title: Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function.
abstract: Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity.
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States.
authors.forename: Silvia
authors.initials: S
authors.lastname: Portugal
authors.affiliation: Departments of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tipton
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States.
authors.forename: Haewon
authors.initials: H
authors.lastname: Sohn
authors.affiliation: Malaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, Bamako, Mali.
authors.forename: Younoussou
authors.initials: Y
authors.lastname: Kone
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States.
authors.forename: Shanping
authors.initials: S
authors.lastname: Li
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States.
authors.forename: Jeff
authors.identifier: http://orcid.org/0000-0001-5697-0442
authors.initials: J
authors.lastname: Skinner
authors.affiliation: Rocky Mountain Laboratory Research Technologies Section, Genomics Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, United States.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.affiliation: Rocky Mountain Laboratory Research Technologies Section, Genomics Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Sturdevant
authors.affiliation: Rocky Mountain Laboratory Research Technologies Section, Genomics Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, United States.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.affiliation: Malaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Malaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, Bamako, Mali.
authors.forename: Safiatou
authors.initials: S
authors.lastname: Doumbo
authors.affiliation: Malaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, Bamako, Mali.
authors.forename: Kassoum
authors.initials: K
authors.lastname: Kayentao
authors.affiliation: Malaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, Bamako, Mali.
authors.forename: Aissata
authors.initials: A
authors.lastname: Ongoiba
authors.affiliation: Malaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, Bamako, Mali.
authors.forename: Boubacar
authors.initials: B
authors.lastname: Traore
authors.affiliation: Departments of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, United States.
authors.forename: Inaki
authors.initials: I
authors.lastname: Sanz
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, United States.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
mesh_terms: D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D002648:Child; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006790:Host-Parasite Interactions; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007156:Immunologic Memory; D016130:Immunophenotyping; D008288:Malaria / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000276:immunology / Q000472:pathogenicity; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D007073:Immunoglobulin E; C489855:dual specificity phosphatase 12; D054637:Dual-Specificity Phosphatases
keywords: Plasmodium falciparum; atypical memory B cells; human; immunology; infectious disease; malaria; microbiology