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Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy

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dc.contributor.authorAYDINER, ELİF
dc.contributor.authorsLo, Bernice; Zhang, Kejian; Lu, Wei; Zheng, Lixin; Zhang, Qian; Kanellopoulou, Chrysi; Zhang, Yu; Liu, Zhiduo; Fritz, Jill M.; Marsh, Rebecca; Husami, Ammar; Kissell, Diane; Nortman, Shannon; Chaturvedi, Vijaya; Haines, Hilary; Young, Lisa R.; Mo, Jun; Filipovich, Alexandra H.; Bleesing, Jack J.; Mustillo, Peter; Stephens, Michael; Rueda, Cesar M.; Chougnet, Claire A.; Hoebe, Kasper; McElwee, Joshua; Hughes, Jason D.; Karakoc-Aydiner, Elif; Matthews, Helen F.; Price, Susan; Su, Helen C.; Rao, V. Koneti; Lenardo, Michael J.; Jordan, Michael B.
dc.date.accessioned2022-03-12T20:26:59Z
dc.date.available2022-03-12T20:26:59Z
dc.date.issued2015
dc.description.abstractMutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional Tcells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.
dc.identifier.doi10.1126/science.aaa1663
dc.identifier.eissn1095-9203
dc.identifier.issn0036-8075
dc.identifier.pubmed26206937
dc.identifier.urihttps://hdl.handle.net/11424/233601
dc.identifier.wosWOS:000358381400045
dc.language.isoeng
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.relation.ispartofSCIENCE
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectCOMMON VARIABLE IMMUNODEFICIENCY
dc.subjectREGULATORY T-CELLS
dc.subjectLONG-TERM SAFETY
dc.subjectRHEUMATOID-ARTHRITIS
dc.subjectMUTATIONS
dc.subjectACTIVATION
dc.subjectDISORDERS
dc.subjectDISEASE
dc.subjectGENE
dc.subjectLYMPHOPROLIFERATION
dc.titlePatients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
dc.typearticle
dspace.entity.typePublication
local.avesis.id804170ce-4511-4861-9655-3730b910043e
local.import.packageSS17
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.numberofpages5
oaire.citation.endPage440
oaire.citation.issue6246
oaire.citation.startPage436
oaire.citation.titleSCIENCE
oaire.citation.volume349
relation.isAuthorOfPublication787c2629-584b-4b3e-9850-bf85838f2973
relation.isAuthorOfPublication.latestForDiscovery787c2629-584b-4b3e-9850-bf85838f2973

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