Mistry, A, Scambler, T, Parry, D et al. (5 more authors) (2017) Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications. Frontiers in Immunology, 8. 1485. ISSN 1664-3224
Abstract
G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients’ monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients’ cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2017 Mistry, Scambler, Parry, Wood, Barcenas-Morales, Carter, Doffinger and Savic. 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) or licensor 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: | G6PC3, systemic autoinflammatory syndromes, PID, neutropenia, adalimumab |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 Dec 2017 16:43 |
Last Modified: | 18 Dec 2017 16:43 |
Status: | Published |
Publisher: | Frontiers Media |
Identification Number: | 10.3389/fimmu.2017.01485 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:125264 |