IRAK-4-and MyD88-Dependent Pathways Are Essential for the Removal of Developing Autoreactive B Cells in Humans

Isnardi I., Ng Y., Srdanovic I., Motaghedi R., Rudchenko S., von Bernuth H., ...More

IMMUNITY, vol.29, no.5, pp.746-757, 2008 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 29 Issue: 5
  • Publication Date: 2008
  • Doi Number: 10.1016/j.immuni.2008.09.015
  • Journal Name: IMMUNITY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.746-757
  • Istanbul University Affiliated: Yes

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.