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Title: IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens
Authors: Maglione, Paul J ×
Simchoni, Noa
Black, Samuel
Radigan, Lin
Overbey, Jessica R
Bagiella, Emilia
Bussel, James B
Bossuyt, Xavier
Casanova, Jean-Laurent
Meyts, Isabelle
Cerutti, Andrea
Picard, Capucine
Cunningham-Rundles, Charlotte #
Issue Date: Dec-2014
Publisher: W.B. Saunders
Series Title: Blood vol:124 issue:24 pages:3561-71
Article number: 10.1182/blood-2014-07-587824
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.
URI: 
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Pediatric Immunology
Experimental Laboratory Immunology
Department of Health and Technology - UC Leuven
× corresponding author
# (joint) last author

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