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

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Presentation transcript:

Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects Polina Stepensky, MD, Baerbel Keller, MSc, Mary Buchta, Anne-Kathrin Kienzler, MSc, Orly Elpeleg, MD, Raz Somech, MD, PhD, Sivan Cohen, MSc, Idit Shachar, PhD, Lisa A. Miosge, PhD, Michael Schlesier, PhD, Ilka Fuchs, MSc, Anselm Enders, MD, Hermann Eibel, PhD, Bodo Grimbacher, MD, Klaus Warnatz, MD Journal of Allergy and Clinical Immunology Volume 131, Issue 2, Pages 477-485.e1 (February 2013) DOI: 10.1016/j.jaci.2012.11.050 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Pedigree of the CARD11-deficient family. Circles, Female subjects; squares, male subjects; solid symbols, homozygous subjects; half-solid symbols, heterozygous subjects; crossed-out symbols, deceased subjects. The pedigree shows 5 generations of the family. The arrow indicates the index patient. Journal of Allergy and Clinical Immunology 2013 131, 477-485.e1DOI: (10.1016/j.jaci.2012.11.050) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Abnormal lymphocyte homeostasis in CARD11 deficiency. A and B, CD127−CD25hi Treg cells gated on CD4+CD3+ lymphocytes (Fig 2, A) and CD38highCD10+ transitional B cells (top) and CD27/IgD expression gated on CD19+ lymphocytes (bottom; Fig 2, B) of the patient (Pat) compared with an age-matched control subject (HD). C, BAFF-R expression on the indicated subpopulations. Journal of Allergy and Clinical Immunology 2013 131, 477-485.e1DOI: (10.1016/j.jaci.2012.11.050) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Molecular analysis of CARD11 deficiency. A, RT-PCR covering cDNA of exons 16-22 of CARD11 (left) and schematic representation of the deletion in CARD11, as depicted by the gray shaded box (right). B, PCR products amplified from gDNA flanking exon 21 of CARD11 of a healthy donor (HD), the patient’s father and mother, the patient (Pat), and the patient's brother (left). Sanger sequencing of the gDNA including exon 21 of CARD11 (right). C, Immunoblot for CARD11 protein expression in EBV lines of the patient and 3 control subjects. β-Actin was used as a loading control. Journal of Allergy and Clinical Immunology 2013 131, 477-485.e1DOI: (10.1016/j.jaci.2012.11.050) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Signaling in CARD11-deficient lymphocytes. A, Degradation of IκBα (upper panels) and phosphorylation of p65 (pp65, lower panels) gated on CD19+ B cells on stimulation, as indicated. B, Degradation of IκBα (upper panels) and phosphorylation of p65 (lower panels) on stimulation of PBMCs with PMA (dashed line) and unstimulated conditions gated on CD3+ T cells. C, Phosphorylation of ERK1/2 (pERK) in CD19+ B cells after stimulation. D, Phosphorylation of ERK in CD3+ T cells after stimulation with PMA and unstimulated. E, Calcium mobilization in CD19+CD27+IgG−IgA− B cells on anti-IgM stimulation. Depicted is the bound/unbound Indo-1 ratio. Arrows indicate time points of the addition of anti-IgM and ionomycin. HD, Healthy donor; Pat, patient. Journal of Allergy and Clinical Immunology 2013 131, 477-485.e1DOI: (10.1016/j.jaci.2012.11.050) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 B-cell function in CARD11 deficiency. A, Intercellular adhesion molecule 1 (ICAM-1), CD25, CD69, and CD86 expression after stimulation of PBMCs gated on CD19+ cells. B, Differentiation of plasmablasts, defined as CD38hiCD27hi B cells, after in vitro stimulation of PBMCs with IL-21 and CD40L (upper panel). IgG+ and IgA+ plasmablasts are depicted after gating on CD38hiCD27hi B cells (lower panel). C, IgM, IgG, and IgA levels from cell-culture supernatants of the patient’s PBMCs or cord blood after in vitro stimulation with IL-21 and CD40L. HD, Healthy donor; Pat, patient. Journal of Allergy and Clinical Immunology 2013 131, 477-485.e1DOI: (10.1016/j.jaci.2012.11.050) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 T-cell and NK cell function in CARD11 deficiency. A, PBMCs were stimulated with PMA/ionomycin to determine IL-2 (upper left), IL-4, and IFN-γ production (upper right) and IL-17 and IFN-γ production (lower right) on CD4+ T cells. B, Expression of CD69, CD40L, OX40, ICOS, and CD25 after stimulation of CD4+ T cells, as indicated (top). The percentage of positive cells for indicated markers of CD4+ T cells of the patient (open circles) compared with healthy control subjects (closed circles, bottom). C, Proliferation of CD4+ T cells on stimulation with anti-CD3/anti-CD28 (left) and PHA (right). D, IFN-γ production in CD3−CD56+ NK cells after stimulation with PMA/ionomycin compared with unstimulated samples. HD, Healthy donor; Pat, patient. Journal of Allergy and Clinical Immunology 2013 131, 477-485.e1DOI: (10.1016/j.jaci.2012.11.050) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Expression of Baff-R and T-cell activation markers in Card11 mutant mice. A, Expression of Baff-R on CD93+ immature and CD93− mature splenic B cells from Card11unm/unm mice and age-matched control animals (top panel). After staining for IgM and CD23, the CD93+ immature B cells were further divided into T1 (IgM+CD23−), T2 (IgM+CD23+), and T3 (IgMlowCD23+) stages (bottom panel). B, Expression of CD69, CD25, CD40L, Ox40, and Icos on 7-amino-actinomycin D-negative CD4+ T cells after stimulation, as indicated. Triangles, Mice from a C57BL/6 background; circles, mice from a B10.BR background. Statistical analysis was done with ANOVA, followed by the Bonferroni post-test. MFI, Mean fluorescence intensity. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2013 131, 477-485.e1DOI: (10.1016/j.jaci.2012.11.050) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions