Common variable immune deficiency disorder (CVID) is the most clinically relevant cause of antibody failure. It is a highly heterogeneous disease with different underlying etiologies. CVID has been associated with a quantitative B cell defect, however, little is known about the quality of B cells present. Here, we studied the naïve and antigen selected B-cell receptor (BCR) repertoire in 33 CVID patients using next generation sequencing, to investigate B cells quality. Analysis for each individual patient revealed whether they have a defect in immune repertoire formation [V(D)J recombination] or specification (somatic hypermutation, subclass distribution, or selection). The naïve BCR repertoire was normal in most of the patients, although alterations in repertoire diversity and the junctions were found in a limited number of patients indicating possible defects in early B-cell development or V(D)J recombination in these patients. In contrast, major differences were found in the antigen selected BCR repertoire. Here, most patients (15/17) showed a reduced frequency of somatic hypermutation (SHM), changes in subclass distribution and/or minor alterations in antigen selection. Together these data show that in our CVID cohort only a small number of patients have a defect in formation of the naïve BCR repertoire, whereas the clear majority of patients have disturbances in their antigen selected repertoire, suggesting a defect in repertoire specification in the germinal centers of these patients. This highlights that CVID patients not only have a quantitative B cell defect, but that also the quality of, especially post germinal center B cells, is impaired.

B-cell receptor repertoire, common variable immune deficiency disorder, germinal center, repertoire formation, repertoire specification, somatic hypermutation,
Frontiers in Immunology
Department of Immunology

van Schouwenburg, P.A, Jspeert, H.I. (Hanna I.), Pico-Knijnenburg, I, Dalm, V.A.S.H, van Hagen, P.M, van Zessen, D, … van der Burg, M. (2018). Identification of CVID patients with defects in immune repertoire formation or specification. Frontiers in Immunology, 9(NOV). doi:10.3389/fimmu.2018.02545