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

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