title: Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge.
abstract: Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC). Recent studies of MBC development and function after protein immunization have uncovered significant MBC heterogeneity. To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice. Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M(+) (IgM(+)) and IgG(+) MBC subsets and an unmutated IgD(+) MBC population. Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium-specific IgM(+) MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge. IgM(+) MBCs also gave rise to T cell-dependent IgM(+) and IgG(+)B220(+)CD138(+) plasmablasts or T cell-independent B220(-)CD138(+) IgM(+) plasma cells. Thus, even in competition with IgG(+) MBCs, IgM(+) MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Akshay T
authors.initials: AT
authors.lastname: Krishnamurty
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Thouvenel
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Portugal
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Gladys J
authors.initials: GJ
authors.lastname: Keitany
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Kim
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Holder
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. Electronic address: mpepper@uw.edu.
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D000953:Antigens, Protozoan / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D000939:Epitopes; D005260:Female; D006801:Humans; D056724:Immunity, Humoral; D007117:Immunization, Secondary; D007075:Immunoglobulin M / Q000378:metabolism; D007156:Immunologic Memory; D008288:Malaria / Q000276:immunology*; D017780:Malaria Vaccines / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010961:Plasmodium / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D000939:Epitopes; D007075:Immunoglobulin M; D017780:Malaria Vaccines