Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.
SUMMARY
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 IRAK-4, and
MyD88, whose cells do not respond to TLRs except TLR3 and from UNC-93B-deficient
patients whose cells are irresponsive 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
normally prevent the recruitment of developing autoreactive B cells in healthy
donors. Paradoxically, IRAK-4-, MyD88- and UNC-93B-deficient patients do not
display autoreactive antibodies in their serum nor develop autoimmune diseases
revealing that IRAK-4/MyD88/UNC-93B pathways blockade is likely to
thwart the development of autoimmunity in humans.
The influence of a synthetic retroviral peptide, CKS-17, on T helper type 1 (Thl)-or Th2-related cytokines was investigated in human blood mononuclear cells. Cells were stimulated with staphylococcal enterotoxin
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