Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 131, Issue 2, Pages 477-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.11.050
Keywords
CARD11; human; combined immunodeficiency; hypogammaglobulinemia; profound combined immunodeficiency disorder; transitional B cell; nuclear factor kappa B; B cell-activating factor receptor; inducible T-cell costimulator; germinal center
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFB 620]
- Federal Ministry of Education and Research [BMBF 01 EO0803]
- Dahlia Greidinger Cancer Research Fund
- Clive and Vera Ramaciotti Foundation
- NHMRC [APP1035858]
- Bundesministerium fur Bildung und Forschung (BMBF)
- Federal Ministry of Education and Research
- BMBF
- Baxter
- GlaxoSmithKline
- CSL Behring
- Pfizer
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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 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 kappa B (NF-kappa B) 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-kappa B 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-kappa B activation and specifically CARD11 in the antigen-specific immune response in human subjects. (J Allergy Clin Immunol 2013;131:477-85.)
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