T-cell and monocyte DNA methylation and Wnt dysregulation in common variable immunodeficiency: an exploratory study.

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 Methods: Whole-genome bisulphite sequencing was performed on purified CD3 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.