title: Deletion of WASp and N-WASp in B cells cripples the germinal center response and results in production of IgM autoantibodies.
abstract: Humoral immunodeficiency caused by mutations in the Wiskott-Aldrich syndrome protein (WASp) is associated with failure to respond to common pathogens and high frequency of autoimmunity. Here we addressed the question how deficiency in WASp and the homologous protein N-WASp skews the immune response towards autoreactivity. Mice devoid of WASp or both WASp and N-WASp in B cells formed germinal center to increased load of apoptotic cells as a source of autoantigens. However, the germinal centers showed abolished polarity and B cells retained longer and proliferated less in the germinal centers. While WASp-deficient mice had high titers of autoreactive IgG, B cells devoid of both WASp and N-WASp produced mainly IgM autoantibodies with broad reactivity to autoantigens. Moreover, B cells lacking both WASp and N-WASp induced somatic hypermutation at reduced frequency. Despite this, IgG1-expressing B cells devoid of WASp and N-WASp acquired a specific high affinity mutation, implying an increased BCR signaling threshold for selection in germinal centers. Our data provides evidence for that N-WASp expression alone drives WASp-deficient B cells towards autoimmunity.
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Carin I M
authors.initials: CI
authors.lastname: Dahlberg
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Magda-Liz
authors.initials: ML
authors.lastname: Torres
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Sven H
authors.initials: SH
authors.lastname: Petersen
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Marisa A P
authors.initials: MA
authors.lastname: Baptista
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Marton
authors.initials: M
authors.lastname: Keszei
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volpi
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Emilie K
authors.initials: EK
authors.lastname: Grasset
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Mikael C I
authors.initials: MC
authors.lastname: Karlsson
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Pediatric Immunodeficiency Program, Division of Allergy, Massachusetts General Hospital for Children, Boston, MA 02114, USA.
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.affiliation: Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 171 77, Sweden. Electronic address: Lisa.Westerberg@ki.se.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D000917:Antibody Formation; D018941:Antigens, CD19 / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D017353:Gene Deletion; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism*; D006241:Haptens; D006433:Hemocyanins / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018183:Transplantation Chimera; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics*
chemical_list: C098951:4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin; D000974:Antibodies, Antinuclear; D018941:Antigens, CD19; D001323:Autoantibodies; D001324:Autoantigens; D006241:Haptens; D007075:Immunoglobulin M; D051316:Wiskott-Aldrich Syndrome Protein; D006433:Hemocyanins
keywords: Autoimmunity; B cells; Germinal center; N-WASp; Primary immunodeficiency; Wiskott-Aldrich syndrome