Patients with tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) are hypersensitive to Toll-like receptor 9 stimulation

Autor:	Elizabeth M. McDermott, Ola H. Negm, W Abduljabbar, Patrick J. Tighe, Lucy C. Fairclough, Paul M. Radford, Elizabeth Drewe, Sonali Singh, Mohamed R. Hamed, Ian Todd
Rok vydání:	2019
Předmět:	Adult Male 0301 basic medicine Immunology Inflammation Autoimmune Diseases Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Interferon Humans Immunology and Allergy Medicine Aged Genes Dominant business.industry TOLLIP Genetic Diseases Inborn Syndrome Original Articles Middle Aged medicine.disease Vascular endothelial growth factor 030104 developmental biology Gene Expression Regulation Oligodeoxyribonucleotides chemistry Receptors Tumor Necrosis Factor Type I TNF receptor associated periodic syndrome Toll-Like Receptor 9 Mutation Cytokines Female Tumor necrosis factor alpha medicine.symptom business Signal Transduction 030215 immunology Transforming growth factor medicine.drug
Zdroj:	Clin Exp Immunol
ISSN:	1365-2249 0009-9104
DOI:	10.1111/cei.13306
Popis:	Summary Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNFRSF1A, which encodes tumour necrosis factor receptor 1 (TNF-R1). Our aim was to understand the influence of TRAPS mutations on the response to stimulation of the pattern recognition Toll-like receptor (TLR)-9. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from TRAPS patients and healthy controls: serum levels of 15 proinflammatory cytokines were measured to assess the initial inflammatory status. Interleukin (IL)-1β, IL-6, IL-8, IL-17, IL-22, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor (TGF)-β were significantly elevated in TRAPS patients’ sera, consistent with constitutive inflammation. Stimulation of PBMCs with TLR-9 ligand (ODN2006) triggered significantly greater up-regulation of proinflammatory signalling intermediates [TNF receptor-associated factor (TRAF 3), IL-1 receptor-associated kinase-like 2 (IRAK2), Toll interacting protein (TOLLIP), TRAF6, phosphorylated transforming growth factor-β-activated kinase 1 (pTAK), transforming growth factor-β-activated kinase-binding protein 2 (TAB2), phosphorylated TAK 2 (pTAB2), IFN-regulatory factor 7 (IRF7), receptor interacting protein (RIP), nuclear factor kappa B (NF-κB) p65, phosphorylated NF-κB p65 (pNF-κB p65) and mitogen-activated protein kinase kinase (MEK1/2)] in TRAPS patients’ PBMCs. This up-regulation of proinflammatory signalling intermediates and raised serum cytokines occurred despite concurrent anakinra treatment and no overt clinical symptoms at time of sampling. These novel findings further demonstrate the wide-ranging nature of the dysregulation of innate immune responses underlying the pathology of TRAPS and highlights the need for novel pathway-specific therapeutic treatments for this disease.
Databáze:	OpenAIRE
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