Vav1 Haploinsufficiency in Common Variable Hypogammaglobulinemia with Defective T Cell Function

摘要

Common variable immunodeficiency (CVID) is a primary immune disorder characterized by impaired antibody production, which is in many instances secondary to defective T cell function (T-CVID). A subset of TCVID patients are characterized by defective expression of Vav1, a guanine nucleotide exchanger which couples the T-cell antigen receptor to reorganization of the actin cytoskeleton. Vav1-deficient patients with CVID display a defective Th2 cell polarization and an alteration in the Th1/Th2 balance, as assessed by the consistent significant reduction in IL-4 and the overall enhancement in IFN production. Furthermore Vav1-deficient patients have impaired expression of the Th2 lineage–specific transcription factors c-Maf and GATA-3. Of note, reconstitution of Vav1 expression in T cells from patients with T-CVID resulted in their functional rescue, measured as the capacity to provide B-cell help and antibody production. We identified in one T-CVID patient a heterozygous deletion in Vav1. The gene deletion, spanning exons 2-27, accounts for the reduction in Vav1 mRNA and protein in T cells from this patient. The disease related pedigree of this patient suggests a de novo origin of the Vav1 deletion. The findings highlights Vav1 as an autosomal dominant disease gene associated with CVID with defective T-cell function.