title: IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses.
abstract: BACKGROUND
  IL-10-producing regulatory B cells suppress immune responses, and lack of these cells leads to exacerbated symptoms in mouse models of chronic inflammation, transplantation, and chronic infection. IgG4 is a blocking antibody isotype with anti-inflammatory potential that is induced in human high-dose antigen tolerance models.
  
  
  OBJECTIVE
  We sought to characterize human inducible IL-10-secreting B regulatory 1 (BR1) cells and to investigate their immunoregulatory capacity through suppression of cellular immune responses and production of anti-inflammatory immunoglobulins.
  
  
  METHODS
  Highly purified IL-10-secreting B cells were phenotypically and functionally characterized by means of whole-genome expression analysis, flow cytometry, suppression assay, and antibody production. B cells specific for the major bee venom allergen phospholipase A2 (PLA) were isolated from beekeepers who displayed tolerance to bee venom antigens and allergic patients before and after specific immunotherapy.
  
  
  RESULTS
  Human IL-10+ BR1 cells expressed high surface CD25 and CD71 and low CD73 levels. Sorting of CD73-CD25+CD71+ B cells allowed enrichment of human BR1 cells, which produced high levels of IL-10 and potently suppressed antigen-specific CD4+ T-cell proliferation. IgG4 was selectively confined to human BR1 cells. B cells specific for the major bee venom allergen PLA isolated from nonallergic beekeepers show increased expression of IL-10 and IgG4. Furthermore, the frequency of IL-10+ PLA-specific B cells increased in allergic patients receiving allergen-specific immunotherapy.
  
  
  CONCLUSIONS
  Our data show the characterization of IL-10+ BR1 cells and in vivo evidence for 2 essential features of allergen tolerance: the suppressive B cells and IgG4-expressing B cells that are confined to IL-10+ BR1 cells in human subjects.
authors: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
authors: Willem
authors: W
authors: van de Veen
authors: Barbara
authors: B
authors: Stanic
authors: Görkem
authors: G
authors: Yaman
authors: Marcin
authors: M
authors: Wawrzyniak
authors: Stefan
authors: S
authors: Söllner
authors: Deniz G
authors: DG
authors: Akdis
authors: Beate
authors: B
authors: Rückert
authors: Cezmi A
authors: CA
authors: Akdis
authors: Mübeccel
authors: M
authors: Akdis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D001514:Bee Venoms / Q000276:immunology*; D056630:Beekeeping; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D003888:Desensitization, Immunologic; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D008875:Middle Aged; D061166:Peripheral Tolerance; D054467:Phospholipases A2 / Q000276:immunology
chemical_list: D000941:Antigens; D015703:Antigens, CD; D001514:Bee Venoms; D007074:Immunoglobulin G; D016753:Interleukin-10; D054467:Phospholipases A2