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

• Published in: Journal of allergy and clinical immunology Vol. 131; no. 2; pp. 477 - 485.e1
• Main Authors: Stepensky, Polina, Keller, Baerbel, Buchta, Mary, Kienzler, Anne-Kathrin, Elpeleg, Orly, Somech, Raz, Cohen, Sivan, Shachar, Idit, Miosge, Lisa A., Schlesier, Michael, Fuchs, Ilka, Enders, Anselm, Eibel, Hermann, Grimbacher, Bodo, Warnatz, Klaus
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.02.2013; Elsevier; Elsevier Limited
• Subjects: Agammaglobulinemia - enzymology; Agammaglobulinemia - genetics; Agammaglobulinemia - immunology; Allergy and Immunology; antigens; B cell-activating factor receptor; B-lymphocytes; Biological and medical sciences; CARD Signaling Adaptor Proteins - deficiency; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - immunology; CARD11; caspases; combined immunodeficiency; cytokines; exons; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; germinal center; Guanylate Cyclase - deficiency; Guanylate Cyclase - genetics; Guanylate Cyclase - immunology; homozygosity; human; Humans; humoral immunity; hypogammaglobulinemia; immune response; Immune system; Immunologic Deficiency Syndromes - enzymology; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunopathology; immunosuppression; inducible T-cell costimulator; Infant; Kinases; Lymphocytes; Medical sciences; nuclear factor κB; patients; Pneumocystis; pneumonia; profound combined immunodeficiency disorder; protein synthesis; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sequence Deletion; T cell receptors; T-lymphocytes; transcription factor NF-kappa B; transitional B cell; CD40L; TCR; nuclear factor κB; hypogammaglobulinemia; BCL10; MALT1; BAFF-R; NF-κB; FITC; transitional B cell; B cell-activating factor receptor; GC; ICOS; human; pCID; CID; gDNA; PMA; KREC; Treg; germinal center; inducible T-cell costimulator; BCR; APC; profound combined immunodeficiency disorder; PE; TREC; PerCP; NK; CARD11; combined immunodeficiency; ERK; Caspase recruitment domain family, member 11; T-cell receptor excision circle; Peridinin-chlorophyll-protein complex; T-cell receptor; Regulatory T; Natural killer; Fluorescein isothiocyanate; B-cell receptor; κ-Deleted receptor excision circle; Mucosa associated lymphoid tissue lymphoma translocation gene 1; Genomic DNA; Allophycocyanin; B cell–activating factor receptor; Extracellular signal-regulated kinase; B-cell lymphoma 10; CD40 ligand; Phycoerythrin; Phorbol 12-myristate 13-acetate; Cysteine endopeptidases; Recruitment; B cell activating factor receptor; Immunology; Cause; T-Lymphocyte; Family environment; Transcription factor NFκB; Human; Immunopathology; Enzyme; Germinative center; Family study; Deficiency; Agammaglobulinemia; Caspase; Inducible costimulator; B-Lymphocyte; Peptidases; Hydrolases; Combined immune deficiency
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2012.11.050

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. We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. Molecular, immunologic, and functional assays were performed. 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. 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.