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

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 IL-1R-associated kinase (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 naïve 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 nor developed autoimmune diseases, suggesting that IRAK-4, MyD88 and UNC-93B pathway blockade may thwart autoimmunity in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE13300 | GEO | 2008/10/23

SECONDARY ACCESSION(S): PRJNA109873

REPOSITORIES: GEO

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Transcription profiling of human single B cells isolated from patients deficient for IL-1R-associated kinase (IRAK)-4, myeloid differentiation factor 88 (MyD88) and UNC-93B

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