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 IgMCD27 B cells are not true memory cells, but rather B cells that guard against T cell-independent pathogens. Here we show that human XLP IgMCD27 B cells resemble normal memory B cells both morphologically and phenotypically. Additionally, IgMCD27 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 IgMCD27 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 IgMCD27 B cells may protect against pathogens to which a normal immune response is elicited in XLP patients.
Ma
Cindy S
CS
Lymphocyte Differentiation Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia.
Pittaluga
Stefania
S
Avery
Danielle T
DT
Hare
Nathan J
NJ
Maric
Irina
I
Klion
Amy D
AD
Nichols
Kim E
KE
Tangye
Stuart G
SG
D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D006801:Humans; D017578:Immunoglobulin Class Switching; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D007156:Immunologic Memory / Q000502:physiology*; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D008875:Middle Aged; D010641:Phenotype; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology*
D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7