Cooray, S;
Price-Kuehne, F;
Hong, Y;
Omoyinmi, E;
Burleigh, A;
Gilmour, KC;
Ahmad, B;
... Brogan, PA; + view all
(2023)
Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4.
Frontiers in Immunology
, 14
, Article 1231749. 10.3389/fimmu.2023.1231749.
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Abstract
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.
Type: | Article |
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Title: | Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4 |
Location: | Switzerland |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.3389/fimmu.2023.1231749 |
Publisher version: | https://doi.org/10.3389/fimmu.2023.1231749 |
Language: | English |
Additional information: | 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. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: | IRAK-4, NASA, anemia, autoinflammation, neuroinflammation, splenomegaly, toll-like receptor, Humans, Leukocytes, Mononuclear, Interleukin-1 Receptor-Associated Kinases, Splenomegaly, Interleukin-6, Neuroinflammatory Diseases, Anemia, Mutation |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
URI: | https://discovery.ucl.ac.uk/id/eprint/10178178 |
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