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      B–helper neutrophils stimulate immunoglobulin diversification and production in the marginal zone of the spleen

      1 , 2 , 1 , 2 , 1 , 1 , 3 , 2 , 2 , 2 , 1 , 4 , 4 , 5 , 6 , 3 , 7 , 3 , 3 , 3 , 3 , 3 , 8 , 9 , 10 , 10 , 11 , 12 , 13 , 14 , 2 , 15 , 16 , 2 , 17 , 17 , 18 , 19 , 19 , 20 , 21 , 22 , 22 , 23 , 23 , 23 , 24 , 25 , 2 , 1 , 2 , 26

      Nature Immunology

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          Abstract

          Neutrophils utilize immunoglobulins (Igs) to clear antigen, but their role in Ig production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T-independent Ig responses to circulating antigen. Neutrophils colonized peri-MZ areas after post-natal mucosal colonization by microbes and enhanced their B-helper function upon receiving reprogramming signals from splenic sinusoidal endothelial cells, including interleukin 10 (IL-10). Splenic neutrophils induced Ig class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism involving the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and less preimmune Igs to T-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial Ig defense by interacting with MZ B cells.

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          Most cited references 35

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          Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.

          Induced overexpression of AID in CH12F3-2 B lymphoma cells augmented class switching from IgM to IgA without cytokine stimulation. AID deficiency caused a complete defect in class switching and showed a hyper-IgM phenotype with enlarged germinal centers containing strongly activated B cells before or after immunization. AID-/- spleen cells stimulated in vitro with LPS and cytokines failed to undergo class switch recombination although they expressed germline transcripts. Immunization of AID-/- chimera with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma-globulin induced neither accumulation of mutations in the NP-specific variable region gene nor class switching. These results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation.
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            Maintenance of serological memory by polyclonal activation of human memory B cells.

            Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.
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              BAFF, a Novel Ligand of the Tumor Necrosis Factor Family, Stimulates B Cell Growth

              Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M–stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center–like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature Immunology
                1529-2908
                1529-2916
                6 December 2011
                25 December 2011
                01 August 2012
                : 13
                : 2
                : 170-180
                Affiliations
                [1 ]Institut Municipal d'Investigació Mèdica-Hospital del Mar, Barcelona, Spain
                [2 ]Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA
                [3 ]Department of Pathology, Hospital del Mar, Universitat Autònoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain
                [4 ]Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York, USA
                [5 ]Department of Pathology, Brigham and Woman's Hospital, Harvard Medical School, Boston, Massachusetts, USA
                [6 ]Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA
                [7 ]Department of Urology, Hospital del Mar, Barcelona, Spain
                [8 ]Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
                [9 ]Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
                [10 ]Department of Hematology, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain
                [11 ]Department of Pediatrics, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain
                [12 ]Department of Pathology, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain
                [13 ]Children Hematology Unit, Hospital de la Fe, Valencia, Spain
                [14 ]Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA
                [15 ]Unit of Immunodeficiency, Hospital Erasme-ULB, Brussels, Belgium
                [16 ]Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
                [17 ]Hematology Unit, G. Gaslini Children's Institute, Genova, Italy
                [18 ]Oncohematology and Bone Marrow Transplantation Unit, Children's Hospital, Brescia, Italy
                [19 ]Pediatric Clinic and Institute of Molecular Medicine “A. Nocivelli”,University of Brescia and Children's Hospital, Brescia, Italy
                [20 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
                [21 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de Santé et de la Recherche Médicale U550 and Necker-Enfants Malades Medical School, Paris, France
                [22 ]Institute of Medical Microbiology & Hygiene, University of Freiburg, Freiburg, Germany
                [23 ]Immunology Service, Hospital Clínic of Barcelona, Barcelona, Spain
                [24 ]CEREDIH, The French National Reference Center for Primary Immune Deficiencies and Paediatric Haematology-Immunolgy and Rheumatology Unit, Hôpital Necker-Enfants Malades, Paris, France
                [25 ]Service d'Hémato Oncologie Pédiatrique, Registre des Neutropénies Congénitales, Hôpital Trousseau, Paris, France
                [26 ]Catalan Institute for Research and Advanced Studies, Barcelona Biomedical Research Park, Barcelona, Spain
                Author notes
                [27]

                These authors contributed equally to this work.

                Correspondence should be addressed to A.C ( acerutti@ 123456imim.es or andrea.cerutti@ 123456mssm.edu ).
                Article
                NIHMS340279
                10.1038/ni.2194
                3262910
                22197976

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                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: U01 AI095613-01 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI074378-06 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI074378-05 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI074378-04 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI096187-01 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: P01 AI061093-08 || AI
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                Immunology

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