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Lookup NU author(s): Joanne Topping, Dr Gavin Spickett
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021, The Author(s). The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3-AID with recurrent episodes of sore throat and extensive oropharyngeal ulceration. Unlike previously reported patients, who responded well to anakinra, her oral ulcers did not significantly improve until the PDE4 inhibitor, apremilast, was added to her treatment regimen. Here, we show that this mutation enhances interactions between NLRP3 and its endogenous inhibitor, NIMA-related kinase 7 (NEK7), by affecting charge complementarity between the two proteins. We also demonstrate that additional inflammatory mediators, including the NF-кB and IL-17 signalling pathways and IL-8 chemokine, are upregulated in the patient’s macrophages and may be directly involved in disease pathogenesis. These results highlight the role of the NLRP3 LRR domain in NLRP3-AIDs and demonstrate that the p.R920Q mutation can cause diverse phenotypes between families.
Author(s): Caseley EA, Lara-Reyna S, Poulter JA, Topping J, Carter C, Nadat F, Spickett GP, Savic S, McDermott MF
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Immunology
Year: 2021
Volume: 42
Pages: 158-170
Online publication date: 21/10/2021
Acceptance date: 15/10/2021
Date deposited: 01/11/2021
ISSN (print): 0271-9142
ISSN (electronic): 1573-2592
Publisher: Springer
URL: https://doi.org/10.1007/s10875-021-01161-w
DOI: 10.1007/s10875-021-01161-w
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