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

J Allergy Clin Immunol. 2013 Feb;131(2):477-85.e1. doi: 10.1016/j.jaci.2012.11.050.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinemia / enzymology
  • Agammaglobulinemia / genetics
  • Agammaglobulinemia / immunology
  • CARD Signaling Adaptor Proteins / deficiency*
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / immunology
  • Female
  • Guanylate Cyclase / deficiency*
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / immunology
  • Humans
  • Immunologic Deficiency Syndromes / enzymology*
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology
  • Infant
  • Sequence Deletion*


  • CARD Signaling Adaptor Proteins
  • CARD11 protein, human
  • Guanylate Cyclase