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Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications.
Arthritis Rheum 2006; 54(3):998-1008AR

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 TNFalpha. 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.

Authors+Show Affiliations

Istituto G. Gaslini, Genoa, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16508982

Citation

D'Osualdo, Andrea, et al. "Neutrophils From Patients With TNFRSF1A Mutations Display Resistance to Tumor Necrosis Factor-induced Apoptosis: Pathogenetic and Clinical Implications." Arthritis and Rheumatism, vol. 54, no. 3, 2006, pp. 998-1008.
D'Osualdo A, Ferlito F, Prigione I, et al. Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. Arthritis Rheum. 2006;54(3):998-1008.
D'Osualdo, A., Ferlito, F., Prigione, I., Obici, L., Meini, A., Zulian, F., ... Gattorno, M. (2006). Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. Arthritis and Rheumatism, 54(3), pp. 998-1008.
D'Osualdo A, et al. Neutrophils From Patients With TNFRSF1A Mutations Display Resistance to Tumor Necrosis Factor-induced Apoptosis: Pathogenetic and Clinical Implications. Arthritis Rheum. 2006;54(3):998-1008. PubMed PMID: 16508982.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: 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 - 2006/3/2/pubmed PY - 2006/4/14/medline PY - 2006/3/2/entrez SP - 998 EP - 1008 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 54 IS - 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 TNFalpha. 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. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/16508982/Neutrophils_from_patients_with_TNFRSF1A_mutations_display_resistance_to_tumor_necrosis_factor_induced_apoptosis:_pathogenetic_and_clinical_implications_ L2 - https://doi.org/10.1002/art.21657 DB - PRIME DP - Unbound Medicine ER -