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

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

Isabelle Isnardi ¹, Yen-Shing Ng, Iva Srdanovic, Roja Motaghedi, Sergei Rudchenko, Horst von Bernuth, Shen-Ying Zhang, Anne Puel, Emmanuelle Jouanguy, Capucine Picard, Ben-Zion Garty, Yildiz Camcioglu, Rainer Doffinger, Dinakantha Kumararatne, Graham Davies, John I Gallin, Soichi Haraguchi, Noorbibi K Day, Jean-Laurent Casanova, Eric Meffre

Affiliations

Affiliation

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

PMID: 19006693 DOI: 10.1016/j.immuni.2008.09.015

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.

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