IgG4 production is confined to human IL-10–producing regulatory B cells that suppress antigen-specific immune responses

• Published in: Journal of allergy and clinical immunology 2013-04, Vol.131 (4), p.1204-1212
• Main Authors: van de Veen, Willem, MSc, Stanic, Barbara, PhD, Yaman, Görkem, MD, Wawrzyniak, Marcin, MSc, Söllner, Stefan, Sci Tec, Akdis, Deniz G, Rückert, Beate, Sci Tec, Akdis, Cezmi A., MD, Akdis, Mübeccel, MD, PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Allergy and Immunology; Antigens - immunology; Antigens, CD - genetics; Antigens, CD - immunology; B-Lymphocytes, Regulatory - immunology; B-Lymphocytes, Regulatory - pathology; Bee Venoms - immunology; Beekeeping; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Cell Proliferation; Desensitization, Immunologic; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Hypersensitivity, Immediate - genetics; Hypersensitivity, Immediate - immunology; Hypersensitivity, Immediate - pathology; IgG4; IL-10; Immune tolerance; Immunoglobulin G - biosynthesis; Immunoglobulin G - immunology; Immunopathology; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Medical sciences; Middle Aged; Peripheral Tolerance; Phospholipases A2 - immunology; regulatory B cells; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.01.014

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 (BR 1) 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+ BR 1 cells expressed high surface CD25 and CD71 and low CD73 levels. Sorting of CD73− CD25+ CD71+ B cells allowed enrichment of human BR 1 cells, which produced high levels of IL-10 and potently suppressed antigen-specific CD4+ T-cell proliferation. IgG4 was selectively confined to human BR 1 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. Conclusion Our data show the characterization of IL-10+ BR 1 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+ BR 1 cells in human subjects.