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Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP

Palendira, Umaimainthan; Low, Carol; Chan, Anna; Hislop, Andrew D.; Ho, Edwin; Phan, Tri Giang; Deenick, Elissa; Cook, Matthew C.; Riminton, D. Sean; Choo, Sharon; Loh, Richard; Alvaro, Frank; Booth, Claire; Gaspar, H. Bobby; Moretta, Alessandro; Khanna, Rajiv; Rickinson, Alan B.; Tangye, Stuart G.

Description

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe...[Show more]

dc.contributor.authorPalendira, Umaimainthan
dc.contributor.authorLow, Carol
dc.contributor.authorChan, Anna
dc.contributor.authorHislop, Andrew D.
dc.contributor.authorHo, Edwin
dc.contributor.authorPhan, Tri Giang
dc.contributor.authorDeenick, Elissa
dc.contributor.authorCook, Matthew C.
dc.contributor.authorRiminton, D. Sean
dc.contributor.authorChoo, Sharon
dc.contributor.authorLoh, Richard
dc.contributor.authorAlvaro, Frank
dc.contributor.authorBooth, Claire
dc.contributor.authorGaspar, H. Bobby
dc.contributor.authorMoretta, Alessandro
dc.contributor.authorKhanna, Rajiv
dc.contributor.authorRickinson, Alan B.
dc.contributor.authorTangye, Stuart G.
dc.date.accessioned2015-10-13T22:53:14Z
dc.date.available2015-10-13T22:53:14Z
dc.identifier.issn1545-7885
dc.identifier.urihttp://hdl.handle.net/1885/15910
dc.description.abstractX-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP(+) and SAP(-) cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8(+) T cells specific for CMV and influenza were distributed across SAP(+) and SAP(-) populations, EBV-specific cells were exclusively SAP(+). The preferential recruitment of SAP(+) cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8(+) T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP(-) clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP(-) CD8(+) T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited.
dc.description.sponsorshipThe Tangye lab is supported by grants and fellowships awarded by the XLP Research Trust (UK) (www.xlpresearchtrust.org), Cancer Council New South Wales (Australia) [www.cancercouncil.com.au], the Association for International Cancer Research (UK) [www.aicr.org.uk], and the National Health and Medical Research Council of Australia [www.nhmrc.gov.au].
dc.format17 pages
dc.publisherPublic Library of Science
dc.rights© 2011 Palendira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.sourcePLoS Biology
dc.subjectantigens, cd
dc.subjectb-lymphocytes
dc.subjectcd8-positive t-lymphocytes
dc.subjectdendritic cells
dc.subjectepstein-barr virus infections
dc.subjectfemale
dc.subjectgenotype
dc.subjectherpesvirus 4, human
dc.subjecthumans
dc.subjectimmunoglobulin class switching
dc.subjectinfluenza, human
dc.subjectintracellular signaling peptides and proteins
dc.subjectleukocytes, mononuclear
dc.subjectlymphoproliferative disorders
dc.subjectorthomyxoviridae
dc.subjectreceptors, cell surface
dc.subjectreceptors, immunologic
dc.subjectsignal transduction
dc.subjectx chromosome inactivation
dc.titleMolecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume9
dcterms.dateAccepted2011-09-16
dc.date.issued2011
local.identifier.absfor110704
local.identifier.ariespublicationu4971216xPUB22
local.publisher.urlhttps://www.plos.org/
local.type.statusPublished Version
local.contributor.affiliationPalendira, Umamainthan, Garvan Institute of Medical Research, Australia
local.contributor.affiliationLow, Carol, Garvan Institute of Medical Research, Australia
local.contributor.affiliationChan, Anna , Garvan Institute of Medical Research, Australia
local.contributor.affiliationHislop, Andrew D, University of Birmingham, United Kingdom
local.contributor.affiliationHo, Edwin , Garvan Institute of Medical Research, Australia
local.contributor.affiliationPhan, Tri Giang , University of New South Wales, Australia
local.contributor.affiliationDeenick, Elissa, Garvan Institute of Medical Research, Australia
local.contributor.affiliationCook, Matthew, College of Medicine, Biology and Environment, CMBE John Curtin School of Medical Research, Division of Molecular Medicine, The Australian National University
local.contributor.affiliationRiminton, Sean, Concord Hospital, Australia
local.contributor.affiliationChoo, Sharon, Royal Childrens' Hospital Melbourne, Australia
local.contributor.affiliationLoh, Richard , Princess Margaret Hospital for Children, Australia
local.identifier.essn1545-7885
local.bibliographicCitation.issue11
local.bibliographicCitation.startpagee1001187
local.bibliographicCitation.lastpage17
local.identifier.doi10.1371/journal.pbio.1001187
dc.date.updated2015-12-08T03:16:03Z
local.identifier.scopusID2-s2.0-82455175808
CollectionsANU Research Publications

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