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Abstract Defects of memory B cells and of somatic hypermutation (SHM) are involved in the pathogenesis of common variable immunodeficiency (CVID). Here we report for the first time a systematic study of the relationship between memory B cell deficiency and SHM abnormalities in CVID, and relate these variables to prediagnostic infections. Isotype switched Vh3-23 transcripts were undetectable or low in 30% (IgG) and 63% (IgA) of the patients, but never in controls (P < 0.001). When measurable, the SHM fraction of transcripts was significantly lower in patients (IgM: median 32% vs. 56% (P = 0.0002); IgG: 72% vs. 87% (P = 0.0002); IgA: 81% vs. 88% (P = 0.04)). The concentration of switched (CD19+/CD27+/IgG+) and unswitched (CD19+/CD27+/IgM+/IgD+) memory cells was reduced in 75% and 58% of the patients, respectively. Patients with reduced concentrations of switched memory B cells had normal or low SHM, and only the IgG SHM fraction correlated with prediagnostic incidence of severe respiratory tract infections (P = 0.004). [ABSTRACT FROM AUTHOR]