Abstract
Objective. 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. Methods. 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. Results. 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. Conclusion. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 998-1008 |
| Number of pages | 11 |
| Journal | Arthritis and Rheumatism |
| Volume | 54 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2006 |
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ASJC Scopus subject areas
- Immunology
- Rheumatology
Cite this
Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis : Pathogenetic and clinical implications. / D'Osualdo, Andrea; Ferlito, Francesca; Prigione, Ignazia; Obici, Laura; Meini, Antonella; Zulian, Francesco; Pontillo, Alessandra; Corona, Fabrizia; Barcellona, Roberto; Di Duca, Marco; Santamaria, Giuseppe; Traverso, Francesco; Picco, Paolo; Baldi, Maurizia; Plebani, Alessandro; Ravazzolo, Roberto; Ceccherini, Isabella; Martini, Alberto; Gattorno, Marco.
In: Arthritis and Rheumatism, Vol. 54, No. 3, 03.2006, p. 998-1008.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis
T2 - Pathogenetic and clinical implications
AU - D'Osualdo, Andrea
AU - Ferlito, Francesca
AU - Prigione, Ignazia
AU - Obici, Laura
AU - Meini, Antonella
AU - Zulian, Francesco
AU - Pontillo, Alessandra
AU - Corona, Fabrizia
AU - Barcellona, Roberto
AU - Di Duca, Marco
AU - Santamaria, Giuseppe
AU - Traverso, Francesco
AU - Picco, Paolo
AU - Baldi, Maurizia
AU - Plebani, Alessandro
AU - Ravazzolo, Roberto
AU - Ceccherini, Isabella
AU - Martini, Alberto
AU - Gattorno, Marco
PY - 2006/3
Y1 - 2006/3
N2 - Objective. 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. Methods. 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. Results. 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. Conclusion. 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.
AB - Objective. 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. Methods. 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. Results. 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. Conclusion. 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.
UR - http://www.scopus.com/inward/record.url?scp=33644878847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644878847&partnerID=8YFLogxK
U2 - 10.1002/art.21657
DO - 10.1002/art.21657
M3 - Article
C2 - 16508982
AN - SCOPUS:33644878847
VL - 54
SP - 998
EP - 1008
JO - Arthritis care and research : the official journal of the Arthritis Health Professions Association
JF - Arthritis care and research : the official journal of the Arthritis Health Professions Association
SN - 0893-7524
IS - 3
ER -