1. IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens.
- Author
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Maglione PJ, Simchoni N, Black S, Radigan L, Overbey JR, Bagiella E, Bussel JB, Bossuyt X, Casanova JL, Meyts I, Cerutti A, Picard C, and Cunningham-Rundles C
- Subjects
- Adolescent, Adult, Animals, Antibodies, Bacterial genetics, B-Lymphocytes pathology, Bacterial Infections genetics, Bacterial Infections pathology, Cells, Cultured, Child, Child, Preschool, Female, Humans, Immunoglobulin G immunology, Immunoglobulin M genetics, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes pathology, Infant, Interleukin-1 Receptor-Associated Kinases genetics, Interleukin-1 Receptor-Associated Kinases immunology, Male, Middle Aged, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 immunology, Primary Immunodeficiency Diseases, Toll-Like Receptor 7 genetics, Toll-Like Receptor 7 immunology, Toll-Like Receptor 9 genetics, Toll-Like Receptor 9 immunology, Antibodies, Bacterial immunology, Antigens, Bacterial immunology, B-Lymphocytes immunology, Bacterial Infections immunology, Immunoglobulin M immunology, Immunologic Deficiency Syndromes immunology, Polysaccharides, Bacterial immunology
- 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., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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