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., ...Daha Fazla

IMMUNITY, cilt.29, ss.746-757, 2008 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 29 Konu: 5
  • Basım Tarihi: 2008
  • Doi Numarası: 10.1016/j.immuni.2008.09.015
  • Dergi Adı: IMMUNITY
  • Sayfa Sayıları: ss.746-757

Özet

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.