Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor–induced apoptosis: Pathogenetic and clinical implications

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 TNF␣. 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.

Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome

“…on March 21, 2019. by guest www.bloodjournal.org From neutrophil apoptosis. 10 In conclusion, we have shown decreased apoptosis of circulating lymphocytes ex vivo in fever-free patients with HIDS after stimulation with anisomycin. This lymphocytic defect was not seen in TRAPS or FMF.…”

“…FMF is characterized by infiltrates that are almost exclusively composed of neutrophils, whereas the urticarial response in certain cryopyrin-associated periodic syndromes could point to a role of mast cells. This hypothesis of cell-type specificity is supported by the study by D'Osualdo et al, 10 showing abnormal neutrophil apoptosis in 8 patients with TRAPS. In this study, one patient with HIDS was measured and found to have normal For personal use only.…”

“…9 A third study showed decreased TNF-induced neutrophil apoptosis in patients with TRAPS. 10 We included 2 symptom-free patients with FMF who showed no defect in lymphocyte apoptosis. We did not find an apoptosis defect in 7 patients with TRAPS.…”

Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis

“…The mutant receptors self-interact and trigger an inflammatory response [38,41,43]. They are also unable to activate the TNF-a-induced NF-kB transcription pathway, which leads to a reduction in apoptosis [44] and prolonged survival of the activated inflammatory cells, contributing to the inflammatory phenotype of the disease [45,46].…”

“…It has been observed that neutrophils of patients carrying this mutation are resistant to TNF-ainduced apoptosis [44]; defective shedding is not found in all cases, and only subtle abnormalities have been described in surface receptor expression in the endothelial cell line [26,34]. Much work is under way to try to understand the pathophysiology of the disease in patients with this substitution.…”