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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
- Source :
- Europe PubMed Central, Journal of leukocyte biology 99 (2016): 761–769. doi:10.1189/jlb.3A0915-399R, info:cnr-pdr/source/autori:Pucino V.; Lucherini O.M.; Perna F.; Obici L.; Merlini G.; Cattalini M.; Torre F.L.; Maggio M.C.; Lepore M.T.; Magnotti F.; Galgani M.; Galeazzi M.; Marone G.; De Rosa V.; Talarico R.; Cantarini L.; Matarese G./titolo:Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome/doi:10.1189%2Fjlb.3A0915-399R/rivista:Journal of leukocyte biology/anno:2016/pagina_da:761/pagina_a:769/intervallo_pagine:761–769/volume:99
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Abstract
- TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4+CD25− and regulatory CD4+CD25+ T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR-associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR-associated periodic syndrome involving both CD4+ conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.
- Subjects :
- Male
0301 basic medicine
Penetrance
Autoimmunity
medicine.disease_cause
T-Lymphocytes, Regulatory
Immune tolerance
Settore MED/38 - Pediatria Generale E Specialistica
TRAPS
Tconvs
Tregs
autoimmunity
immune tolerance
Immunology and Allergy
IL-2 receptor
Child
Genetics
Mutation
Tconv
TOR Serine-Threonine Kinases
hemic and immune systems
Middle Aged
Acquired immune system
Treg
STAT Transcription Factors
medicine.anatomical_structure
Receptors, Tumor Necrosis Factor, Type I
Cytokines
Female
biological phenomena, cell phenomena, and immunity
Signal Transduction
Adult
Adolescent
Fever
T cell
Cell Biology
Immunology
Receptors, Antigen, T-Cell
Context (language use)
[object Object]
Biology
Immunophenotyping
Young Adult
03 medical and health sciences
Immune system
medicine
Humans
Aged
Cell Proliferation
Demography
Hereditary Autoinflammatory Diseases
biological factors
030104 developmental biology
Cancer research
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Europe PubMed Central, Journal of leukocyte biology 99 (2016): 761–769. doi:10.1189/jlb.3A0915-399R, info:cnr-pdr/source/autori:Pucino V.; Lucherini O.M.; Perna F.; Obici L.; Merlini G.; Cattalini M.; Torre F.L.; Maggio M.C.; Lepore M.T.; Magnotti F.; Galgani M.; Galeazzi M.; Marone G.; De Rosa V.; Talarico R.; Cantarini L.; Matarese G./titolo:Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome/doi:10.1189%2Fjlb.3A0915-399R/rivista:Journal of leukocyte biology/anno:2016/pagina_da:761/pagina_a:769/intervallo_pagine:761–769/volume:99
- Accession number :
- edsair.doi.dedup.....dab8a9a0a4a71d12cede9a614b8295a0