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Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects.

Stepensky, Polina; Keller, Baerbel; Buchta, Mary; Kienzler, Ann-Kathrin; Elpeleg, Orly; Somech, Raz; Cohen, Sivan; Shachar, Idit; Miosge, Lisa A; Schlesier, Michael; Fuchs, Ilka; Enders, Anselm; Eibel, Hermann; Grimbacher, Bodo; Warnatz, Klaus

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BACKGROUND: Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. OBJECTIVE: We sought to identify the genetic alteration in a patient...[Show more]

dc.contributor.authorStepensky, Polina
dc.contributor.authorKeller, Baerbel
dc.contributor.authorBuchta, Mary
dc.contributor.authorKienzler, Ann-Kathrin
dc.contributor.authorElpeleg, Orly
dc.contributor.authorSomech, Raz
dc.contributor.authorCohen, Sivan
dc.contributor.authorShachar, Idit
dc.contributor.authorMiosge, Lisa A
dc.contributor.authorSchlesier, Michael
dc.contributor.authorFuchs, Ilka
dc.contributor.authorEnders, Anselm
dc.contributor.authorEibel, Hermann
dc.contributor.authorGrimbacher, Bodo
dc.contributor.authorWarnatz, Klaus
dc.date.accessioned2014-02-05T02:52:22Z
dc.date.available2014-02-05T02:52:22Z
dc.identifier.issn0091-6749
dc.identifier.urihttp://hdl.handle.net/1885/11324
dc.description.abstractBACKGROUND: Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. OBJECTIVE: We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. METHODS: Molecular, immunologic, and functional assays were performed. RESULTS: The immunologic characterization revealed only subtle changes in the T-cell and natural killer cell compartment, whereas B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage. Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect. This deletion abrogated protein expression and activation of the canonical nuclear factor κB (NF-κB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved. The abrogated activation of the canonical NF-κB pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40, cytokine production, proliferation of T cells, and B cell-activating factor receptor expression on B cells. CONCLUSION: Thus in patients with CARD11 deficiency, the combination of impaired activation and especially upregulation of inducible T-cell costimulator on T cells, together with severely disturbed peripheral B-cell differentiation, apparently leads to a defective T-cell/B-cell cooperation and probably germinal center formation and clinically results in severe immunodeficiency. This report discloses the crucial and nonredundant role of canonical NF-κB activation and specifically CARD11 in the antigen-specific immune response in human subjects.
dc.format9 pages
dc.publisherElsevier
dc.rightshttp://www.sherpa.ac.uk/romeo/issn/0091-6749/author can archive pre-print (ie pre-refereeing); author can archive post-print (ie final draft post-refereeing) As at 5/2/14.
dc.sourceJournal of Allergy and Clinical Immunology 131.2 (2013):477-485
dc.subjectCARD 11
dc.subjecthuman
dc.subjectcombined immunodeficiency
dc.subjecthypogammaglobulinemia
dc.subjectprofound combined immunodeficiency disorder
dc.subjecttransitional B cell
dc.subjectnuclear factor κB
dc.subjectB cell-activating factor receptor
dc.subjectinducible T-cell costimulator
dc.subjectgerminal center
dc.titleDeficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects.
dc.typeJournal article
local.identifier.citationvolume131
dc.date.issued2013-02
local.identifier.absfor110700 - IMMUNOLOGY
local.identifier.ariespublicationf5625xPUB2414
local.publisher.urlhttp://www.elsevier.com/
local.type.statusSubmitted version
local.contributor.affiliationMiosge, Lisa A, Department of Immunology, John Curtin School of Medical Research, Australian National University
local.contributor.affiliationEnders, Anselm, Ramaciotti Immunisation Genomics Laboratory, Department of Immunology, John Curtin School of Medical Research, Australian National University
dc.relationhttp://purl.org/au-research/grants/nhmrc/1035858
local.bibliographicCitation.issue2
local.bibliographicCitation.startpage477
local.bibliographicCitation.lastpage485.e1
local.identifier.doi10.1016/j.jaci.2012.11.050
dc.date.updated2015-12-11T07:24:39Z
local.identifier.scopusID2-s2.0-84873348862
local.identifier.thomsonID000314661500027
CollectionsANU Research Publications

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