title: Amplified B lymphocyte CD40 signaling drives regulatory B10 cell expansion in mice.
abstract: BACKGROUND
  Aberrant CD40 ligand (CD154) expression occurs on both T cells and B cells in human lupus patients, which is suggested to enhance B cell CD40 signaling and play a role in disease pathogenesis. Transgenic mice expressing CD154 by their B cells (CD154(TG)) have an expanded spleen B cell pool and produce autoantibodies (autoAbs). CD22 deficient (CD22(-/-)) mice also produce autoAbs, and importantly, their B cells are hyper-proliferative following CD40 stimulation ex vivo. Combining these 2 genetic alterations in CD154(TG)CD22(-/-) mice was thereby predicted to intensify CD40 signaling and autoimmune disease due to autoreactive B cell expansion and/or activation.
  
  
  RESULTS
  CD154(TG)CD22(-/-) mice were assessed for their humoral immune responses and for changes in their endogenous lymphocyte subsets. Remarkably, CD154(TG)CD22(-/-) mice were not autoimmune, but instead generated minimal IgG responses against both self and foreign antigens. This paucity in IgG isotype switching occurred despite an expanded spleen B cell pool, higher serum IgM levels, and augmented ex vivo B cell proliferation. Impaired IgG responses in CD154(TG)CD22(-/-) mice were explained by a 16-fold expansion of functional, mature IL-10-competent regulatory spleen B cells (B10 cells: 26.7×10(6)±6 in CD154(TG)CD22(-/-) mice; 1.7×10(6)±0.4 in wild type mice, p<0.01), and an 11-fold expansion of B10 cells combined with their ex vivo-matured progenitors (B10+B10pro cells: 66×10(6)±3 in CD154(TG)CD22(-/-) mice; 6.1×10(6)±2 in wild type mice, p<0.01) that represented 39% of all spleen B cells.
  
  
  CONCLUSIONS
  These results demonstrate for the first time that the IL-10-producing B10 B cell subset has the capacity to suppress IgG humoral immune responses against both foreign and self antigens. Thereby, therapeutic agents that drive regulatory B10 cell expansion in vivo may inhibit pathogenic IgG autoAb production in humans.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Poe
authors.forename: Susan H
authors.initials: SH
authors.lastname: Smith
authors.forename: Karen M
authors.initials: KM
authors.lastname: Haas
authors.forename: Koichi
authors.initials: K
authors.lastname: Yanaba
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsubata
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D060151:B-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002452:Cell Count; D056724:Immunity, Humoral / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001323:Autoantibodies; D019013:CD40 Antigens; D007074:Immunoglobulin G; D051918:Sialic Acid Binding Ig-like Lectin 2; D023201:CD40 Ligand