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
  • 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.