Th127 - Proteomic Signatures Distinguish Common Variable Immunodeficiency with Immune Dysregulation from Related Immune-mediated Inflammatory Diseases

Abstract Text: Introduction
Common Variable Immunodeficiency with immune dysregulation (CVIDid) is the primary cause of morbidity and mortality in CVID patients. Clinically, CVIDid may resemble other immune-mediated inflammatory diseases (IMIDs) like Sjögren’s Syndrome and rheumatological conditions. Through comparing serum proteomic profiles of CVID and related IMIDs we aimed to clarify whether CVIDid should be regarded as a dinstinct disease entity.

Methods
We analyzed 315 serum samples, quantifying 92 immune-related proteins using a proximity extension assay in healthy controls and patients with Atopic Dermatitis, Sjögren’s Syndrome, Checkpoint Inhibition toxicity, Rheumatoid Arthritis, CVIDid, and CVID with infections only (CVIDio). Feature selection was performed via elastic net regression, followed by cluster analysis to identify distinct proteomic patterns.

Results
CVIDid exhibited a unique T/NK‐cell cluster featuring CRTAM, KLRD1, CD8A, but also IL10, suggesting heightened cytotoxic activity and chronic inflammation. Atopic Dermatitis showed a prominent Th2-skewed profile (MCP4, CCL17), whereas Rheumatoid Arthritis and Sjögren’s Syndrome showed more pronounced proinflammatory (IL-6, TNF) and IFN-driven (CXCL11, Galectin-9) signatures, respectively. Checkpoint Inhibition toxicity showed exceptionally high PDCD1 and IFN-γ. Notably, lymphoid organ related proteins (CXCL13, CCL19, ICOSLG, LAMP3) were more pronounced in CVIDid, underscoring a dysregulated yet active lymphoid microenvironment. CVIDio showed a dampened inflammatory signature, emphasizing distinct immunopathology from CVIDid.

Conclusions
Proteomic profiles confirm CVIDid as a distinct disease entity, characterized by high T/NK-cell activity and an active lymphoid microenvironment, despite poor antibody production. This paradox points to a chronic inflammatory state where multi-targeted therapies, such as JAK-inhibitors, may be effective treatment options.