Common variable immunodeficiency: a multifaceted and puzzling disorder.

Common variable immunodeficiencies (CVIDs) encompass a heterogeneous group of disorders characterized by hypogammaglobulinemia, recurrent infections and a variety of sequelae. Recently, genetic defects in ICOS, TACI, CD19, Msh5 and BAFF-R have been attributed as monogenic disease-causing or risk-increasing factors in the pathogenesis of CVIDs, but may explain only a minority of cases. By contrast, numerous immunological studies have revealed more- or less-common phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells in patients with CVID. Impaired terminal differentiation of peripheral B cells is found in approximately 80% of CVID patients and provides a framework for classification models. Several recent multicenter clinical studies delineate clinical phenotypes, predictive clinical and immunological markers, and report on the long-term outcomes in large cohorts of CVID patients. Identification of distinct immunological and clinical subtypes in CVID, and the interrelations between genetic defects, immunological abnormalities and clinical phenotypes, will improve our understanding of these diseases and their pathogeneses.