title: IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens.
abstract: IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood. Using both a 610 carbohydrate array and enzyme-linked immunosorbent assay, we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T-independent bacterial antigens. Moreover, the quantity of specific IgM correlated with IgM(+)IgD(+)CD27(+) B-cell frequencies. As with mouse marginal zone B cells, human IgM(+)CD27(+) B cells activated by TLR7 or TLR9 agonists produced phosphorylcholine-specific IgM. Further linking splenic IgM(+)IgD(+)CD27(+) B cells with production of T-independent IgM, serum from splenectomized subjects, who also have few IgM(+)IgD(+)CD27(+) B cells, had reduced antibacterial IgM. IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell subset, suggesting a means by which loss of this activation pathway leads to reduced cell numbers. Thus, by bolstering the IgM(+)IgD(+)CD27(+) B-cell subset, IRAK-4 and MyD88 promote optimal T-independent IgM antibody responses against bacteria in humans.
authors.affiliation: Division of Clinical Immunology, Department of Medicine.
authors.forename: Paul J
authors.identifier: http://orcid.org/0000-0001-6805-7271
authors.initials: PJ
authors.lastname: Maglione
authors.affiliation: Division of Clinical Immunology, Department of Medicine.
authors.forename: Noa
authors.initials: N
authors.lastname: Simchoni
authors.affiliation: Division of Clinical Immunology, Department of Medicine.
authors.forename: Samuel
authors.initials: S
authors.lastname: Black
authors.affiliation: Division of Clinical Immunology, Department of Medicine.
authors.forename: Lin
authors.initials: L
authors.lastname: Radigan
authors.affiliation: Department of Health Evidence and Policy.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Overbey
authors.affiliation: Department of Health Evidence and Policy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Bagiella
authors.affiliation: Division of Hematology, Departments of Pediatrics and Medicine, Weill Medical College of Cornell University, New York, NY;
authors.forename: James B
authors.initials: JB
authors.lastname: Bussel
authors.affiliation: Experimental Laboratory Immunology, Department of Microbiology and Immunology, Catholic University of Leuven.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bossuyt
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale and St Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Childhood Immunology, and University Hospitals Leuven, Department of Pediatrics, Leuven, Belgium;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meyts
authors.affiliation: Division of Clinical Immunology, Department of Medicine.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale and Study Center of Primary Immunodeficiencies and Pediatric Hematology-Immunology Unit, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; and St Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Division of Clinical Immunology, Department of Medicine, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY;
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000235:genetics / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000276:immunology*; D000081207:Primary Immunodeficiency Diseases; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011135:Polysaccharides, Bacterial; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases