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Immunity. 2008 Nov 14;29(5):746-57. doi: 10.1016/j.immuni.2008.09.015.

IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans.

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1
Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, NY 10021, USA.

Abstract

Most autoreactive B cells are normally counterselected during early B cell development. To determine whether Toll-like receptors (TLRs) regulate the removal of autoreactive B lymphocytes, we tested the reactivity of recombinant antibodies from single B cells isolated from patients deficient for interleukin-1 receptor-associated kinase 4 (IRAK-4), myeloid differentiation factor 88 (MyD88), and UNC-93B. Indeed, all TLRs except TLR3 require IRAK-4 and MyD88 to signal, and UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9. All patients suffered from defective central and peripheral B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive mature naive B cells in their blood. Hence, TLR7, TLR8, and TLR9 may prevent the recruitment of developing autoreactive B cells in healthy donors. Paradoxically, IRAK-4-, MyD88-, and UNC-93B-deficient patients did not display autoreactive antibodies in their serum or develop autoimmune diseases, suggesting that IRAK-4, MyD88, and UNC-93B pathway blockade may thwart autoimmunity in humans.

PMID:
19006693
PMCID:
PMC2666307
DOI:
10.1016/j.immuni.2008.09.015
[Indexed for MEDLINE]
Free PMC Article

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