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Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS)

  • Sinisa SavicEmail author
  • Michael F. McDermott
Chapter

Abstract

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant hereditary disease, caused by heterozygous mutations in TNFRSF1A, which encodes for TNF-receptor 1 (TNFR1). Most of the pathogenic mutations are single-nucleotide missense variants localized in extracellular, cysteine rich domains of the receptor. The pathogenesis of TRAPS is complex and likely involves several mutually non-exclusive molecular mechanisms, however, co-expression of the mutated and wild type of the receptor is required in all cases. The proposed mechanisms include abnormal TNFR1 cleavage; increased activation of nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase; ligand-independent activation of mutant TNFR1; generation of mitochondrial reactive oxygen species (ROS) leading to enhanced activation of the NLRP3 inflammasome; TNFR1 misfolding and retention within the endoplasmic reticulum (ER) leading to activation of ER-associated endonuclease, inositol-requiring enzyme 1 (IRE-1) and resulting in hyper-responsiveness to lipopolysaccharide via selective degradation of microRNAs (miRs).

The majority of patients with TRAPS are symptomatic from childhood, with the median age of symptom onset reported to be about 4 years. Most patients report episodic attacks of fever, with serositis manifesting as abdominal and/or chest pain, myalgia with or without typical overlying migratory rash, arthralgia and arthritis. The minority of patients will have continuous symptoms, and many will have biochemical evidence of systemic inflammatory response even in the absence of symptoms. Prior to effective therapies, systemic amyloidosis was found in up to 15% of patients. The diagnosis of TRAPS still depends on molecular genetic analysis for conformation since formal diagnostic criteria have yet to be developed. Anti-interleukin (IL)-1 biological agents are currently the first choice of treatment for patients who require ongoing therapy.

Keywords

TNF-receptor 1 (TNFR1) Endoplasmic reticulum (ER) stress Mitochondrial reactive oxygen species (ROS) Inositol-requiring enzyme 1 (IRE1) Anakinra, canakinumab 

Abbreviations

3-MA

3-Methyladenine

ADAM

A disintegrin and metalloproteinase

CAPS

Cryopyrin-associated periodic syndrome

CRD

Cysteine-rich domains

CRP

C-reactive protein.

DF

Dermal fibroblasts

DMARDs

Disease-modifying anti-rheumatic drugs

ER

Endoplasmic reticulum

FHF

Familial Hibernian fever

FMF

Familial Mediterranean fever

IĸB

I kappa beta

IKK

I kappa B kinase

IL

Interleukin

IRE1

Inositol-requiring enzyme 1

JNK

c-Jun N-terminal kinase

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

miR

MicroRNA

MKD

Mevalonate kinase deficiency

mROS

Mitochondrial ROS

NADPH

Nicotinamide adenine dinucleotide phosphate

NF-ĸB

Nuclear factor-κB

NLRP3

NACHT, LRR and PYD domains-containing protein 3

NOX

NADPH oxidases

NSAIDs

Nonsteroidal anti-inflammatory drugs

OXPHOS

Oxidative phosphorylation

PCR

Polymerase chain reaction

PERK

Protein kinase (PKR)-like endoplasmic reticulum kinase

PFAPA

Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis

PGA

Physician global assessment

RIP

Receptor-interacting protein

ROS

Reactive oxygen species

SAA

Serum amyloid A

TACE

TNF-alpha converting enzyme

TLR

Toll-like receptor

TNF

Tumor necrosis factor

TNFR1

TNF receptor 1

UPR

Unfolded protein response

XBP1

X-box binding protein 1

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical Immunology and AllergySt James’s University HospitalLeedsUK
  2. 2.Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM)St James’s University HospitalLeedsUK

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