Common variable immunodeficiency (CVID) is a disorder characterized by antibody deficiency. A significant fraction of the patients suffers from immune dysregulation, that leads to increased morbidity and mortality. The pathogenesis of this condition is poorly understood. To find out if 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

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... 9 patients with CVID. Phenotyping of peripheral lymphocytes was done by flow cytometry. The findings were correlated to the burden of immune dysregulation. Unsupervised clustering of plasma protein profiles identified two distinct groups of CVID patients that differed significantly in the degree of complications due to immune dysregulation and in the frequency of activated B- and T-cell subpopulations. Pathway analysis identified interferon-γ and interleukin (IL)-1β as 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 CVID patients with activated T cells and clinical complications due to immune dysregulation. Thus, data indicate that CVID-associated immune dysregulation is a T-helper 1 mediated inflammatory process driven by the interferon-γ pathway. Profiling of plasma protein identifies biomarkers associated with immune dysregulation in CVID that may help delineating the underlying molecular mechanisms and pave the way for tailored treatment strategies.