Diminished secondary recombination and corresponding defective central tolerance in the new emigrant/transitional B cells of CVID group-Ia patients. (A) Receptor editing is mediated by successive rounds of secondary recombination catalyzed by RAG enzymes with replacement of existing Igκ gene rearrangements with newly joined upstream Vκ and downstream Jκ gene segments. Increased Jκ1 (B) combined to decreased upstream Vκ (C) gene segment usage in the new emigrant/transitional B cells of CVID group-Ia patients reveals a unique repertoire niche (D) reflecting a history of decreased secondary recombination compared with healthy controls and non-group-Ia CVID patients. (E) An increased frequency of polyreactive new emigrant B cells in CVID group-Ia patients compared with healthy controls demonstrates a central defect in B-cell tolerance in these patients. Each diamond represents an individual, and the average is shown with a bar.