Drs. D'Osualdo and Ferlito contributed equally to this work.
Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor–induced apoptosis: Pathogenetic and clinical implications
Article first published online: 28 FEB 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 3, pages 998–1008, March 2006
How to Cite
D'Osualdo, A., Ferlito, F., Prigione, I., Obici, L., Meini, A., Zulian, F., Pontillo, A., Corona, F., Barcellona, R., Duca, M. D., Santamaria, G., Traverso, F., Picco, P., Baldi, M., Plebani, A., Ravazzolo, R., Ceccherini, I., Martini, A. and Gattorno, M. (2006), Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor–induced apoptosis: Pathogenetic and clinical implications. Arthritis & Rheumatism, 54: 998–1008. doi: 10.1002/art.21657
- Issue published online: 28 FEB 2006
- Article first published online: 28 FEB 2006
- Manuscript Accepted: 1 DEC 2005
- Manuscript Received: 6 JUL 2005
- Italian Ministry of Health (Ricerca Corrente)
- Fondazione C. Golgi, Brescia
To explore tumor necrosis factor (TNF)–induced apoptosis in neutrophils from patients with TNF receptor–associated periodic syndrome (TRAPS) and to correlate the results with the different kinds of TNFRSF1A mutations.
Two hundred sixty-five patients with clinically suspected inherited autoinflammatory syndrome were screened for mutations of the TNFRSF1A gene. Neutrophils were isolated from heparinized blood by dextran sedimentation and incubated with and without cycloheximide (CHX) and TNFα. Cell apoptosis was assessed by human annexin V binding, and caspase 8 activation was assessed by flow cytometry.
Twenty-one patients were found to carry a variant of the TNFRSF1A gene: 13 patients had an R92Q substitution, and 8 patients presented other missense substitutions, 1 splicing mutation, and 1 in-frame interstitial deletion. Neutrophil stimulation with TNF and CHX was associated with induction of apoptosis in 12 normal controls and in 10 subjects with the R92Q mutation. Conversely, neutrophils from 8 TRAPS patients with mutations of cysteine or threonine residues or interstitial deletion did not show any induction of apoptosis after stimulation. The incidence of the R92Q mutation among patients with recurrent autoinflammatory syndromes was similar to that observed in the normal population.
Resistance to TNF-mediated apoptosis is a feature in TRAPS patients who have mutations of cysteine residues or interstitial deletion, and may play a pathogenic role. The R92Q mutation does not appear to be significantly associated with TRAPS.