Phenotypic analysis of b cells in a pair of identical, HLA∗B44 female twins discordant for common variable immunodeficiency and recurrent sino-pulmonary infection

In our clinic a majority of CVID and RESPI [REcurrent Sino-Pulmonary Infection with normal serum Ig levels] patients are HLA∗B44 or ∗B8. We evaluated B cell subset distributions among 234 CVID, RESPI and control study subjects. CVID patients exhibited the lowest numbers of IgM+IgD+CD27+ marginal zonelike B cells, with RESPI intermediate between CVID and controls. Compared to controls, both CVID and RESPI had similarly depressed numbers of IgM+IgDCD27+ memory B cells; but IgM-IgD-CD27+ class switched cells were low only in CVID. Among our patients was a pair of HLA B∗44 female twins identical by whole genome sequencing, but discordant for CVID [IgG 477 mg/dl] and RESPI [IgG 733 mg/dl]. Compared to the RESPI twin, the blood of the CVID twin exhibited higher numbers of immature B cells, but progressively lower numbers of transitional, mature, memory IgD+ (p=0.01), memory IgD- (p=0.02), and plasmacytes. Deep-sequencing of immunoglobulin transcripts from the transitional, mature, memory IgD+, memory IgD- and plasmacyte fractions revealed a consistently lower prevalence of tyrosine in the CDRH3 loop (p< 0.0001) of the CVID twin. The relative paucity of tyrosine was most pronounced in the plasmacyte fraction (12.4% CVID vs 16.1% control). These findings suggest that in addition to an acquired block in B cell development at the transitional cell stage, the CVID twin produces an immunoglobulin repertoire that is markedly depleted of tyrosine. This may help explain why the function of the antibody repertoire in CVID is more impaired than what might be expected by serum immunoglobulin level alone.