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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS)
European Journal of Immunology, Volume 44, No. 7, Year 2014
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Description
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. © 2014 The Authors. European Journal of Immunology.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC4285816/bin/eji0044-2096-SD1.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC4285816/bin/eji0044-2096-SD2.pdf
Authors & Co-Authors
Negm, Ola H.
United Kingdom, Nottingham
University of Nottingham
Egypt, Mansoura
Faculty of Medicine
Mannsperger, Heiko A.
Germany, Heidelberg
German Cancer Research Center
Germany, Altlussheim
Metasystems Gmbh
McDermott, E. M.
United Kingdom, Nottingham
Nottingham University Hospitals Nhs Trust
Drewe, E.
United Kingdom, Nottingham
Nottingham University Hospitals Nhs Trust
Powell, Richard J.
United Kingdom, Nottingham
University of Nottingham
Todd, Ian D.H.
United Kingdom, Nottingham
University of Nottingham
Fairclough, Lucy C.
United Kingdom, Nottingham
University of Nottingham
Tighe, Patrick J.
United Kingdom, Nottingham
University of Nottingham
Statistics
Citations: 15
Authors: 8
Affiliations: 5
Identifiers
Doi:
10.1002/eji.201344328
e-ISSN:
15214141
Study Design
Randomised Control Trial