Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is a disorder characterized by antibody deficiency. Asignificant fraction of the patients suffer from immune dysregulation, which leads to increased morbidity and mortality. The pathogenesis of this condition is poorly understood. Our aim was to find out whether the plasma protein signature in CVID is associated with clinical characteristics and lymphocyte aberrations. A highly sensitive proximity extension assay was used for targeted profiling of 145 plasma proteins in 29 patients with CVID. Phenotyping of peripheral lymphocytes was done by flow cytometry. The findings were correlated with the burden of immune dysregulation. Unsupervised clustering of plasma protein profiles identified 2 distinct groups of patients with CVID that differed significantly in terms of the degree of complications due to immune dysregulation and in terms of the frequency of activated B- and T-cell subpopulations. Pathway analysis identified IFN-γ and IL-1β as the top enriched upstream regulators associated with higher grade of immune dysregulation. In addition, CVID was found to be associated with increased plasma levels of the B-cell-attracting chemokine CXCL13. Clustering based on plasma protein profiles delineated a subgroup of patients with CVID with activated T cells and clinical complications due to immune dysregulation. Thus, data indicate that CVID-associated immune dysregulation is a TH1-mediated inflammatory process driven by the IFN-γ pathway.