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dc.contributor.authorStanding, Ariane S.I.en
dc.contributor.authorMalinova, Dessislavaen
dc.contributor.authorHong, Yingen
dc.contributor.authorRecord, Julienen
dc.contributor.authorMoulding, Daleen
dc.contributor.authorBlundell, Michael P.en
dc.contributor.authorNowak, Karolinen
dc.contributor.authorJones, Hannahen
dc.contributor.authorOmoyinmi, Ebunen
dc.contributor.authorGilmour, Kimberlyen
dc.contributor.authorMedlar, Alanen
dc.contributor.authorStanescu, Horiaen
dc.contributor.authorKleta, Roberten
dc.contributor.authorAnderson, Glennen
dc.contributor.authorNanthapisal, Siraen
dc.contributor.authorKlein, Nigelen
dc.contributor.authorGomes, Sonia Meloen
dc.contributor.authorThrasher, Adrian J.en
dc.contributor.authorEleftheriou, Despinaen
dc.contributor.authorBrogan, Paul A.en
dc.date.accessioned2019-01-25T12:57:22Z
dc.date.available2019-01-25T12:57:22Z
dc.date.issued2016-12-19
dc.identifier.citationStanding ASI, Malinova D, Hong Y, Record J, Moulding D, Blundell M, Nowak K, Jones H, Omoyinmi E, Gilmour KC, Medlar A, Stanescu H, Kleta R, Anderson G, Nanthapisal S, Klein N, Gomes SM, Thrasher AJ, Eleftheriou D, Brogan PA (2017) 'Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1', The Journal of experimental medicine, 214 (1), pp.59-71.en
dc.identifier.issn1540-9538
dc.identifier.pmid27994071
dc.identifier.doi10.1084/jem.20161228
dc.identifier.urihttp://hdl.handle.net/10547/623090
dc.description.abstractThe importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation.
dc.language.isoenen
dc.publisherRockefeller University Pressen
dc.relation.urlhttp://jem.rupress.org/content/214/1/59en
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206503/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectautoinflammatory periodic feveren
dc.subjectimmunodeficiencyen
dc.subjectactinen
dc.subjectC550 Immunologyen
dc.titleAutoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1en
dc.typeArticleen
dc.contributor.departmentUniversity College Londonen
dc.contributor.departmentUniversity of Bedfordshireen
dc.contributor.departmentGreat Ormond Street Hospital for Children NHS Foundation Trusten
dc.identifier.journalThe Journal of experimental medicineen
dc.identifier.pmcidPMC5206503
dc.date.updated2019-01-25T12:52:21Z
dc.description.noteoa article
html.description.abstractThe importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation.


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