Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

Slides:

Advertisements

Similar presentations

Ectodermal dysplasia with immunodeficiency caused by a branch-point mutation in IKBKG/NEMO Sofie E. Jørgensen, MS, Pernille Bøttger, PhD, Emil Kofod-Olsen,

Advertisements

Maria B. Sukkar, PhD, Shaoping Xie, PhD, Nadia M

Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis Giuliana Giardino,

Combined immunodeficiency due to JAK3 mutation in a child presenting with skin granuloma Alessia Scarselli, MD, Silvia Di Cesare, BSc, Gigliola Di Matteo,

Defects of class-switch recombination

Early-onset monocyte–B–natural killer–dendritic cells’ deficiency successfully treated with hematopoietic stem cell transplantation Caterina Cancrini,

Low E-prostanoid 2 receptor levels and deficient induction of the IL-1β/IL-1 type I receptor/COX-2 pathway: Vicious circle in patients with aspirin-exacerbated.

A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency Haifa H. Jabara, BSc, Toshiro Ohsumi, PhD,

Modulation by aspirin of nuclear phospho–signal transducer and activator of transcription 6 expression: Possible role in therapeutic benefit associated.

Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated.

Epigenetic regulation of established human type 1 versus type 2 cytokine responses Ruey-Chyi Su, PhD, Allan B. Becker, MD, Anita L. Kozyrskyj, PhD, Kent.

Human nuclear factor κB essential modulator mutation can result in immunodeficiency without ectodermal dysplasia Jordan S. Orange, MD, PhD, Ofer Levy,

A case of partial dedicator of cytokinesis 8 deficiency with altered effector phenotype and impaired CD8+ and natural killer cell cytotoxicity Raquel.

Regulation of GM-CSF expression by the transcription factor c-Maf

Epigenetic mechanisms silence a disintegrin and metalloprotease 33 expression in bronchial epithelial cells Youwen Yang, PhD, Hans Michael Haitchi, MD,

IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease

Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation Vassilios Lougaris, MD, Manuela Baronio, PhD, Massimiliano Vitali, PhD,

Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment Federica Cattaneo, MD, Mike.

B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE Haifa H. Jabara,

Julie M. Caldwell, PhD, Carine Blanchard, PhD, Margaret H

NF-κBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL-1β-induced and TNF-α-induced chondrocytes Dr C. Lianxu, Ph.D.,

Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal- dominant gain-of-phosphorylation STAT1 mutations Pamela P.W. Lee,

Deficient glucocorticoid induction of anti-inflammatory genes in nasal polyp fibroblasts of asthmatic patients with and without aspirin intolerance Laura.

Histone deacetylase inhibitors suppress interleukin-1β-induced nitric oxide and prostaglandin E2 production in human chondrocytes N. Chabane, M.Sc.,

Differences in human gingival and dermal fibroblasts may contribute to oral-induced tolerance against nickel Lina Gölz, MD, Elisa Vestewig, Moritz Blankart,

Functional characterization of the atopy-associated gene PHF11

Chronic rhinosinusitis with polyps and without polyps is associated with increased expression of suppressors of cytokine signaling 1 and 3 Se Jin Park,

Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with β2-adrenergic agonists Elena Goleva, PhD, Annegret.

Enhanced nasal cytokine production in human beings after in vivo challenge with diesel exhaust particles David Diaz-Sanchez, PhD, Albert Tsien, MD, Adrian.

The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells Jane Eddleston, PhD, Jack Herschbach,

Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-α John T. Schroeder, PhD,

Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes

NEMO is a key component of NF-κB– and IRF-3–dependent TLR3-mediated immunity to herpes simplex virus Magali Audry, PhD, Michael Ciancanelli, PhD, Kun.

Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,

Bcl2-like protein 12 plays a critical role in development of airway allergy through inducing aberrant TH2 polarization Zhi-Qiang Liu, MD, PhD, Ying Feng,

Jia Guo, MD, Xin Lin, PhD, Marc A

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor–dependent innate antiviral immune responses Douglas R. McDonald, MD, PhD,

Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages Elena Goleva, PhD, Pia J. Hauk, MD, Clifton.

IL-2–inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells Arun K. Kannan, MS, Nisebita.

T-box 21 transcription factor is responsible for distorted TH2 differentiation in human peripheral CD4+ T cells Osamu Kaminuma, DVM, PhD, Fujiko Kitamura,

Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis Giuliana Giardino,

Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide Weishan Huang, PhD, J. Luis Morales,

Fibronectin is a TH1-specific molecule in human subjects

Antiviral activity of human β-defensin 3 against vaccinia virus

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations Giovanna.

A peptide derived from the Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP) restores WAS protein level and actin cytoskeleton reorganization.

Elucidating the effects of disease-causing mutations on STAT3 function in autosomal- dominant hyper-IgE syndrome Simon J. Pelham, MSc, Helen C. Lenthall,

Ectodermal dysplasia with immunodeficiency caused by a branch-point mutation in IKBKG/NEMO Sofie E. Jørgensen, MS, Pernille Bøttger, PhD, Emil Kofod-Olsen,

Downregulation of a disintegrin and metalloproteinase 33 by IFN-γ in human airway smooth muscle cells Isao Ito, MD, PhD, Johanne D. Laporte, PhD, Pierre.

