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

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

doi:10.1111/cei.13306

Cited by 9 publications

(7 citation statements)

References 27 publications

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“…Considering these findings, TRAPS mutations are likely to lower the threshold of inflammatory responses to various TLR ligands, including pathogen‐associated molecular patterns and damage‐associated molecular patterns. Indeed, a recent study has reported that PBMCs from TRAPS patients are susceptible to a TLR‐9 ligand . Apart from TLR ligands, heparin has been suggested to be a natural stimulant of inflammation , which might imply the possible involvement of the transmembrane protein 184A, a receptor for heparin .…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome

Tsuji

Matsuzaki

Iseki

et al. 2019

Clinical and Experimental Immunology

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Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.

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Section: Discussionmentioning

confidence: 99%

Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome

Tsuji

Matsuzaki

Iseki

et al. 2019

Clinical and Experimental Immunology

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“…In addition, TLR-9 activation of PBMCs from a patient carrying the p.C62Y (C33Y) mutation triggered production of many pro-inflammatory cytokines and activated several inflammatory pathways, including NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), JNK (c-Jun N-terminal kinase), and P38 MAPK. Collectively, these data demonstrate hyperactivity of the innate immune reponse in TRAPS patients [41].…”

Section: Pathophysiology In Trapsmentioning

confidence: 62%

Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives

Cudrici

Deuitch

Aksentijevich

2020

IJMS

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Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory syndrome characterized by prolonged and recurrent episodes of fever, abdominal and/or chest pain, arthralgia, myalgia, and erythematous rash. TRAPS is associated with heterozygous variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor 1) receptor. Disease-causing variants are found exclusively in the extracellular domain of TNFR1 and affect receptor structure and binding to the TNF ligand. The precise mechanism of the disease is still unclear, but it is thought that intracellular accumulation of misfolded mutant protein leads to endoplasmic reticulum stress and enhanced inflammatory responses through constitutive activation of various immune pathways. Other possible mechanisms contributing to the disease pathogenesis include defective receptor shedding, TNF-induced cell death, production of reactive oxygen species, and autophagy impairment. Patients’ leucocytes are hyperresponsive to stimulation and produce elevated levels of proinflammatory cytokines. Systemic autoimmune (AA) amyloidosis is an important cause of morbidity and mortality in TRAPS. Over the last two decades, new therapies have changed the progression and outcome of the disease. In this review, we summarize clinical data from 209 patients with validated pathogenic variants reported in the literature and discuss TRAPS diagnosis, pathogenesis, and treatment options.

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“…Some of these signalling patterns contribute to the activation of the adaptive immune system [66]. Therefore, it is understandable that abnormalities of the TLRs pathway are linked to autoinflammation [67] and autoimmunity [68]. Notably, regulation of TLR activation may be used to treat inflammatory conditions.…”

Section: Cellular Components Of the Innate Immune Systemmentioning

confidence: 99%

“…HCQ inhibition of TLR-7 is considered particularly significant for ameliorating SLE disease and anti-RO/SSA antibody-mediated congenital heart block [69], whereas hypersensitivity to TLR-9 was acknowledged in TNF receptor-associated periodic syndrome. This hereditary autoinflammatory disorder is characterized by recurrent episodes of fever and inflammation and autosomal dominant mutations in the TNFRSF1A gene [67]. A role for TLR-4 was suggested in the pathogenesis of ‘deficiency of IL-36Ra’ (DITRA), a systemic autoinflammatory disease that includes generalized pustular psoriatic fever and systemic symptoms [70]…”

Section: Cellular Components Of the Innate Immune Systemmentioning

confidence: 99%

The innate immune perspective of autoimmune and autoinflammatory conditions

et al. 2019

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Innate immunity is one of two immune defence system arms. It is present at birth and does not require ‘learning’ through exposure to foreign organisms. It activates various mechanisms collectively to eliminate pathogens and hold an infection until the adaptive response are mounted. The innate immune system consists of four elements: the epithelial barrier, cells (e.g. macrophages, NK cells), plasma proteins (e.g. complement) and cytokines. These components act in concert to induce complex processes, as well as recruitment, activation and differentiation of adaptive responses. The innate response is more than just the ‘first line of defence’, as it essentially withholds the vast majority of any intruder, has a complex interplay with the adaptive arm and is crucial for survival of the host. Finally, yet importantly, a myriad of diseases has been linked with innate immune dysregulation. In this mini-review we will shed some light on these conditions, particularly regarding autoinflammatory ones.

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

Cited by 9 publications

References 27 publications

Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome

Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome

Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives

The innate immune perspective of autoimmune and autoinflammatory conditions

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