Activation-induced cytidine deaminase expression and activity in the absence of germinal centers: insights into hyper-IgM syndrome.
Somatic hypermutation normally occurs as a consequence of the expression of activation-induced cytidine deaminase (AID) by Ag-activated, mature B cells during T cell-dependent germinal center responses. Nonetheless, despite their inability to express CD154 and initiate GC responses, patients with type 1 hyper-IgM syndrome (HIGM1) support populations of IgM(+)IgD(+)CD27(+) B cells that express mutated Ig genes. The origin of these mutated B cells is unknown; the IgM(+)IgD(+)CD27(+) cells do not express AID and appear to acquire mutations independent of stringent selection by Ag. Here, we demonstrate that immature/transitional 1 B cells from the bone marrow of CD154-deficient mice express AID and acquire Ig mutations that lack the hallmarks of antigenic selection via BCR signaling. Comparable levels of AID expression was found in developmentally immature B cells recovered from murine fetal liver and from human immature/transitional 1 B cells recovered from umbilical cord blood. AID expression in human fetal liver was also robust, approaching that of human tonsil tissue and the human germinal center B cell line, Ramos. These observations led us to conclude that AID expression in developing human B cells is the origin of the mutated IgM(+)IgD(+)CD27(+) B cells present in HIGM1 patients, and we propose that both mice and humans share a latent, AID-dependent pathway for the preimmune diversification of B lymphocytes that is more prominent in chicken, sheep, and rabbits.
Kuraoka
Masayuki
M
Department of Immunology, Duke University, Durham, NC 27710, USA.
Liao
Dongmei
D
Yang
Kaiyong
K
Allgood
Sallie D
SD
Levesque
Marc C
MC
Kelsoe
Garnett
G
Ueda
Yoshihiro
Y
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D018858:Germinal Center / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D013234:Stem Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D011947:Receptors, Antigen, B-Cell; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase