Immunodeficiency-11 is an autosomal recessive primary immunodeficiency characterized by normal numbers of T and B lymphocytes, but defective intracellular signaling. There is a block in B-cell differentiation with increased numbers of transitional B cells and hypogammaglobulinemia, as well ... Immunodeficiency-11 is an autosomal recessive primary immunodeficiency characterized by normal numbers of T and B lymphocytes, but defective intracellular signaling. There is a block in B-cell differentiation with increased numbers of transitional B cells and hypogammaglobulinemia, as well as decreased numbers of regulatory T cells and defects in T-cell function (summary by Greil et al., 2013 and Stepensky et al., 2013).
Greil et al. (2013) reported a girl, born of consanguineous parents of central European descent, with severe combined immunodeficiency. The patient presented at 6 months of age with interstitial pneumonia due to Pneumocystis jirovecii infection and was found ... Greil et al. (2013) reported a girl, born of consanguineous parents of central European descent, with severe combined immunodeficiency. The patient presented at 6 months of age with interstitial pneumonia due to Pneumocystis jirovecii infection and was found to be severely immunodeficient. Although laboratory studies showed normal numbers of T and B cells, she had agammaglobulinemia. Immunophenotyping of both T and B cells showed naive or transitional populations and severely decreased numbers of regulatory T cells. There was impaired proliferation in response to T-cell mitogens and decreased expression of proinflammatory cytokines after LPS stimulation. The findings suggested a severe impairment of TCR-mediated T-lymphocyte function. The patient underwent successful hematopoietic stem cell transplantation. Stepensky et al. (2013) reported a girl, born of consanguineous parents of Palestinian descent, with CARD11 immunodeficiency. The patient presented in infancy with recurrent respiratory infections and later developed P. jirovecii pneumonia. Two sibs had died in infancy with recurrent infections. Laboratory studies of the proband showed hypogammaglobulinemia with normal numbers of B and T cells. Flow cytometric studies showed decreased numbers of regulatory T cells and reduced numbers of differentiated T cells compared to naive cells. B cells were predominantly transitional cells, with decreased numbers of differentiated B cells. Patient lymphocytes showed defective NFKB (164011) signaling upon activation. The abrogated activation of the canonical NFKB pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40 (600315), cytokine production, proliferation of T cells, and B cell-activating factor receptor expression on B cells. The patient underwent successful bone marrow transplantation.
In a girl, born of consanguineous parents of Central European descent, with immunodeficiency-11, Greil et al. (2013) identified a homozygous truncating mutation in the CARD11 gene (607210.0003). Stepensky et al. (2013) reported another patient with immunodeficiency who was ... In a girl, born of consanguineous parents of Central European descent, with immunodeficiency-11, Greil et al. (2013) identified a homozygous truncating mutation in the CARD11 gene (607210.0003). Stepensky et al. (2013) reported another patient with immunodeficiency who was homozygous for a truncating CARD11 mutation (607210.0004). Both mutations were identified by exome sequencing. In vitro functional expression studies showed defective NFKB signaling in patient lymphocytes upon activation. The reports indicated an important role for the CARD11 scaffold protein in linking TCR and BCR signaling with NFKB activation.