Patients with TNF Receptor Associated Periodic Syndrome (TRAPS) are hypersensitive to Toll‐like receptor 9 stimulation

Negm, Ola H.; Singh, Sonali; Abduljabbar, Wesam; Hamed, Mohamed R.; Radford, Paul; McDermott, Elizabeth M.; Drewe, Elizabeth; Fairclough, Lucy; Todd, Ian; Tighe, Patrick J.

Abstract

Tumour necrosis factor receptor‐associated periodic syndrome (TRAPS) is an hereditary autoinflammatory disorder characterised by recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNFRSF1A, which encodes tumour necrosis factor receptor‐1 (TNFR1). Our aim was to understand the influence of TRAPS mutations on the response to stimulation of the pattern recognition receptor TLR9. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from TRAPS patients and healthy controls: Serum levels of fifteen pro‐inflammatory cytokines were measured to assess the initial inflammatory status. IL‐1β, IL‐6, IL‐8, IL17, IL22, TNF‐α, VEGF, IFN‐γ, MCP‐1 and TGF‐β were significantly elevated in TRAPS patients sera, consistent with constitutive inflammation. Stimulation of PBMCs with TLR9 ligand (ODN2006) triggered significantly greater upregulation of pro‐inflammatory signalling intermediates (TRAF3, IRAK2, TOLLIP, TRAF6, pTAK, TAB2, pTAB2, IRF7, RIP, NF‐kB p65, pNF‐κB p65, and MEK1/2) in TRAPS patients’ PBMCs. This upregulation 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.

Citation

Negm, O. H., Singh, S., Abduljabbar, W., Hamed, M. R., Radford, P., McDermott, E. M., …Tighe, P. J. (2019). Patients with TNF Receptor Associated Periodic Syndrome (TRAPS) are hypersensitive to Toll‐like receptor 9 stimulation. Clinical and Experimental Immunology, 197(3), 352-360. https://doi.org/10.1111/cei.13306

• Journal Article Type: Article
• Acceptance Date: Apr 11, 2019
• Online Publication Date: Apr 22, 2019
• Publication Date: Apr 22, 2019
• Deposit Date: May 2, 2019
• Publicly Available Date: Apr 23, 2020
• Journal: Clinical & Experimental Immunology
• Print ISSN: 0009-9104
• Electronic ISSN: 1365-2249
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 197
• Issue: 3
• Pages: 352-360
• DOI: https://doi.org/10.1111/cei.13306
• Public URL: https://nottingham-repository.worktribe.com/output/2014639
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1111/cei.13306
• Additional Information: This is the peer reviewed version of the following article: Negm, O. H., Singh, S. , Abduljabbar, W. , Hamed, M. R., Radford, P. , McDermott, E. M., Drewe, E. , Fairclough, L. , Todd, I. and Tighe, P. J. (2019), Patients with TNF Receptor Associated Periodic Syndrome (TRAPS) are hypersensitive to Toll‐like receptor 9 stimulation. Clin Exp Immunol. Accepted Author Manuscript. doi:10.1111/cei.13306, which has been published in final form at https://doi.org/10.1111/cei.13306. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.