Differential impact of high and low penetrance <i>TNFRSF1A</i> gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome

Pucino, Valentina; Lucherini, Orso Maria; Perna, Francesco; Obici, Laura; Merlini, Giampaolo; Cattalini, Marco; Torre, Francesco La; Maggio, Maria Cristina; Lepore, Maria Teresa; Magnotti, Flora; Galgani, Mario; Gargiulo, Mauro; Marone, Gianni; Rosa, Veronica De; Talarico, Rosaria; Cantarini, Luca; Matarese, Giuseppe

doi:10.1189/jlb.3a0915-399r

Cited by 16 publications

(9 citation statements)

References 41 publications

(41 reference statements)

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“…Although most previous studies focused on the effect of TRAPS mutations in monocytes , such variations might also affect the functions of lymphocytes. This notion is supported by a previous study showing the dysregulation of T cell subsets in TRAPS patients . Although dysfunctions in autoimmune systems are not attributed to the development of TRAPS, the dysregulation of adaptive immune cell components might contribute to the autoinflammatory features of TRAPS, in association with activated innate immune responses.…”

Section: Discussionsupporting

confidence: 69%

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: Discussionsupporting

confidence: 69%

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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“…Other data, in patients with multiple sclerosis, point toward the enhancement of the interaction between the receptor and its ligand by the R92Q variant, resulting in the potentiation of TNF-mediated pathways (23). In addition, several authors have postulated a potential role of low-penetrance TNFRSF1A variants (including R92Q, P46L, and other recently reported, such as V95M, D12E, and R104Q) in causing different autoinflammatory phenotypes (6, 21). These low-penetrance variants might also contribute, as a possible susceptibility factor in the development of multifactorial polygenic inflammatory or autoimmune conditions, such as idiopathic recurrent acute pericarditis, Behçet’s disease, juvenile idiopathic arthritis, and other autoinflammatory diseases (6, 14, 24–27).…”

Section: Discussionmentioning

confidence: 96%

“…While forms of TNFRSF1A cysteine mutations clearly destabilize the protein structure and produce defects in cell surface expression and TNF binding, R92Q mutants, which share structural similarities with the wild-type protein, also share similar mechanisms of action with wild-type TNFRSF1A (20). In this sense, structural mutations have also shown to produce deeper disturbances in T-cell function than R92Q and other low-penetrance variants (21). However, recent investigations have demonstrated a constitutive activity of R92Q mutants associated with TRAPS, which might be explained by configurational changes induced after ligand binding that can act as the trigger for TNFR1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Disease Phenotype and Outcome Depending on the Age at Disease Onset in Patients Carrying the R92Q Low-Penetrance Variant in TNFRSF1A Gene

et al. 2017

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BackgroundTumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene. R92Q, a low-penetrance variant, is usually associated with a milder TRAPS phenotype than structural or pathogenic mutations. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date.ObjectiveTo analyze clinical features and disease outcomes in patients diagnosed with TRAPS associated with R92Q variant and to investigate differences between patients with pediatric and adult disease onset.MethodsA retrospective review of patients with R92Q-related disease from four reference centers for autoinflammatory diseases was performed. Clinical and laboratory features, family history of autoinflammatory diseases, treatments received, and outcomes during follow-up were recorded and separately analyzed in pediatric and adult patients. Our results were included in the analysis with other reported pediatric and adult R92Q-related disease series.ResultsOur series encompassed 18 patients (9 females and 9 males) with R92Q variant. In 61% of patients, disease onset occurred during infancy and in 39%, during adulthood, with a median diagnostic delay of 5 years and a follow-up of 5.4 years. A positive family history of autoinflammatory disease was detected in 28% of patients. All patients presented with febrile recurrent episodes. Other common symptoms included arthralgia/arthritis (61%), myalgia (39%), asthenia/fatigue (44%), abdominal pain (39%), headache (33%), odynophagia (33%), skin rash (28%), and chest pain (22%). During attacks, 80% of patients increased acute phase reactants levels. No patient had developed amyloidosis during the study period. At the end of follow-up, 28% of patients were asymptomatic and treatment free, 50% were receiving non-steroidal anti-inflammatory drugs or glucocorticoids on demand, and 22% were being treated with biologic agents. When differences between pediatric and adult patients were globally analyzed, adults tended to have longer attacks duration and presented more frequently with chest pain and headache, while abdominal pain, vomiting, cervical adenitis, and pharyngitis predominated in pediatric patients. No differences in outcomes and treatment requirements were observed in both age groups.ConclusionThis study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset.

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“…Together with AMPK, mTOR is a central integrator of environmental signals and nutrient availability with cellular functions (Delgoffe and Powell, 2015;Pollizzi and Powell, 2015;Pucino et al, 2016). Indeed, aberrant mTOR activation is associated with cellular senescence, and rapamacyin, the mTOR complex 1 inhibitor, has been investigated as a therapeutic agent to treat degenerative, autoimmune and hyperproliferative diseases (Perl, 2016).…”

Section: Tanscription Factors As Metabolic Sensorsmentioning

confidence: 99%

Metabolic Checkpoints in Rheumatoid Arthritis

et al. 2020

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Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipocytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.

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Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome

Cited by 16 publications

References 41 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

Disease Phenotype and Outcome Depending on the Age at Disease Onset in Patients Carrying the R92Q Low-Penetrance Variant in TNFRSF1A Gene

Metabolic Checkpoints in Rheumatoid Arthritis

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