Purpose of review: In human primary immunodeficiencies, more than 100 different genetic defects have been described. For the most prevalent primary immunodeficiency requiring medical attention, however, termed common variable immunodeficiency, no genetic cause had been defined until recently. In this review we will summarize the current progress in the molecular genetics of common variable immunodeficiency and put them in context with other important developments in the field.
Recent findings: In recent years the first three monogenetic defects in the inducible costimulator, transmembrane activator and CAML interactor (TACI), and CD19 were discovered in patients with common variable immunodeficiency revealing a multifaceted genetic background for this disease. As a concise phenotype cannot be assigned to each of these genetic defects, there is a need for further development of classification systems for common variable immunodeficiency and the search of epigenetic factors influencing the course of the disease. Subgroups of common variable immunodeficiency patients with low IgM memory B cells may suffer from an increased rate of infections. Human herpes virus type 8 infections were identified as a risk factor for the development of granulomatous disease complications.
Summary: The pathogenesis of common variable immunodeficiency shows a convergence on impaired terminal B cell differentiation. Recently discovered genetic defects support this view. A combined effort of genetic analysis and standardized assessment of immunological and clinical phenotypes will be necessary to further unravel the conundrum of common variable immunodeficiency.