Patterns of constitutively phosphorylated kinases in B cells are associated with disease severity in common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) constitute a clinically and immunologically heterogeneous group characterized by B-cell dysfunction with hypogammaglobulinemia and defective immunoglobulin class switch of unknown etiology. Current classification systems are insufficient to achieve precise disease management. Characterization of signaling pathways essential for B-cell differentiation and class switch could provide new means to stratify patients. We evaluated constitutive and induced signaling by phospho-specific flow cytometry in 26 CVID patients and 18 healthy blood donors. Strong responses were induced both in CVID and healthy donor B cells upon activation. In contrast, constitutive phosphorylation levels of STAT3,-5,-6, Erk, PLC-γ and Syk were significantly increased in CVID B cells only. Hierarchical clustering revealed a subgroup of CVID patients with elevated constitutive phosphorylation of Syk and PLC-γ. All these patients had non-infectious complications, indicating that a distinct phosphorylation pattern of kinases in B cells identifies a clinically important subgroup of CVID patients.