title: Salmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation.
abstract: The B cell response to Salmonella typhimurium (STm) occurs massively at extrafollicular sites, without notable germinal centers (GCs). Little is known in terms of its specificity. To expand the knowledge of antigen targets, we screened plasmablast (PB)-derived monoclonal antibodies (mAbs) for Salmonella specificity, using ELISA, flow cytometry, and antigen microarray. Only a small fraction (0.5%-2%) of the response appeared to be Salmonella-specific. Yet, infection of mice with limited B cell receptor (BCR) repertoires impaired the response, suggesting that BCR specificity was important. We showed, using laser microdissection, that somatic hypermutation (SHM) occurred efficiently at extrafollicular sites leading to affinity maturation that in turn led to detectable STm Ag-binding. These results suggest a revised vision of how clonal selection and affinity maturation operate in response to Salmonella. Clonal selection initially is promiscuous, activating cells with virtually undetectable affinity, yet SHM and selection occur during the extrafollicular response yielding higher affinity, detectable antibodies.
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Laboratory Medicine and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Niro
authors.affiliation: Center for Comparative Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Seung-Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Vander Heiden
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Elsner
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Trivedi
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bannock
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
authors.forename: Namita T
authors.initials: NT
authors.lastname: Gupta
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: AbVitro Inc., Boston, MA 02210, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Vigneault
authors.affiliation: AbVitro Inc., Boston, MA 02210, USA.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Gilbert
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Center for Comparative Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McSorley
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Laboratory Medicine and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: mshlomch@pitt.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell