Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease

Individuals with X-linked lymphoproliferative disease (XLP) display defects in B cell differentiation in vivo. Specifically, XLP patients do not generate a normal number of CD27(+) memory B cells, and those few that are present are IgM(+). Recent studies have suggested that IgM(+)CD27(+) B cells are not true memory cells, but rather B cells that guard against T cell-independent pathogens. Here we show that human XLP IgM(+)CD27(+) B cells resemble normal memory B cells both morphologically and phenotypically. Additionally, IgM(+)CD27(+) B cells exhibited functional characteristics of normal memory B cells, including the ability to secrete more Ig than naive B cells in response to both T cell-dependent and -independent stimuli. Analysis of spleens from XLP patients revealed a paucity of germinal centers (GCs), and the rare GCs detected were poorly formed. Despite this, Ig variable region genes expressed by XLP IgM(+)CD27(+) B cells had undergone somatic hypermutation to an extent comparable to that of normal memory B cells. These findings reveal a differential requirement for the generation of IgM(+) and Ig isotype-switched memory B cells, with the latter only being generated by fully formed GCs. Production of affinity-matured IgM by IgM(+)CD27(+) B cells may protect against pathogens to which a normal immune response is elicited in XLP patients.