Objectives We aim to investigate the genetic basis of a case of late-onset autoinflammatory disease characterised by arthritis, recurrent fever and skin rashes.
Methods We performed whole-exome/genome sequencing and digital droplet PCR (ddPCR) to identify the pathogenic somatic mutation. We used single-cell RNA sequencing (scRNA-seq), intracellular cytokine staining, quantitative PCR, immunohistochemistry and western blotting to define inflammatory signatures and to explore the pathogenic mechanism.
Results We identified a somatic mutation in NLRC4 (p.His443Gln) with the highest mosaicism ratio in the patient’s monocytes (5.69%). The somatic mutation resulted in constitutive NLRC4 activation, spontaneous apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) aggregation, caspase-1 hyperactivation and increased production of interleukin (IL)-1β and IL-18. Moreover, we demonstrated effective suppression of inflammatory cytokine production by targeting gasdermin D, an approach that could be considered as a novel treatment strategy for patients with NLRC4-associated autoinflammatory syndrome.
Conclusions We reported a case of a late-onset autoinflammatory disease caused by a somatic NLRC4 mutation in a small subset of leucocytes. We systemically analysed this condition at a single-cell transcriptomic level and revealed specific enhancement of inflammatory response in myeloid cells.
- immune system diseases
- arthritis, rheumatoid
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Handling editor Josef S Smolen
JW, QY and WZ contributed equally.
Contributors QZ, TJ designed the study, directed and supervised the research. TJ, JW, XY and RF performed experiments and analysed the data. QY, WZ, FL, YS, ZD and PYL enrolled the patients, collected and interpreted clinical information. QZ, TJ, JW and PYL wrote the manuscript with input from others. All authors contributed to the review and approval of the manuscript. QZ is the author acting as guarantor.
Funding QZ received the grant 2018YFC1004903 from National Key Research and Development Project, grants 31771548 and 81971528 from the National Natural Science Foundation of China, grant LR19H100001 from Zhejiang Provincial Natural Science Foundation of China.
Competing interests ZD is the employee of MyGenostics.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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