CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans

Somatically mutated IgM(+)-only and IgM(+)IgD(+)CD27(+) B lymphocytes comprise ≈25% of the human peripheral B cell pool. These cells phenotypically resemble class-switched B cells and have therefore been classified as postgerminal center memory B cells. X-linked hyper IgM patients have a genetic defect characterized by a mutation of the CD40L gene. These patients, who do not express a functional CD40 ligand, cannot switch Ig isotypes and do not form germinal centers and memory B cells. We report here that an IgM(+)IgD(+)CD27(+) B cell subset with somatically mutated Ig receptors is generated in these patients, implying that these cells expand and diversify their Ig receptors in the absence of classical cognate T–B collaboration. The presence of this sole subset in the absence of IgM(+)-only and switched CD27(+) memory B cells suggests that it belongs to a separate diversification pathway.