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PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity  Anne-Laure Mathieu, PhD, Estelle Verronese,

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Presentation on theme: "PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity  Anne-Laure Mathieu, PhD, Estelle Verronese,"— Presentation transcript:

1 PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity  Anne-Laure Mathieu, PhD, Estelle Verronese, BS, Gillian I. Rice, PhD, Fanny Fouyssac, MD, Yves Bertrand, MD, PhD, Capucine Picard, MD, PhD, Marie Chansel, MSc, Jolan E. Walter, MD, PhD, Luigi D. Notarangelo, MD, Manish J. Butte, MD, PhD, Kari Christine Nadeau, MD, PhD, Krisztian Csomos, PhD, David J. Chen, PhD, Karin Chen, MD, Ana Delgado, BS, Chantal Rigal, BS, Christine Bardin, BS, Catharina Schuetz, MD, PhD, Despina Moshous, MD, PhD, Héloïse Reumaux, MD, François Plenat, MD, PhD, Alice Phan, MD, PhD, Marie-Thérèse Zabot, PharmD, PhD, Brigitte Balme, MD, Sébastien Viel, PharmD, Jacques Bienvenu, PharmD, PhD, Pierre Cochat, MD, PhD, Mirjam van der Burg, PhD, Christophe Caux, PhD, E. Helen Kemp, BSc, PhD, Isabelle Rouvet, PharmD, PhD, Christophe Malcus, PharmD, PhD, Jean-Francois Méritet, PharmD, PhD, Annick Lim, MSc, Yanick J. Crow, MD, PhD, Nicole Fabien, PharmD, PhD, Christine Ménétrier-Caux, PhD, Jean-Pierre De Villartay, PhD, Thierry Walzer, PhD, Alexandre Belot, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 135, Issue 6, Pages e5 (June 2015) DOI: /j.jaci Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Clinical features of patients with PRKDC mutations. Pt1: A, family tree; B, positive antinuclear antibody levels; C, computed tomographic scan showing nodular lung lesions with infiltrate (left panel) and spleen granulomatous lesions (right panel); D, skin granulomatous lesion of the limb (left panel) and elbow (right panel); and E, epithelioid noncaseating granulomas from skin biopsy specimens. Pt 2: F, family tree; G, hepatomegaly with splenic granulomatosis (computed tomographic scan); H, caseating granulomas from spleen biopsy specimens; and I, schematic representation of the DNA-PKcs protein and the mutations identified in Pt1 and Pt2. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 DSB repair defect and T-cell receptor oligoclonal repertoire. A, Clonogenic survival assays in fibroblasts from a control subject, a Cernunnos-deficient subject, Pt1, and Pt2. B, Numbers of γ-53BP1 foci (FOCI)/nucleus after irradiation in fibroblasts from a control subject, Pt2, and a Cernunnos-deficient subject. ****P < C, Quantitative analysis of Vβ distribution in CD3+ T cells. Vβ underrepresentation (asterisks) or overrepresentation (arrows). D, Three-dimensional graph of immune combinatorial diversity in Pt1. E, Immunoscope of Vβ repertoire for the control subject and Pt2. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Cytokine expression in whole blood and on activation in T cells. A and B, RT-PCR of a panel of 6 interferon-stimulated genes (mean ± SD; Fig 3, A) and RT-PCR of a panel of 3 cytokines (Fig 3, B) in whole blood. C, BAFF, IFN-γ, and TNF-α measurements in sera of control subjects and Pt1 and Pt2. D-H, Cytokine expression in both CD4 and CD8 positive and CD45RA negative T cells as measured by using fluorescence-activated cell sorting in pediatric or adult control subjects (pCtl or aCtl, respectively) and Pt1 and Pt2. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 PRKDC mutations prevent AIRE-dependent IGFL-1 expression. A, RT-PCR analysis of 5 transcripts after AIRE transfection in control fibroblasts. B, AIRE-dependent IGFL-1 expression in Pt1 and Pt2 or in the previously reported PRKDC mutant with SCID (Pt3). C and D, Detection of anti-CaSR autoantibodies in positive and negative control sera and Pt1's serum. E, Autoimmune markers in Pt1 before and after BMT. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E1 53BP1 foci after X-irradiation of Pt2's fibroblasts. Time points were 1 and 24 hours. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E2 A, Quantitative RT-PCR of a panel of 3 cytokines in whole blood measured in Pt1 (before BMT) and Pt2 and 29 control subjects (mean ± SD). B, BAFF measurement in sera of Pt1 (before and after BMT) and Pt2, one Artemis-deficient patient, and 6 control subjects by using ELISA. C, CD39 expression in regulatory T cells (CD4+CD25+CD127low) in Pt1 (before BMT) and Pt2 compared with that in age-matched control subjects. pCtl, Pediatric control subject; aCtl, adult control subject. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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