Interleukin 1 receptor–associated kinase 4 deficiency

Members of interleukin-1 receptor (Il-1R) and the Toll-like receptor superfamily share an intracytoplasmic Toll-IL-1 receptor (TLR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. Three unrelated, otherwise healthy children with recurrent pyogenic infections due to pneumococci and staphylococci had normal immunocompetence by standard immune studies. They had normal titers of antipneumococcal antibodies. However, their blood and fibroblast cells did not activate nuclear factor κB and mitogen-activated protein kinase and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. Each was found to have an inherited deficiency of IRAK-4. Thus, the TIR-IRAK signaling pathway appears to be crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.