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.
Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.
van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, van Deuren RC, Steehouwer M, van Reijmersdal SV, Jaeger M, Hofste T, Astuti G, Corominas Galbany J, van der Schoot V, van der Hoeven H, Hagmolen Of Ten Have W, Klijn E, van den Meer C, Fiddelaers J, de Mast Q, Bleeker-Rovers CP, Joosten LAB, Yntema HG, Gilissen C, Nelen M, van der Meer JWM, Brunner HG, Netea MG, van de Veerdonk FL, Hoischen A
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Presence of Genetic Variants Among Young Men With Severe COVID-19.
Fejtkova M, Sukova M, Hlozkova K, Skvarova Kramarzova K, Rackova M, Jakubec D, Bakardjieva M, Bloomfield M, Klocperk A, Parackova Z, Sediva A, Aluri J, Novakova M, Kalina T, Fronkova E, Hrusak O, Malcova H, Sedlacek P, Liba Z, Kudr M, Stary J, Cooper MA, Svaton M, Kanderova V
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TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins.
