Journal
BLOOD
Volume 124, Issue 24, Pages 3561-3571Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-07-587824
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Funding
- Thrasher Research Fund Early Career Award
- Baxter-Clinical Immunology Society Senior Fellowship Award
- Jeffrey Modell Foundation
- Fondation pour la Recherche Medicale [DMI20091117320]
- March of Dimes [1-FY12-440]
- National Center for Research Resources
- National Center for Advancing Sciences of the National Institutes of Health [8UL1TR000043]
- National Institutes of Health [AI048693, AI061093, T32 GM007280]
- David S. Gottesman Immunology Chair
- St. Giles Foundation
- Rockefeller University
- INSERM
- Paris Descartes University
- Icahn School of Medicine at Mount Sinai
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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.
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