Tackling the heterogeneity of CVID

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Abstract
Common variable immunodeficiency is clinically the most relevant primary immunodeficiency of the adult. Its heterogeneity has hindered progress in the pathogenetic understanding of the majority of common variable immunodeficiency patients. This abstract summarizes recent aspects of the field and emphasizes the need for a commonly accepted approach to classify common variable immunodeficiency. In the last 2 years, the first genetic defects underlying common variable immunodeficiency, including ICOS, TACI, BAFF-R and CD19, have been identified. The analysis of dendritic cells demonstrated alterations in a majority of patients in addition to the disturbed T and B-cell function. Several changes of the adaptive immune system might be secondary to an underlying chronic inflammatory setting possibly due to a HHV8 infection in a subgroup of patients with granulomatous disease, autoimmune phenomena and T-cell dysfunction. The occurrence of granulomatous inflammation is associated with a worse prognosis compared with common variable immunodeficiency patients without granuloma. The pathogenesis of common variable immunodeficiency includes disturbances of the adaptive as well as innate immune system. Identified monogenic defects account for about 10% of cases, leaving the majority of defects undefined and certainly in part epigenetic. To combine the known aspects of the pathogenesis of common variable immunodeficiency to a conclusive picture, the clinical and immunologic phenotyping of patients needs to be standardized.