Definition:

Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- and TLR4-interferon (IFN)-a/b pathways. IRAK-4 is a kinase that plays a crucial role downstream of individual TLR and IL-1R receptors and upstream of TNF receptor-associated factor-6 (TRAF-6). Patients with IRAK-4 deficiency thus fail to produce TNF-alpha, IL-6, and IFN-gamma in response to IL-1beta and IL-18, respectively. Their blood cells also fail to produce IL-1beta, IL-6, IL-8, IL-12, and TNF-alpha upon stimulation with known TLR agonists. Despite the broad impairment at the two subsequent levels of onset (TLR) and propagation (IL-1R) of inflammation, the clinical phenotype of IRAK-4 deficiency is relatively mild. Patients present no developmental defect and a restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. Recently, other monogenic defects of toll-like receptor signaling that cause severe immunodeficiency have been reported.