mechanisms as a potential contributor to CVID immunopathology that should be further explored.
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BibTeX
@article{myhre2026tcell,
title = {{T-cell and monocyte DNA methylation and Wnt dysregulation in common variable immunodeficiency: an exploratory study}},
author = {Vegard Myhre and Mingyi Yang and Mari Kaarbø and Mai Sasaki Aanensen Fraz and Annika E. Michelsen and Børre Fevang and Pål Aukrust and Thor Ueland and Magnar Bjørås and Silje Fjellgård Jørgensen},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1931297},
url = {https://europepmc.org/article/PMC/PMC13668603},
note = {CC BY},
}
RIS
TY - JOUR
TI - T-cell and monocyte DNA methylation and Wnt dysregulation in common variable immunodeficiency: an exploratory study
AU - Vegard Myhre
AU - Mingyi Yang
AU - Mari Kaarbø
AU - Mai Sasaki Aanensen Fraz
AU - Annika E. Michelsen
AU - Børre Fevang
AU - Pål Aukrust
AU - Thor Ueland
AU - Magnar Bjørås
AU - Silje Fjellgård Jørgensen
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1931297
UR - https://europepmc.org/article/PMC/PMC13668603
AB - Background: Many patients with common variable immunodeficiency (CVID) develop inflammatory/autoimmune complications associated with T-cell and monocyte dysregulation which may involve epigenetic modifications. Objective: To characterize genome-wide CpG methylation in CD3 ⁺ T-cells and CD14 ⁺ monocytes in CVID and relate epigenetic alterations to gene expression and circulating proteins. Methods: Whole-genome bisulphite sequencing was performed on purified CD3 ⁺ T-cells and CD14 ⁺ monocytes from three CVID patients with inflammatory complications and three healthy controls per cell type. Differentially methylated cytosines were identified and analysed by pathway over-representation. Selected pathway-related proteins were measured in plasma from 60 CVID patients and 30 controls and evaluated in three public CVID transcriptomic datasets. Results: In this small discovery cohort, CVID was associated with widespread, cell type-specific methylation differences in T-cells and monocytes. T-cells showed a predominance of hypomethylated cytosines and regions, whereas monocytes displayed a more mixed pattern with roughly balanced hypo- and hypermethylation at individual sites. In T-cells, pathway analysis identified Wnt signalling, T-cell differentiation and actin organisation among the top differentially methylated processes. As Wnt signalling is underexplored in CVID and key Wnt modulators are measurable in plasma, we measured Wnt-related proteins in a larger CVID cohort and controls. In plasma, the Wnt antagonists DKK1 and DKK3 were reduced and Wnt agonist RSPO3 increased in CVID. Analyses of three public CVID transcriptomic datasets showed differential expression of Wnt-related genes. Monocyte pathway signals, mainly related to cell adhesion and actin organisation, were more heterogeneous and should be regarded as exploratory given the very small discovery cohort and the inclusion of a patient with a TNFAIP3 variant. Conclusion: In this explorative study we found that CVID is associated with extensive, cell type-specific epigenetic remodelling, particularly in T cells. Wnt signalling emerges as a recurrently altered pathway across DNA methylation, circulating proteins and gene expression, supporting Wnt-related mechanisms as a potential contributor to CVID immunopathology that should be further explored.
SN - 1664-3224
ER -