| Summary: | Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant disease caused by TNFRSF1A mutations, encoding tumour necrosis factor receptor 1 (TNFRl). TRAPS is characterized by recurrent fever episodes and systemic inflammation. The pathophysiology of TRAPS is unclear; one hypothesis is that mutant receptor misfolding leads to intracellular retention in the endoplasmic reticulum (ER) causing a proinflammatory unfolded protein response (UPR). A branch of the UPR involves IREla activation, leading to splicing of the transcription factor X-box binding protein 1 (sXBPl) in response to Toll-like receptor (TLR) ligation. Furthermore, TNF and Il-6 have been identified as additional transcriptional targets of sXBPl. Activated UPR is associated with reactive oxygen species (ROS) production. This study aimed to investigate the hypothesis that ER stress, caused by retention of mutant TNFRl, facilitates activation of inflammatory pathways. Results presented show that TRAPS patients displayed increased sXBPl mRNA transcript, as well as increased levels of protein kinase•like ER kinase (PERK) and phosphorylated-PERK, compared to healthy controls (HC). However, other UPR-associated transcripts didn't show evidence of upregulation, indicating a non-classical UPR. TRAPS patients' monocytes had increased basal ROS levels that were not accompanied by an increase in the antioxidant defences. When stimulated with lipopolysaccharide (LPS), TRAPS patients' PBMC demonstrated upregulated IL-6 secretion and sXBPl transcript; however, sXBPl upregulation was only seen in the patients and not in HC. Both of these responses were reduced with antioxidant co-treatment demonstrating dependence on ROS. These results indicate that high ROS levels and sXBPl in TRAPS patients may predispose patients to hyper-inflammatory responses to pathogenic stimuli. Although a full UPR was not evident it is possible that the intracellular accumulation of TNFRI is precipitating both of these events. Despite the ongoing identification of new hereditary periodic fever genes, there are still many patients with undiagnosed fever syndromes. This project also investigated the genetic basis of disease in a number of patients with a TRAPS-like phenotype by Caspase 1 (CASP1) screening and exome sequencing. However, these studies were not able to identify any disease-associated mutations but did reveal a novel 4bp deletion SNP in fR aminopeptidase 1 (ERAP1) in one family.
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