Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects.
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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.author | Stepensky, Polina | |
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dc.contributor.author | Keller, Baerbel | |
dc.contributor.author | Buchta, Mary | |
dc.contributor.author | Kienzler, Ann-Kathrin | |
dc.contributor.author | Elpeleg, Orly | |
dc.contributor.author | Somech, Raz | |
dc.contributor.author | Cohen, Sivan | |
dc.contributor.author | Shachar, Idit | |
dc.contributor.author | Miosge, Lisa A | |
dc.contributor.author | Schlesier, Michael | |
dc.contributor.author | Fuchs, Ilka | |
dc.contributor.author | Enders, Anselm | |
dc.contributor.author | Eibel, Hermann | |
dc.contributor.author | Grimbacher, Bodo | |
dc.contributor.author | Warnatz, Klaus | |
dc.date.accessioned | 2014-02-05T02:52:22Z | |
dc.date.available | 2014-02-05T02:52:22Z | |
dc.identifier.issn | 0091-6749 | |
dc.identifier.uri | http://hdl.handle.net/1885/11324 | |
dc.description.abstract | 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 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.format | 9 pages | |
dc.publisher | Elsevier | |
dc.rights | http://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.source | Journal of Allergy and Clinical Immunology 131.2 (2013):477-485 | |
dc.subject | CARD 11 | |
dc.subject | human | |
dc.subject | combined immunodeficiency | |
dc.subject | hypogammaglobulinemia | |
dc.subject | profound combined immunodeficiency disorder | |
dc.subject | transitional B cell | |
dc.subject | nuclear factor κB | |
dc.subject | B cell-activating factor receptor | |
dc.subject | inducible T-cell costimulator | |
dc.subject | germinal center | |
dc.title | Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. | |
dc.type | Journal article | |
local.identifier.citationvolume | 131 | |
dc.date.issued | 2013-02 | |
local.identifier.absfor | 110700 - IMMUNOLOGY | |
local.identifier.ariespublication | f5625xPUB2414 | |
local.publisher.url | http://www.elsevier.com/ | |
local.type.status | Submitted version | |
local.contributor.affiliation | Miosge, Lisa A, Department of Immunology, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Enders, Anselm, Ramaciotti Immunisation Genomics Laboratory, Department of Immunology, John Curtin School of Medical Research, Australian National University | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1035858 | |
local.bibliographicCitation.issue | 2 | |
local.bibliographicCitation.startpage | 477 | |
local.bibliographicCitation.lastpage | 485.e1 | |
local.identifier.doi | 10.1016/j.jaci.2012.11.050 | |
dc.date.updated | 2015-12-11T07:24:39Z | |
local.identifier.scopusID | 2-s2.0-84873348862 | |
local.identifier.thomsonID | 000314661500027 | |
Collections | ANU Research Publications |
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Stepensky et al Deficiency of caspase 2013.docx.pdf | Submitted version | 1.17 MB | Adobe PDF | |
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