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

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Abstract

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.

Authors

Cindy S. Ma, Stefania Pittaluga, Danielle T. Avery, Nathan J. Hare, Irina Maric, Amy D. Klion, Kim E. Nichols, Stuart G. Tangye