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.
Highlights
Systemic autoinflammatory disorders (SAIDs) can manifest as periodic sterile fevers, with or without tissue specific signs and symptoms such as skin rashes, serositis, synovitis, and mucosal ulceration
This was associated with increased release of apoptosis associated speck-like protein containing a CARD (ASC) specks (Figure 4C), which are typically released after stimulation of the NLRP3 inflammasome as the activated cells die by pyroproptosis
These reports suggest that the incidence of inflammatory bowel disease (IBD) in patients with glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is higher compared with the general population [6]
Summary
Systemic autoinflammatory disorders (SAIDs) can manifest as periodic sterile fevers, with or without tissue specific signs and symptoms such as skin rashes, serositis, synovitis, and mucosal ulceration. Further immunological assessment showed that brothers had a normal neutrophil oxidative burst in response to lipopolysaccharide (LPS) and phorbol myristate acetate stimulation (Figure 1C) Since their clinical phenotypes were in keeping with SAID, we tested their ability to produce pro-inflammatory cytokines in vitro. We wondered if the metabolic changes we observed in granulocytes and monocytes had a more specific effect on NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex, which is responsible for processing of pro-IL-1β and pro-IL-18 into their active components and is frequently dysregulated in many monogenic SAIDs. We found that the production of IL-1β and IL-18 from patients’ monocytes was significantly increased, compared with HC, after stimulation of NLRP3 by priming and activation with LPS and ATP, respectively (Figures 4A,B). This was associated with increased release of apoptosis associated speck-like protein containing a CARD (ASC) specks (Figure 4C), which are typically released after stimulation of the NLRP3 inflammasome as the activated cells die by pyroproptosis
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