Defects of toll-like receptor signaling

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.

References:

[1]. Arvind Kumar, et al. Current perspectives on primary immunodeficiency diseases. Clin Dev Immunol. 2006 Jun-Dec;13(2-4):223-59. [Content Brief]

[2]. Capucine Picard, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003 Mar 28;299(5615):2076-9. [Content Brief]

[3]. Caspar I van der Made, et al. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA. 2020 Aug 18;324(7):663-673. [Content Brief]

[4]. Massimo Morra, et al. Genetic diagnosis of primary immune deficiencies. Immunol Allergy Clin North Am. 2008 May;28(2):387-412, x. [Content Brief]

[5]. Michael J Ciancanelli, et al. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science. 2015 Apr 24;348(6233):448-53. [Content Brief]

[6]. Raif S Geha, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007 Oct;120(4):776-94. [Content Brief]

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