Fibronectin is a TH1-specific molecule in human subjects

Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: Potential role of histamine in airway remodeling Steffen Kunzmann,

Josée Lamoureux, PhD, Jana Stankova, PhD, Marek Rola-Pleszczynski, MD

Autoimmune lymphoproliferative syndrome caused by a homozygous FasL mutation that disrupts FasL assembly Ali Sobh, MD, Elena Crestani, MD, Brittney Cangemi,

The L412F variant of Toll-like receptor 3 (TLR3) is associated with cutaneous candidiasis, increased susceptibility to cytomegalovirus, and autoimmunity

Immunologic reconstitution following hematopoietic stem cell transplantation despite lymph node paucity in NF-κB–inducing kinase deficiency Khaoula Ben.

IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts Séverine Létuvé, PhD, Stéphane Lajoie-Kadoch, MSc, Séverine Audusseau,

A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome Hidenori Ohnishi, MD, PhD, Rie Miyata, MD,

Amplification of Toll-like receptor–mediated signaling through spleen tyrosine kinase in human B-cell activation Shigeru Iwata, MD, PhD, Kunihiro Yamaoka,

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

A novel hypomorphic mutation in STIM1 results in a late-onset immunodeficiency Heidi Schaballie, MD, Rémy Rodriguez, MS, Emmanuel Martin, PhD, Leen Moens,

MicroRNA-4443 regulates mast cell activation by T cell–derived microvesicles Irit Shefler, PhD, Pazit Salamon, PhD, Francesca Levi-Schaffer, PharmD, Adam.

Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-κB essential modulator.

Toll-like receptor 2 ligands activate human basophils for both IgE-dependent and IgE- independent secretion Anja P. Bieneman, BS, Kristin L. Chichester,

Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency Douglas.

Janet Chou, MD, Maxim Lutskiy, MD, PhD, Erdyni Tsitsikov, PhD, Luigi D

Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation Venkateswara.

Combined immunodeficiency in a patient with c-Rel deficiency

Presentation transcript:

Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of the NEMO gene Jana L. Mooster, Caterina Cancrini, MD, PhD, Alessandra Simonetti, MD, Paolo Rossi, MD, PhD, Gigliola Di Matteo, PhD, Maria Luisa Romiti, PhD, Silvia Di Cesare, Luigi Notarangelo, MD, Raif S. Geha, MD, Douglas R. McDonald, MD, PhD Journal of Allergy and Clinical Immunology Volume 126, Issue 1, Pages 127-132.e7 (July 2010) DOI: 10.1016/j.jaci.2010.04.026 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Impaired TLR-induced NF-κB–dependent cytokine production by patient PBMCs. PBMCs were incubated with medium or TLR ligands for 24 hours, and TNF-α (A) and IFN-α (B) were quantified. Graphs show the mean and SD of 4 independent experiments using PBMCs from the index patient and healthy controls (n = 4). ∗P < .05; ∗∗∗P < .001. C, TNF-α production in PBMCs from the patient's affected brother. PMA, Phorbol 12-myristate 13-acetate. Journal of Allergy and Clinical Immunology 2010 126, 127-132.e7DOI: (10.1016/j.jaci.2010.04.026) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Decreased NEMO protein and mRNA levels in the patient. Western blots from PBMC lysates from control, index patient, affected brother, and unaffected mother (A) and EBV B-cell lysates (B). C, Scanning densitometry of NEMO protein levels for each EBV B cell line, normalized to actin. Controls arbitrarily set to 1. D, qPCR analysis of NEMO mRNA levels, normalized to GAPDH, in EBV B-cell lines from index patient, brother, and 8 controls. Bar represents the mean. Dashed lines span the 95% CI. Journal of Allergy and Clinical Immunology 2010 126, 127-132.e7DOI: (10.1016/j.jaci.2010.04.026) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 The patients' NEMO mutation results in 2 aberrant mRNA products. A, Representation of normal NEMO splicing. ∗Patient's mutation. mRNA splicing using exon 1A, 1B, or 1C is depicted; arrows represent PCR primers used. B, Agarose gel showing control and patient NEMO RT-PCR products containing exons 1A, 1C, and 1B. C, Schematic of aberrant NEMO exon 1B transcripts in the patient. Journal of Allergy and Clinical Immunology 2010 126, 127-132.e7DOI: (10.1016/j.jaci.2010.04.026) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 NF-κB signaling is reduced in the patient. A, Western blot of lysates from fibroblasts stimulated with IL-1β. B, Western blot of p65 nuclear translocation in TLR7-stimulated EBV B cells. C, NF-κB–luciferase reporter assay in fibroblasts treated 6 hours with IL-1β. Fold activation represents mean and SD of 8 experiments using patient fibroblasts and 3 healthy controls. Journal of Allergy and Clinical Immunology 2010 126, 127-132.e7DOI: (10.1016/j.jaci.2010.04.026) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Normal ectodermal development in the index patient at 11 years of age Normal ectodermal development in the index patient at 11 years of age. Notice normal dentition and hairline. Journal of Allergy and Clinical Immunology 2010 126, 127-132.e7DOI: (10.1016/j.jaci.2010.04.026) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Western blot showing expression of NEMO cDNA isoforms amplified from normal and patient cells. NEMO cDNA using exons 1B and 1C were amplified from cDNA isolated from normal fibroblasts, and the misspliced 1B isoforms were amplified from cDNA isolated from patient fibroblasts. The PCR products were cloned into the pCMV-Tag4a vector and expressed in T293 HEK cells (top) or in NEMO–/– mouse embryonic fibroblasts (bottom). Note the presence of the endogenous NEMO band in T293 cells but not in NEMO-deficient murine embryonic fibroblasts (MEFs). Journal of Allergy and Clinical Immunology 2010 126, 127-132.e7DOI: (10.1016/j.jaci.2010.04.026) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions