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Functional characterisation of tumour necrosis factor receptor superfamily 1A (TNFRSF1A) mutations that cause systemic inflammation

Siebert, Stefan 2005. Functional characterisation of tumour necrosis factor receptor superfamily 1A (TNFRSF1A) mutations that cause systemic inflammation. PhD Thesis, Cardiff University.

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Abstract

This work describes a study into the effects of clinically relevant TNF receptor superfamily 1A (TNFRSF1A) mutations associated with the TNF receptor-associated periodic syndrome (TRAPS). TRAPS is a dominantly inherited autoinflammatory disorder characterised by episodes of systemic inflammation. The first part focuses on a novel TNFRSF1A mutation (C43S) from a patient with TRAPS. A primary dermal fibroblast line was established from the patient and used to study the functional effects of this TRAPS mutation. Experiments revealed that the C43S TNFRSF1A mutation resulted in reduced activation of the transcription factors NF-kB and AP-1 in fibroblasts, while production of the pro-inflammatory cytokines IL-6 and IL-8 was maintained at relatively normal levels. TNFa-induced apoptosis was also reduced in fibroblasts and peripheral blood mononuclear cells from this patient with TRAPS. TNFRSF1A shedding from neutrophils was normal. The work was extended by generating and expressing plasmids for four recombinant TNFRSF1A TRAPS mutants, including C43S, in B-cell lines by transient transfection. All four recombinant TNFRSF1A mutants resulted in reduced NF-kB activation, suggesting that reduced TNFRSF1A signalling may be general feature of TRAPS. The four TRAPS mutants all displayed reduced surface expression of TNFRSF1 A, with the receptor predominantly localised intracellularly. The signalling and expression studies also suggest that there may be subtle differences between the various TRAPS mutants. In conclusion, the TRAPS mutations studied alter TNFRSF1A expression and localisation, and reduce TNFRSF1 A-mediated signalling, revealing new insights into TNFRSF1A.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
ISBN: 9781303170904
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Feb 2016 23:14
URI: http://orca.cardiff.ac.uk/id/eprint/55610

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