title: High affinity IgM(+) memory B cells are generated through a germinal center-dependent pathway.
abstract: During a T cell-dependent immune response, B cells undergo clonal expansion and selection and the induction of isotype switching and somatic hypermutation (SHM). Although somatically mutated IgM(+) memory B cells have been reported, it has not been established whether they are really high affinity B cells. We tracked (4-hydroxy-3-nitrophenyl) acetyl hapten-specific GC B cells from normal immunized mice based on affinity of their B cell receptor (BCR) and performed BCR sequence analysis. SHM was evident by day 7 postimmunization and increased with time, such that high affinity IgM(+) as well as IgG(+) memory B cells continued to be generated up to day 42. In contrast, class-switch recombination (CSR) was almost completed by day 7 and then the ratio of IgG1(+)/IgM(+) GC B cells remained unchanged. Together these findings suggest that IgM(+) B cells undergo SHM in the GC to generate high affinity IgM(+) memory cells and that this process continues even after CSR is accomplished.
authors.affiliation: Laboratory for Structural Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Laboratory for Structural Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan; Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Laboratory for Structural Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
authors.forename: Akikazu
authors.initials: A
authors.lastname: Murakami
authors.affiliation: Laboratory for Structural Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Department of Immunology, Kochi Medical School, Kochi University, Oko-cho Kohasu, Nankoku, Kochi 783-8505, Japan.
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan; Laboratory for Cytokine Regulation, Riken Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, UAB 406 SHEL, 1530 Third Avenue South, Birmingham, AL 35294, USA; Department of Genetics, University of Alabama at Birmingham, UAB 406 SHEL, 1530 Third Avenue South, Birmingham, AL 35294, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Burrows
authors.affiliation: Laboratory for Structural Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan; Antibody Technology Research Center, Co., Ltd., 2361-1-S401 Yamazaki, Noda, Chiba 278-0022, Japan. Electronic address: tazuma@rs.noda.tus.ac.jp.
authors.forename: Takachika
authors.initials: T
authors.lastname: Azuma
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001483:Base Sequence; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology
chemical_list: D007075:Immunoglobulin M
keywords: Affinity maturation; Class switch recombination; Germinal center reaction; IgM; Somatic hypermutation