title: Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome.
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.
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II," Napoli, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Pucino
authors.affiliation: Centro di Ricerca sulle Malattie Autoinfiammatorie e Malattie di Behçet, Dipartimento di Scienze Mediche Chirurgiche e Neuroscienze, Università degli Studi di Siena, Siena, Italy;
authors.forename: Orso Maria
authors.initials: OM
authors.lastname: Lucherini
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli "Federico II," Napoli, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Perna
authors.affiliation: Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, Fondazione IRCCS Policlinico San Matteo e Dipartimento di Medicina Molecolare, Università degli Studi di Pavia, Pavia, Italy;
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.affiliation: Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, Fondazione IRCCS Policlinico San Matteo e Dipartimento di Medicina Molecolare, Università degli Studi di Pavia, Pavia, Italy;
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.affiliation: Dipartimento di Immunologia e Reumatologia, Clinica Pediatrica, Università degli Studi di Brescia e Spedali Civili di Brescia, Brescia, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Cattalini
authors.affiliation: Dipartimento di Pediatria, Ospedale A. Perrino, Brindisi, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: La Torre
authors.affiliation: Dipartimento Pro.S.A.M.I., c/o Ospedale dei Bambini G. Di Cristina, ARNAS Palermo, Palermo, Italy;
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Maggio
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II," Napoli, Italy;
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Lepore
authors.affiliation: Centro di Ricerca sulle Malattie Autoinfiammatorie e Malattie di Behçet, Dipartimento di Scienze Mediche Chirurgiche e Neuroscienze, Università degli Studi di Siena, Siena, Italy;
authors.forename: Flora
authors.initials: F
authors.lastname: Magnotti
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Galgani
authors.affiliation: Centro di Ricerca sulle Malattie Autoinfiammatorie e Malattie di Behçet, Dipartimento di Scienze Mediche Chirurgiche e Neuroscienze, Università degli Studi di Siena, Siena, Italy;
authors.forename: Mauro
authors.initials: M
authors.lastname: Galeazzi
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II," Napoli, Italy; Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche (CISI), Università degli Studi di Napoli "Federico II," Napoli, Italy;
authors.forename: Gianni
authors.initials: G
authors.lastname: Marone
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy; Unità di NeuroImmunologia, IRCCS-Santa Lucia, Roma, Italy;
authors.forename: Veronica
authors.initials: V
authors.lastname: De Rosa
authors.affiliation: Unità di Reumatologia, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Pisa, Pisa, Italy;
authors.forename: Rosaria
authors.initials: R
authors.lastname: Talarico
authors.affiliation: Centro di Ricerca sulle Malattie Autoinfiammatorie e Malattie di Behçet, Dipartimento di Scienze Mediche Chirurgiche e Neuroscienze, Università degli Studi di Siena, Siena, Italy; cantariniluca@hotmail.com.
authors.forename: Luca
authors.initials: L
authors.lastname: Cantarini
authors.affiliation: Dipartimento di Medicina e Chirurgia, Facoltà di Medicina e Chirurgia, Università degli Studi di Salerno, Baronissi Campus, Baronissi, Salerno, Italy; and IRCCS-MultiMedica, Milano, Italy gmatarese@unisa.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matarese
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003710:Demography; D005260:Female; D005334:Fever / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D019683:Penetrance; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D047888:Receptors, Tumor Necrosis Factor, Type I; D050791:STAT Transcription Factors; C506235:TNFRSF1A protein, human; D058570:TOR Serine-Threonine Kinases
keywords: TRAPS; Tconvs; Tregs; autoimmunity; immune tolerance