Skip to main content

Research Repository

Advanced Search

A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS)

Negm, Ola H.; Mannsperger, Heiko A.; McDermott, Elizabeth M.; Drewe, Elizabeth; Powell, Richard J.; Todd, Ian; Fairclough, Lucy C.; Tighe, Patrick J.


Assistant Professor

Heiko A. Mannsperger

Elizabeth M. McDermott

Elizabeth Drewe

Richard J. Powell

Ian Todd

Patrick J. Tighe


Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients' PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients' PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.


Negm, O. H., Mannsperger, H. A., McDermott, E. M., Drewe, E., Powell, R. J., Todd, I., …Tighe, P. J. (2014). A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS). European Journal of Immunology, 44(7), 2096-2110.

Journal Article Type Article
Acceptance Date Mar 21, 2014
Online Publication Date Jun 10, 2014
Publication Date 2014-07
Deposit Date Oct 2, 2017
Publicly Available Date Oct 2, 2017
Journal European Journal of Immunology
Print ISSN 0014-2980
Electronic ISSN 1521-4141
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 44
Issue 7
Pages 2096-2110
Keywords Autoinflammation; Protein microarray; Signalome; TNF receptor 1; TRAPS
Public URL
Publisher URL


eji0044-2096.pdf (2.4 Mb)

Copyright Statement
Copyright information regarding this work can be found at the following address:

You might also like

Downloadable Citations