title: Mitochondrial reactive oxygen species suppress humoral immune response through reduction of CD19 expression in B cells in mice.
abstract: Reactive oxygen species (ROS) are implicated in the modulation of diverse processes including immune responses. To evaluate the effects of metabolic ROS produced by mitochondria on B-cell function and development, we created transgenic (Tg) mice expressing a phosphorylation-defective mutant of succinate dehydrogenase A in B cells (bSDHAY215F). Splenic B cells in male, but not female, bSDHAY215Fmice produced three times more ROS than those in the control mice, and had decreased production of IgM, IgG1, and IgG3, and affinity maturation of IgG1against T-cell-dependent antigens. Following immunization, the male bSDHAY215Fmice further displayed suppressed germinal center (GC) formation, and proliferation of GC B cells. Signaling analysis revealed defects in the intrinsic BCR responses, such as activation of Lyn, Btk, and PLCγ2, thus resulting in reduced intracellular Ca2+mobilization. Notably, the expression levels of B-cell co-receptor CD19 and its interaction with Lyn after BCR ligation were significantly reduced in B cells from male bSDHAY215Fmice. These results suggest that mitochondrial ROS suppress humoral immune responses through reduction of CD19 expression and resultant BCR signaling in B cells. Therefore, B-cell immunity may be more labile to oxidative stress in male mice than in female mice.
authors.affiliation: Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Laboratory of Lymphocyte Differentiation, World Premier International Immunology Frontier Research Center and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamaki
authors.affiliation: Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Miwako K
authors.initials: MK
authors.lastname: Homma
authors.affiliation: Laboratory of Lymphocyte Differentiation, World Premier International Immunology Frontier Research Center and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.|Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Homma
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism*; D005260:Female; D056724:Immunity, Humoral; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018941:Antigens, CD19; D017382:Reactive Oxygen Species; D011947:Receptors, Antigen, B-Cell; D042963:Electron Transport Complex II; C511268:SDHA protein, human
keywords: B cells; Gender difference; Immune responses; Mitochondria; ROS