Phenotypic analysis of B cell subsets in HLA*B44 positive identical twins discordant for common variable immunodeficiency and recurrent sino-pulmonary infection (P3331)

Abstract

Abstract Depressed serum immunoglobulin levels (sIgs) and recurrent sinopulmonary infections mark Common Variable Immune Deficiency (CVID). Many family members of CVID patients also suffer recurrent sinopulmonary infection (RESPI) but have normal sIg. We identified HLAB44 positive identical female twins who suffer sinopulmonary infections and are discordant for CVID and RESPI. Flow cytometry subsets showed equivalent numbers of immature B cells (BC) in both twins, but lower numbers of transitional and mature BC in the CVID twin. Deep sequencing of the immunoglobulin (Ig) repertoires expressed by the transitional and mature BC showed a significant divergence in the utilization of VH1 and VH4 family gene segments, with CVID favoring VH4 and RESPI VH1. RESPI twin used JH6 more frequently, whereas CVID twin used JH3. The amino acid composition of CDR-H3 repertoire was compared with a control; the twin and control tyrosine usage in transitional BC was similar (~15%) but greatly diverged in mature BC (control 15%, RESPI 25%, CVID < 10%). Whole genome sequencing revealed homozygosity for a rare CD21 S639N polymorphism and heterozygosity for CD19 L174V. These findings suggest that in addition to an acquired block in BC development at the transitional stage, the CVID twin produces an Ig repertoire that is markedly depleted of tyrosine. This may explain why the function of the Ig repertoire in CVID is more impaired than what might be expected by sIgs levels.