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Murine LRBA deficiency causes CTLA-4 deficiency in Tregs without progression to immunune dysregulation

Burnett, Deborah L.; Parish, Ian; Masle-Farquhar, Etienne; Brink, Robert; Goodnow, Christopher C.

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Inherited mutations in lipopolysaccharide-responsive beige-like anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B-cell and antibody deficiency (common variable immunodeficiency), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene...[Show more]

dc.contributor.authorBurnett, Deborah L.
dc.contributor.authorParish, Ian
dc.contributor.authorMasle-Farquhar, Etienne
dc.contributor.authorBrink, Robert
dc.contributor.authorGoodnow, Christopher C.
dc.date.accessioned2021-08-17T04:53:30Z
dc.identifier.issn0818-9641
dc.identifier.urihttp://hdl.handle.net/1885/243982
dc.description.abstractInherited mutations in lipopolysaccharide-responsive beige-like anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B-cell and antibody deficiency (common variable immunodeficiency), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting. These mice revealed that LRBA has a critical, cell-autonomous role in promoting cytotoxic T-lymphocyte antigen-4 (CTLA-4) accumulation within CD4 effector T cells and FOXP3+T-regulatory cells (Tregs). In young mice, or in chimeric mice where only half of the T cells are LRBA deficient, low CTLA-4 was the only detectable abnormality in Tregs, whereas in old mice FOXP3 was also decreased. Low CTLA-4 did not translate into increased CD86 on B cells unless the LRBA-deficient mice were immunised, and neither immunisation nor chronic lymphocytic choriomeningitis virus infection precipitated immune dysregulation. LRBA deficiency did not alter antigen-specific B-cell activation, germinal centre (GC) formation, isotype switching or affinity maturation. Paradoxically, CD86 was decreased on GC B cells in LRBA-deficient mice, pointing to compensatory mechanisms for controlling CD86 in the face of low CTLA-4. These results add to the experimental rationale for treating LRBA deficiency with the CTLA4-Ig fusion protein, Abatacept, and pose questions about the limitations of laboratory experiments in mice to reproduce human disease in natura.
dc.description.sponsorshipThis work was supported by NHMRC Project Grant 1108800, NHMRC Program Grants 1016953 and 1113904, NIH Grant U19 AI100627 and NHMRC Fellowship 1081858, and by the Ritchie Family Foundation.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherWiley
dc.rights© 2017 The Author(s)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/
dc.sourceImmunology and Cell Biology
dc.titleMurine LRBA deficiency causes CTLA-4 deficiency in Tregs without progression to immunune dysregulation
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume95
dc.date.issued2017
local.identifier.absfor111603 - Systems Physiology
local.identifier.ariespublicationu9505948xPUB197
local.publisher.urlhttps://www.wiley.com/en-gb
local.type.statusPublished Version
local.contributor.affiliationBurnett, Deborah L., Garvan Institute of Medical Research
local.contributor.affiliationParish, Ian, College of Health and Medicine, ANU
local.contributor.affiliationMasle-Farquhar, Etienne, Garvan Institute of Medical Research
local.contributor.affiliationBrink, Robert, Garvan Institute of Medical Research
local.contributor.affiliationGoodnow, Christopher C., Garvan Institute of Medical Research
dc.relationhttp://purl.org/au-research/grants/nhmrc/1108800
dc.relationhttp://purl.org/au-research/grants/nhmrc/1016953
dc.relationhttp://purl.org/au-research/grants/nhmrc/1113904
dc.relationhttp://purl.org/au-research/grants/nhmrc/1081858
local.bibliographicCitation.issue9
local.bibliographicCitation.startpage775
local.bibliographicCitation.lastpage788
local.identifier.doi10.1038/icb.2017.50
local.identifier.absseo920105 - Digestive System Disorders
dc.date.updated2020-11-23T10:51:37Z
local.identifier.scopusID2-s2.0-85027891651
dcterms.accessRightsOpen Access
dc.provenanceThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.licenseCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
CollectionsANU Research Publications

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