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Immunodeficiency Diseases
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Autosomal recessive mutations of IRAK4 and MYD88 are associated with severe and invasive pyogenic infections early in life (Von Bernuth et al. 2008). Heterozygous mutations in TLR3 and biallelic mutations in UNC93B have been associated with reduced production of type 1 IFN and selective susceptibility to herpes simplex encephalitis (Casrogue et al. 2006).
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
Clinical manifestations of deficient pattern recognition are based on the type of innate immune receptor or on the signaling pathway involved, leading to susceptibility to bacterial, parasitic and protozoal, mycobacterial, or viral infections. Predisposition to invasive bacterial infections is seen in IRAK4 and MYD88 deficiency critical to signaling through TLR 1, 2, 5, 6, 10, 4, and IL-1R. All of these receptors signal through MY88 and IRAK4 and deliver nuclear signals that enable the production of pro-inflammatory cytokines IL-1, IL-6, and TNFα. As a result, severe pyogenic infections occur without fever.
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Waldenström’s macroglobulinemia (WM) has a key driver mutation, MYD88L265P, in >95% of the patients; other important mutations are CXCR4 (40%), ARID1A (17%) and CD79B (15%). Copy number alterations (CNAs) resulting in gene losses occur in PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MLKN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%) and FOXP1 (37%). The most common cytogenetic deletions are in chromosome 6q, which mostly overlaps with the CNAs, and comprise of losses in PLEKHG1, HIVEP2, ARID1B and BCLAF1. Mutations in MYD88, which is associated with Toll-like receptor (TLR) and interleukin-1 receptor signalling, mediating IRAK1 and IRAK4, is involved in the NFĸB signalling by direct interaction with BTK.
Intraocular Inflammation Associated with IRAK4 Deficiency
Published in Ocular Immunology and Inflammation, 2023
John A. Gonzales, Jeremy Nortey, Amit Reddy, Thuy Doan, Nisha R. Acharya
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase involved in the signaling pathway stimulated by Toll-like receptors (TLRs) and Interleukin-1 (IL-1). Its function is crucial to the body’s innate immunity where its recruitment by adaptor proteins, such as MYD88, leads to the release of pro-inflammatory cytokines involved in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) pathway.1 Appreciation for the role of IRAK4 in the body’s natural defense has grown over the years, and work has progressed to explore the kinase’s role in treating autoimmune diseases.2,3 In contrast, deficient IRAK4 activation can lead to serious systemic sequelae such as bacterial infections and bacteremia. Less is known about ocular manifestations in the setting of IRAK4 deficiency. While endogenous endophthalmitis has been described, non-infectious inflammation (uveitis) is rarely reported.4
Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Chao Wang, Yujing Zhang, Lingyu Shi, Shanbo Yang, Jing Chang, Yingjie Zhong, Qian Li, Dongming Xing
Interleukin-1 receptor-associated kinase 4 (IRAK4) belongs to a family of four kinases (IRAK4, IRAK1, nterleukin-1 receptor-associated kinase 4 (IRAK4) IRAK2, and IRAK-M). IRAK4 is a serine/threonine kinase that is involved in transduction pathways stimulated by the Tolllike receptors (TLRs) and the interleukin-1 (IL-1) family of receptors. Recognition of foreign pathogens and inflammatory signals by these receptors promotes IRAK4 binding to the adapter protein myeloid differentiation primary response gene (88) (MyD88) resulting in IRAK4 activation that in turn leads to the production of pro-inflammatory cytokines via the NFκβ pathway. IRAK4 deficiency or loss of function has been reported to increase susceptibility to several pathogens, while kinase activation has been linked with various autoimmune diseases such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, and cancer96,97.
Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
In 2002 the existence of a previously unknown kinase involved in the TIR signaling cascade was reported [1]. This Ser/Thr kinase was named interleukin-1 receptor-associated kinase 4 (IRAK4) and joined IRAK1, IRAK2, and IRAK3 (also called IRAKM) as known participants in TIR signaling [2]. Within the following year two reports confirming the role of IRAK4 in immune response in mammals appeared: knockout of IRAK4 in mice rendered the animals resistant to the TLR4 agonist lipopolysaccharide (LPS) and led to decreased response to viral and bacterial infection [3], and a group of three unrelated children was identified that possessed mutations to the IRAK4 gene resulting in translation of nonfunctional IRAK4 protein [4]. Blood and fibroblast cells from these patients did not respond to activation of the TIR system. The children themselves were normal with the exception of displaying an increased susceptibility to Gram-positive infections. The frequency of infection diminished as the children aged. Collectively these findings motivated a variety of organizations to further investigate the role of IRAK4 in immune signaling and offered the possibility of using this knowledge to develop a therapeutic agent to treat immune-related disorders.