Objectives: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumor necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site.
Methods: Patients with symptoms suggestive of TRAPS and twenty-two healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by enzyme-linked immunosorbent assays. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNF-α in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS.
Results: TNFRSF1A sequencing revealed a novel V173D/p.Val202Asp substitution encoded by exon 6 in one family, the c.194-14G>A splice variant in another, and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over a 18 months follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNF-α-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC.
Conclusions: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to play a pathogenetic role in affected patients.
- <it>TNFRSF1A</it> cleavage site mutation
- TNF receptor-associated periodic fever syndrome
- cardiovascular complications