Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4 .

Autor:	Cooray S; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom., Price-Kuehne F; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom., Hong Y; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom., Omoyinmi E; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom., Burleigh A; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom.; Centre for Adolescent Rheumatology Versus Arthritis, University College London, London, United Kingdom., Gilmour KC; Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Ahmad B; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea., Choi S; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea., Bahar MW; Division of Structural Biology, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, United Kingdom., Torpiano P; Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Gagunashvili A; Faculty of Life and Environmental Sciences, University of Iceland, Reykjavík, Iceland., Jensen B; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom., Bellos E; Section of Paediatric Infectious Diseases, Imperial College London, London, United Kingdom.; Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, United Kingdom., Sancho-Shimizu V; Section of Paediatric Infectious Diseases, Imperial College London, London, United Kingdom.; Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, United Kingdom., Herberg JA; Section of Paediatric Infectious Diseases, Imperial College London, London, United Kingdom.; Department of Paediatric Infectious Diseases, St Mary's Hospital, Imperial College NHS Healthcare Trust, London, United Kingdom., Mankad K; Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Kumar A; Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Kaliakatsos M; Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Worth AJJ; Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Eleftheriou D; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom., Whittaker E; Section of Paediatric Infectious Diseases, Imperial College London, London, United Kingdom.; Department of Paediatric Infectious Diseases, St Mary's Hospital, Imperial College NHS Healthcare Trust, London, United Kingdom., Brogan PA; Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Sep 06; Vol. 14, pp. 1231749. Date of Electronic Publication: 2023 Sep 06 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1231749
Abstrakt:	We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in IRAK4 . IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in IRAK4 result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in IRAK4 (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1β), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon β (IFN-β); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in IRAK4 may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Cooray, Price-Kuehne, Hong, Omoyinmi, Burleigh, Gilmour, Ahmad, Choi, Bahar, Torpiano, Gagunashvili, Jensen, Bellos, Sancho-Shimizu, Herberg, Mankad, Kumar, Kaliakatsos, Worth, Eleftheriou, Whittaker and Brogan.)
Databáze:	MEDLINE
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