Clinical and functional characterisation of a novel TNFRSF1A c.605T > A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment.

摘要

Objectives: To study the clinical outcome, treatmentresponse, T-cell subsets and functional consequences of anovel tumour necrosis factor (TNF) receptor type 1(TNFRSF1A) mutation affecting the receptorcleavage site.Methods: Patients with symptoms suggestive of tumournecrosis factor receptor-associated periodic syndrome(TRAPS) and 22 healthy controls (HC) were screened formutations in the TNFRSF1A gene. Soluble TNFRSF1A andinflammatory cytokines were measured by ELISAs.TNFRSF1A shedding was examined by stimulation ofperipheral blood mononuclear cells (PBMCs) with phorbol12-myristate 13-acetate followed by flow cytometricanalysis (FACS). Apoptosis of PBMCs was studied bystimulation with TNFa in the presence of cycloheximideand annexin V staining. T cell phenotypes were monitoredby FACS.Results: TNFRSF1A sequencing disclosed a novel V173D/p.Val202Asp substitution encoded by exon 6 in onefamily, the c.194–14G.A splice variant in another andthe R92Q/p.Arg121Gln substitution in two families.Cardiovascular complications (lethal heart attack andperipheral arterial thrombosis) developed in two V173Dpatients. Subsequent etanercept treatment of the V173Dcarriers was highly effective over an 18-month follow-upperiod. Serum TNFRSF1A levels did not differ betweenTRAPS patients and HC, while TNFRSF1A cleavage frommonocytes was significantly reduced in V173D and R92Qpatients. TNFa-induced apoptosis of PBMCs and T-cellsenescence were comparable between V173D patientsand HC.Conclusions: The TNFRSF1A V173D cleavage sitemutation may be associated with an increased risk forcardiovascular complications and shows a strongresponse to etanercept. T-cell senescence does not seemto have a pathogenetic role in affected patients.