Distinct Proteomic and Transcriptomic Profiles in T-cells and Monocytes in Patients with Common Variable Immunodeficiency: an Exploratory Study

A substantial proportion of Common Variable Immunodeficiency (CVID) patients has autoimmune and inflammatory complications (CVID COMP ), associated with T‑cell and monocyte pathology, but the underlying molecular mechanisms remain unclear. We aimed to identify novel immunopathogenic pathways in this inflammation‑prone CVID phenotype. We performed RNA‑seq and mass‑spectrometry–based proteomics on isolated CD3⁺ T cells and CD14⁺ monocytes from CVID patients and healthy controls (HC). Differentially expressed genes (DEGs), proteins (DEPs) and pathways (Hallmark GSEA) were assessed. Plasma IL‑1β and CXCL10 were measured by multiplex assay, IL‑18 and CXCL9 by EIA. CVID COMP patients (RNAseq: n = 5, proteomics: n = 13) showed broader transcriptional and proteomic changes in CD14⁺ monocytes than in CD3⁺ T cells. In CD14⁺ monocytes, RNAseq revealed enrichment of “TNFα/NF-κB” signalling and “Interferon γ response”, while proteomics showed enrichment of “Interferon α response”. Conversely, proteomic analyses of cells from CVID without inflammatory/autoimmune complications (n = 5–9) showed only minor differences compared with HC (n = 10). In CVID COMP , GBP1, GBP4, GBP5, STAT1 and LGALS3BP were upregulated at both mRNA and protein levels, and several of these interferon‑/inflammasome‑related genes were upregulated in an independent CVID cohort from a public dataset. Plasma levels of IL‑1β, IL‑18, CXCL9 and CXCL10, reflecting inflammasome and interferon activity, were increased in two additional CVID cohorts (CVID = 104/60, HC = 22/30), with the highest concentrations in CVID COMP . This integrated analysis supports an inflammatory signature in CVID COMP monocytes, involving interferon‑ and inflammasome‑related pathways. The findings highlight CD14⁺ monocytes and their downstream mediators as potential targets for future mechanistic and therapeutic studies.