title: Lyn signaling to upregulate GANP is critical for the survival of high-affinity B cells in germinal centers of lymphoid organs.
abstract: Signals through BCR and costimulatory molecules play essential roles in selecting high-affinity B cells with Ig V-region mutations in the germinal centers (GCs) of peripheral lymphoid organs. Lyn-deficient (lyn(-/-)) mice show impaired BCR signal triggering for cell proliferation and GC formation, causing hyper-IgM, and display autoimmunity after aging. In this study, we demonstrate that Lyn-mediated signaling to upregulate GANP is essential for the survival of mature GC-like (mGC) B cells with high-affinity type BCR mutations upon Ag immunization. Transgenic ganp expression into lyn(-/-) mice did not recover the Lyn-deficient phenotype with regard to B cell differentiation, serum Igs, and impaired GC formation in spleens after immunization with nitrophenyl-chicken γ-globulin, but it markedly rescued cell survival of mGC B cells by suppressing DNA damage, thereby increasing the frequency of the Trp(33)-to-Leu mutation in the IgV(H)-186.2 region and affinity maturation of nitrophenyl-binding B cells. GANP may play a critical role in Lyn-mediated signaling for the selection of high-affinity B cells in peripheral lymphoid organs.
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Teruo
authors.initials: T
authors.lastname: Nakaya
authors.forename: Suchada
authors.initials: S
authors.lastname: Phimsen
authors.forename: Teppei
authors.initials: T
authors.lastname: Toda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kitabatake
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaji
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takemori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C481510:GANP protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases