DOCSLIB.ORG

The Role of DOCK8 in Human Lymphocytes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of DOCK8 in Human Lymphocytes The Role of DOCK8 in Human Lymphocytes Bethany Pillay A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy St Vincent’s Clinical School, Faculty of Medicine UNSW Sydney Immunology Division Garvan Institute of Medical Research Supervisors: Professor Stuart Tangye and Associate Professor Cindy Ma September 2019 Thesis/Dissertation Sheet Surname/Family Name : PILLAY Given Name/s : BETHANY ANN Abbreviation for degree as give in the University : PhD calendar Faculty : MEDICINE School : ST VINCENT’S CLINICAL SCHOOL Thesis Title : THE ROLE OF DOCK8 IN HUMAN LYMPHOCYTES Abstract 350 words maximum: (PLEASE TYPE) Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor that is highly expressed in lymphocytes and is involved in cytoskeletal rearrangement. Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency which is characterised by severe viral, bacterial and fungal infections, eczema, allergies and impaired humoral responses and which requires haematopoietic stem cell transplant (HSCT) to overcome. However, the cellular defects underlying these clinical symptoms have not been fully investigated. This thesis firstly examines the contribution of the CD4+ T cell compartment to the clinical features of DOCK8 deficiency by using cell cultures of DOCK8-deficient patients. This revealed skewed in vivo differentiation explaining patient susceptibility to infections and their propensity towards allergic conditions. To explore the cellular alterations which enable the clinical improvement of patients following HSCT, a comprehensive study of lymphocyte phenotype and function in DOCK8- deficient patients before and after HSCT was undertaken. This study found key functional differences which provided explanation for resolution of symptoms in patients post HSCT and noted persistent defects which may influence continuing patient care. Furthermore, investigation of a DOCK8-revertant patient allowed for the analysis of both DOCK8-deficient and DOCK8- revertant cells within the same individual and enabled the elucidation of the influence of environment on the identified defects of DOCK8 deficiency. Lastly, the extent of cellular impairment that was due to the involvement of DOCK8 in previously identified signalling pathways was examined with the use of immunodeficiency patients with mutations in DOCK8- related proteins. The findings of this analysis suggested that the outcomes of DOCK8 deficiency were not due solely to the role of DOCK8 in a single signalling pathway. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). ……………………………………………… ……………………………………..…… ……….……………………...…….… Signature Witness Signature Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: ii iii iv Acknowledgements To my supervisors Stu and Cindy – thank you for agreeing to take me on despite me not having an immunology background. Thanks for all the help along the way and time spent with experiments and meetings and presentations and editing and countless emails to clinicians and collaborators to chase up details and ensure patient samples. To Danielle – thank you for being my first port of call for almost any issue I had (including super gluing things back together) and for the tremendous number of things you do for the lab to make it a better place for us all. To Kat and Geetha – thank you for showing me the ropes and putting up with me following you around and asking constant questions when I first started in the lab and then for agreeing to spend time with me outside the lab as a friend. To my office buddies – thank you Simon for the interesting youtube rabbit holes we went down and thank you to my work wife Julia for being the person I talk to most. To Emily and Frenchie – thank you to my English duo for all their vital words of encouragement and support as well as their friendship along the way. To the rest of the lab – thanks for helping me out when I needed it, all the fun times and listening to my rants. I’m telling you, our tv show “Lab rats” would have been a hit! To level 9 – thanks for always being happy to lend a hand or have a chat. It has been a privilege to be part of the department most obsessed with trivia. To my family and friends – thank you for the support and for knowing to ask just enough questions to show you care but not to hassle me about when I would be finished. To Alex – thank you for not knowing what you were getting into but for hanging in there with me anyway. v vi vii Publications arising from this work Pillay BA, Avery DT, Smart JM, Cole T, Choo S, Chan D, Gray PE, Frith K, Mitchell R, Phan TG, Wong M, Campbell DE, Hsu P, Ziegler JB, Peake J, Alvaro F, Picard C, Bustamante J, Neven B, Cant AJ, Uzel G, Arkwright PD, Casanova JL, Su HC, Freeman AF, Shah N, Hickstein DD, Tangye SG, Ma CS. JCI Insight. 2019; 25(5) Tangye SG, Bucciol G, Casas-Martin J, Pillay B, Ma CS, Moens L, Meyts I. Human inborn errors of the actin cytoskeleton affecting immunity: way beyond WAS and WIP. Immunology Cell Biol. 2019; 97(4):389-402 Béziat V, Li J, Lin JX, Ma CS, Li P, Bousfiha A, Pellier I, Zoghi S, Baris S, Keles S, Gray P, Du N, Wang Y, Zerbib Y, Lévy R, Leclercq T, About F, Lim AI, Rao G, Payne K, Pelham SJ, Avery DT, Deenick EK, Pillay B, Chou J, Guery R, Belkadi A, Guérin A, Migaud M, Rattina V, Ailal F, Benhsaien I, Bouaziz M, Habib T, Chaussabel D, Marr N, El-Benna J, Grimbacher B, Wargon O, Bustamante J, Boisson B, Müller- Fleckenstein I, Fleckenstein B, Chandesris MO, Titeux M, Fraitag S, Alyanakian MA, Leruez-Ville M, Picard C, Meyts I, Di Santo JP, Hovnanian A, Somer A, Ozen A, Rezaei N, Chatila TA, Abel L, Leonard WJ, Tangye SG, Puel A, Casanova JL. Science Immunology. 2018; 3(24) Tangye SG, Pillay B, Randall KL, Avery DT, Phan TG, Gray P, Ziegler JB, Smart JM, Peake J, Arkwright PD, Hambleton S, Orange J, Goodnow CC, Uzel G, Casanova JL, Lugo Reyes SO, Freeman AF, Su HC, Ma CS. Dedicator of cytokinesis8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells. Journal of Allergy and Clinical Immunology. 2017; 139(3):933-949. Presentations arising from this work Biennial meeting of the European Society for Immunodeficiencies, Lisbon, Portugal, 2018 Annual meeting of the Australasian Society for Immunology, Perth, Australia, 2018 ASI NSW branch meeting, Kiama, Australia, 2018 Annual meeting of the Australasian Society for Immunology, Brisbane, Australia, 2017 International Congress of Immunology, Melbourne, Australia, 2016 viii Experiments that were not the sole work of the author All experiments were performed by the author at the Garvan Institute of Medical Research with the following exceptions: Fig 4.8A experiment performed by Danielle Priestley Fig 6.4B-D (WAS and XLT patients) experiment performed by Danielle Priestley ix Abbreviations ABTS 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) AD autosomal dominant ADA adenosine deaminase deficiency APCs antigen presenting cells AR autosomal recessive BCR b cell receptor BSA bovine serum albumin CADD combined annotation dependent depletion CBA cytometric bead array CCR cc chemokine receptor CD cluster of differentiation CDC42 cell division control protein homolog cDNA complementary deoxyribonucleic acid CFSE carboxyfluorescein succinimidyl ester CMC chronic mucocutaneous candidiasis CMV cytomegalovirus CNS central nervous system CNV copy number variations CRISPR/Ca clustered regularly interspaced short palindromic repeats/ CRISPR- s9 associated protein 9 DC dendritic cells DHR dock homology region DMSO dimethyl sulfoxide DNA deoxyribonucleic acid dNTPs deoxynucleoside triphosphate DOCK2 dedicator of cytokinesis 2 DOCK8 dedicator of cytokinesis 8 DTT dithiothreitol EBV Epstein-Barr virus EDTA ethylenediaminetetraacetic acid ELISA enzyme-linked immunosorbent assay FA formaldehyde FACS fluorescence activated cell sorting F-actin filamentous actin FCS fetal calf serum FSC-A forward scatter area FSC-H forward scatter height GC germinal centre GEF guanine exchange factor gof gain of function GvHD graft vs host disease HIES hyper IgE syndrome x HRP horse radish peroxidase HSCT haematopoietic stem cell transplant HSV herpes simplex virus ICAM-1 intercellular adhesion molecule 1 IFN interferon Ig immunoglobulin IL interleukin IS immune synapse IU international units IVIg intravenous immunoglobulin kU/l kilounit antibody per litre kUa/l kilounit of allergen-specific antibody per litre LB luria broth LCL lymphoblastoid cell line LFA-1 lymphocyte function-associated antigen 1 LN lymph nodes lof loss of function
Load more

Recommended publications
  • Recurrent Infection, Pulmonary Disease, and Autoimmunity As Manifestations of Immune Deficiency Property of Presenter Not for Re
    Recurrent Infection, Pulmonary Disease, and Autoimmunity as Manifestations of Immune Deficiency Presenter of Erwin W. ReproductionGelfand, M.D. Professor, Departmentfor of Pediatrics PropertyNational Jewish Health Professor ofNot Immunology and Pediatrics University of Colorado School of Medicine Presenter of Reproduction for Property Not • Investigator: Boehringer Ingelheim Disclosures Learning Objectives • To understand the interplay between immunodeficiency and allergic and pulmonary disorders. Presenter • To recognize the increasingof numbers of monoallelic immune systemReproduction mutations that have allergic and pulmonaryfor manifestations. • To incorporateProperty genetic testing in the clinical Not evaluation of patients with seemingly common diseases. Presenter of Reproduction for Property Not Hypogammaglobulinemia (Immunodeficiency) Autoimmunity HypersensitivityAllergy Host Defense Specific Non-Specific Presenter of • Adaptive immunity • Innate immunity Reproduction • Barriers for Property Not The Innate and Adaptive Immune Response Specific antigen receptors Presenter of Reproduction for Property Pattern Not recognition receptors Dranoff G. Nature Reviews Cancer 2004;4:11-22. Presenter of Reproduction for Property Not Primary Immunodeficiency Diseases Infection Malignancy Autoimmunity Atopy Primary Immunodeficiency Diseases Infection Autoimmunity Malignancy Presenter of Deficient/defective Deficient/defective effector cells Reproductionregulatory cells for Property Not Primary Immunodeficiency Diseases Infection Autoimmunity
    [Show full text]
  • DOCK8 Regulates Fitness and Function of Regulatory T Cells Through Modulation of IL-2 Signaling
    DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling Akhilesh K. Singh, … , Troy R. Torgerson, Mohamed Oukka JCI Insight. 2017;2(19):e94275. https://doi.org/10.1172/jci.insight.94275. Research Article Immunology Foxp3+ Tregs possess potent immunosuppressive activity, which is critical for maintaining immune homeostasis and self- tolerance. Defects in Treg development or function result in inadvertent immune activation and autoimmunity. Despite recent advances in Treg biology, we still do not completely understand the molecular and cellular mechanisms governing the development and suppressive function of these cells. Here, we have demonstrated an essential role of the dedicator of cytokinesis 8 (DOCK8), guanine nucleotide exchange factors required for cytoskeleton rearrangement, cell migration, and immune cell survival in controlling Treg fitness and their function. Treg-specific DOCK8 deletion led to spontaneous multiorgan inflammation in mice due to uncontrolled T cell activation and production of proinflammatory cytokines. In addition, we show that DOCK8-deficient Tregs are defective in competitive fitness and in vivo suppressive function. Furthermore, DOCK8 controls IL-2 signaling, crucial for maintenance and competitive fitness of Tregs, via a STAT5- dependent manner. Our study provides potentially novel insights into the essential function of DOCK8 in Tregs and immune regulation, and it explains the autoimmune manifestations associated with DOCK8 deficiency. Find the latest version: https://jci.me/94275/pdf RESEARCH ARTICLE DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling Akhilesh K. Singh,1 Ahmet Eken,1 David Hagin,1 Khushbu Komal,1 Gauri Bhise,1 Azima Shaji,1 Tanvi Arkatkar,1 Shaun W.
    [Show full text]
  • The Extended Clinical Phenotype of 64 Patients with Dedicator of Cytokinesis 8 Deficiency
    The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency Karin R. Engelhardt, PhD,a,b,c Michael E. Gertz, PhD,d Sevgi Keles, MD,e,f,g* Alejandro A. Schaffer,€ PhD,d* Elena C. Sigmund, BSc,b Cristina Glocker, PhD,b Shiva Saghafi, MSc,h Zahra Pourpak, MD, PhD,h Ruben Ceja, MSc,e,g Atfa Sassi, PhD,i Laura E. Graham, BSc, MBChB,a Michel J. Massaad, PhD,g Fethi Mellouli, MD,j Imen Ben-Mustapha, MD,i Monia Khemiri, MD,k Sara Sebnem Kilic, MD,l Amos Etzioni, MD,m Alexandra F. Freeman, MD,n Jens Thiel, MD,b Ilka Schulze, MD,b Waleed Al-Herz, MD,o Ayse Metin, MD, PhD,p Ozden€ Sanal, MD,q Ilhan Tezcan, MD,q Mehdi Yeganeh, MD,r Tim Niehues, MD,s Gregor Dueckers, MD,s Sebastian Weinspach, MD,t Turkan Patiroglu, MD,u Ekrem Unal, MD,v Majed Dasouki, MD,w Mustafa Yilmaz, MD,x Ferah Genel, MD,y Caner Aytekin, MD,z Necil Kutukculer, MD,aa Ayper Somer, MD,bb Mehmet Kilic, MD,cc Ismail Reisli, MD,f Yildiz Camcioglu, MD,dd Andrew R. Gennery, MD,c Andrew J. Cant, MD,c Alison Jones, MD,ee Bobby H. Gaspar, MD,ee Peter D. Arkwright, MD, DPhil,ff Maria C. Pietrogrande, MD,gg Zeina Baz, MD,hh Salem Al-Tamemi, MD,ii Vassilios Lougaris, MD,jj Gerard Lefranc, PhD,kk Andre Megarbane, MD, PhD,ll Jeannette Boutros, MD,mm Nermeen Galal, MD,mm Mohamed Bejaoui, MD,j Mohamed-Ridha Barbouche, MD, PhD,i Raif S. Geha, MD,g Talal A.
    [Show full text]
  • Hyper Ige Syndromes and DOCK8 Forms of HIES Table 20:1
    Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases Chapter 20 Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases 6th Edition The development of this publication was supported by Shire, now Takeda. 110 West Road, Suite 300 Towson, MD 21204 800.296.4433 www.primaryimmune.org [email protected] Chapter 20 Hyper IgE Syndromes (HIES): STAT3 Loss of Function, DOCK8 Deficiency and Others Alexandra Freeman, MD, National Institutes of Health, Bethesda, Maryland, USA Jennifer Heimall, MD, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Hyper IgE Syndromes (HIES) are rare forms of primary immunodeficiency diseases (PI) characterized by recurrent eczema, skin abscesses, lung infections, eosinophilia (high numbers of eosinophils in the blood), and high serum levels of immunoglobulin E (IgE). Although initially described as two forms, with autosomal dominant (AD) and autosomal recessive (AR) inheritance, we now recognize that these are two distinct diseases caused by different genetic causes, with the two most common being from harmful mutations in STAT3 causing loss of function (STAT3-LOF) and DOCK8. These diseases share overlapping clinical and laboratory features; however, they also exhibit distinct clinical symptoms, disease courses, and outcomes. In addition, several other genetic variants have since been described to present with similar symptoms. History Clinical Presentation STAT3-LOF was described first as Job Syndrome STAT3 Deficiency in 1966 in two girls with many episodes of STAT3 Deficiency, is associated with heterozygous pneumonia, eczema-like rashes, and recurrent skin loss of function mutations in the transcription factor boils. These boils were remarkable for their lack STAT3. This is the more common form of HIES in of surrounding warmth, redness or tenderness, the U.S.
    [Show full text]
  • DOCK8 Mutation Syndrome: a Diagnostic Challenge for Dermatologists
    Acta Derm Venereol 2016; 96: 991–992 SHORT COMMUNICATION DOCK8 Mutation Syndrome: A Diagnostic Challenge for Dermatologists Joséphine Moreau1, Sarah Beaussant-Cohen2, François Aubin1,3, Pierre-Simon Rohrlich4 and Eve Puzenat1* 1Service de Dermatologie, 2Service d’Hématologie Pédiatrique, Centre Hospitalier Universitaire Besançon, 3 Bd Fleming, FR-25030 Besançon, 3EA3181; SFR FED 4234 IBCT, Université de Franche-Comté, Besançon, and 4Service d’Hématologie Pédiatrique, Centre Hospitalier Universitaire, Nice, France. *E-mail: [email protected] Accepted Nov 12, 2015; Epub ahead of print Nov 16, 2015 Primary immune deficiencies in children may be as- spite the use of immunosuppressive drugs. Six months after the sociated with early diverse cutaneous manifestations transplantation, immunosuppressive drugs were stopped and after one year of follow-up, no recurrence of atopic dermatitis, (1). Among them, hyper IgE syndrome (HIES) was molluscum contagiosa and flat warts and no ear-nose-throat or recently classified into 2 different forms: a well-known pulmonary bacterial infections were observed. autosomal dominant form of STAT3 mutations (called Job’s syndrome) and a recent autosomal recessive form associated with DOCK8 (dedicator of cytokinesis 8) gene DISCUSSION mutations (2, 3). Although the function of Dock8 protein is unclear, Severe atopic disease, repeated viral and bacterial severe atopic disease, repeated viral and bacterial infections and cancer susceptibility are the main cha- infections and cancer predisposition are the main cha- racteristics of DOCK8 mutation syndrome (4, 5), which racteristics of DOCK8 mutation syndrome (4, 5). We is associated with a high morbidity and mortality rate. report here a new case of DOCK8 mutation syndrome Aydin et al.
    [Show full text]
  • The Hyperimmunoglobulin E Syndrome
    Szczawinska-Poplonyk et al. Orphanet Journal of Rare Diseases 2011, 6:76 http://www.ojrd.com/content/6/1/76 REVIEW Open Access The hyperimmunoglobulin E syndrome - clinical manifestation diversity in primary immune deficiency Aleksandra Szczawinska-Poplonyk1*, Zdzislawa Kycler1, Barbara Pietrucha2, Edyta Heropolitanska-Pliszka2, Anna Breborowicz1 and Karolina Gerreth3 Abstract The hyper-IgE syndromes are rare, complex primary immunodeficiencies characterized by clinical manifestation diversity, by particular susceptibility to staphylococcal and mycotic infections as well as by a heterogeneous genetic origin. Two distinct entities - the classical hyper-IgE syndrome which is inherited in an autosomal dominant pattern and the autosomal recessive hyper-IgE syndrome have been recognized. The autosomal dominant hyper- IgE syndrome is associated with a cluster of facial, dental, skeletal, and connective tissue abnormalities which are not observable in the recessive type. In the majority of affected patients with autosomal dominant hyper-IgE syndrome a mutation in the signal transducer and the activator of the transcription 3 gene has been identified, leading to an impaired Th17 cells differentiation and to a downregulation of an antimicrobial response. A mutation in the dedicator of the cytokinesis 8 gene has been identified as the cause of many cases with autosomal recessive hyper-IgE syndrome and, in one patient, a mutation in tyrosine kinase 2 gene has been demonstrated. In this paper, the authors provide a review of the clinical manifestations in the hyper-IgE syndromes with particular emphasis on the diversity of their phenotypic expression and present current diagnostic guidelines for these diseases. Introduction its inclusion in the group of primary immunodeficiency The hyper-IgE syndrome (HIES) was first described in diseases by Hill et al [4], and the term “Hyper-IgE 1966 by Davis, Wedgwood and Schaller [1]; the authors Recurrent Infection Syndrome” (HIERIS) as proposed by perceived the similarity of severe dermatitis associated Buckley was also accepted [5].
    [Show full text]
  • Understanding Wiskott-Aldrich Syndrome
    Understanding Wiskott-Aldrich Syndrome With advances in treatment, WAS patients By Elizabeth Garabedian, RN, MSLS, gain longer life expectancy and more normal and Alexandra F. Freeman, MD adult lives. Wiskott-Aldrich syndrome (WAS) is a rare hereditary Clinical Features disorder of the immune system. It is classified as a primary Eczema, recurrent infections, bleeding tendency, autoim - immunodeficiency and is present at birth, but it may be mild munity and malignancy are the most common symptoms of and go undiagnosed until childhood. It is characterized with a WAS. Most individuals with WAS have recurrent ear, sinus pattern of clinical problems that usually includes abnormal and lung infections, as well as an increase in viral infections bleeding due to small size and low number of blood platelets such as molluscum and warts. The WAS protein is important (microthrombocytopenia), eczema of the skin, recurrent infections , in the structure and function of white blood cells and their a high incidence of autoimmune symptoms and cancers, immune responses to infection. The two main types of white particularly lymphoma. blood cells that are affected in WAS are T and B lymphocyte The disorder was first described in 1937 by a German pediatrician, cells. T cells help defend against yeast and viral infections and Dr. Alfred Wiskott. He reported a family with three brothers some bacterial infections. T cells arise in the bone marrow who all presented in infancy with symptoms of eczema, bloody and are “educated” in the thymus gland. B cells are formed in diarrhea and thrombocytopenia with small platelets. The sisters the bone marrow and work to fight infections caused by other of these boys had none of these conditions.
    [Show full text]
  • DOCK8 Deficiency Without Hyper-Ige in a Child with a Large Deletion
    CASE REPORT published: 14 June 2021 doi: 10.3389/fped.2021.635322 Case Report: DOCK8 Deficiency Without Hyper-IgE in a Child With a Large Deletion Edna Venegas-Montoya 1*, Aidé Tamara Staines-Boone 1, Luz María Sánchez-Sánchez 2, Jorge Alberto García-Campos 3, Rubén Antonio Córdova-Gurrola 4, Yuridia Salazar-Galvez 1, David Múzquiz-Zermeño 1, María Edith González-Serrano 5 and Saul O. Lugo Reyes 5 1 Immunology Service, Hospital de Especialidades Unidad Medica de Alta Especialidad (UMAE) 25 del Instituto Mexicano del Seguro Social (IMSS), Monterrey, Mexico, 2 Pediatrics Service, Hospital de Especialidades Unidad Medica de Alta Especialidad (UMAE) 25 del Instituto Mexicano del Seguro Social (IMSS), Monterrey, Mexico, 3 Infectious Disease Department, Hospital de Especialidades Unidad Medica de Alta Especialidad (UMAE) 25 del Instituto Mexicano del Seguro Social (IMSS), Monterrey, Mexico, 4 Pediatrics Service, General Hospital 1, Saltillo, Mexico, 5 Immunodeficiencies Lab, National Institute of Pediatrics, Mexico City, Mexico Edited by: Stephen Jolles, Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined University Hospital of Wales, primary immune deficiency with impaired actin polymerization that results in altered United Kingdom cell mobility and immune synapse. DOCK8-deficient patients present early in life Reviewed by: Beatriz Elena Marciano, with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial National Institutes of Health (NIH), pneumonia, and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, United States and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before Andrea Taddio, Institute for Maternal and Child Health its genetic etiology was known, patients were described as having a form of Hyper- Burlo Garofolo (IRCCS), Italy IgE syndrome, a name now deprecated in favor of genetic defects.
    [Show full text]
  • Hematopoietic Stem Cell Transplant Effectively Rescues Lymphocyte Differentiation and Function in DOCK8-Deficient Patients
    Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients Bethany A. Pillay, … , Stuart G. Tangye, Cindy S. Ma JCI Insight. 2019;4(11):e127527. https://doi.org/10.1172/jci.insight.127527. Research Article Immunology Infectious disease Biallelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterized by severe pathogen infections, eczema, allergies, malignancy, and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplant (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced, while γδT cells were increased in DOCK8-deficient patients. HSCT improved abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8- deficient patients decreased over time following HSCT. Our results document the extensive catalog of cellular defects in DOCK8-deficient patients and the efficacy of HSCT in correcting these defects, concurrent with improvements in clinical phenotypes. Overall, our findings reveal mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency after HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.
    [Show full text]
  • Hyper Ige Syndrome
    Hyper IgE Syndrome Chapter 17 Hyper IgE Syndrome Hyper IgE Syndrome (HIES) is a rare primary immunodeficiency disease characterized by eczema, recurrent staphylococcal skin abscesses, recurrent lung infections, eosinophilia (a high number of eosinophils in the blood) and high serum levels of IgE. Most cases of HIES are sporadic, but some familial cases of HIES have been reported, with either an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance. Definition of Hyper IgE Syndrome HIES is a rare primary immunodeficiency characterized (AR, or type 2) form. These two forms share overlapping by recurrent eczema, skin abscesses, lung infections, clinical and laboratory features including eczema, eosinophilia and high serum levels of IgE. Two form of recurrent infections, skin abscesses, high IgE level and HIES have been described, including an autosomal increased eosinophil number. However, they also exhibit dominant (AD, or type 1) and an autosomal recessive distinct clinical manifestations, courses and outcomes. History of Hyper IgE Syndrome HIES was described first as ‘‘Job syndrome’’ by Davis this report, elevated IgE was found in the two girls from and colleagues in 1966, in two girls with many episodes the initial report, showing that Job syndrome and of pneumonia, eczema-like rashes and recurrent skin Buckley syndrome represented the same condition. In boils remarkable for their lack of surrounding warmth, 2007, a heterozygous mutation in the gene encoding redness or tenderness (so-called “cold abscesses”). In the transcription factor STAT3 was found to underlie 1972, the syndrome was refined and clarified by most cases of AD (type 1)-HIES. In 2009 mutations and Buckley and colleagues who noted similar infectious deletions in the DOCK8 gene were found to underlie the problems in two boys who also had distinctive facial majority of cases with AR (type 2)-HIES.
    [Show full text]
  • Biomarker Discovery and Food Allergy Profiling Distinguishes DOCK8 Deficiency from Atopic Dermatitis
    ResearchOnline@JCU This file is part of the following work: Jacob, Minnie (2019) Biomarker discovery and food allergy profiling distinguishes DOCK8 deficiency from atopic dermatitis. PhD Thesis, James Cook University. Access to this file is available from: https://doi.org/10.25903/myqs%2D6y84 Copyright © 2019 Minnie Jacob. The author has certified to JCU that they have made a reasonable effort to gain permission and acknowledge the owners of any third party copyright material included in this document. If you believe that this is not the case, please email [email protected] BIOMARKER DISCOVERY AND FOOD ALLERGY PROFILING DISTINGUISHES DOCK8 DEFICIENCY FROM ATOPIC DERMATITIS. Thesis submitted by Minnie Jacob M.Sc ( Biochemistry) For the degree of Doctor of Philosophy In the College of Public Health, Medical and Veterinary Sciences James Cook University September 2019 Statement of Contribution STATEMENT OF THE CONTRIBUTION OF OTHERS Nature of Assistance Contribution Name and Affiliation Intellectual Project plan and Dr. Anas Abdel Rahman, King Faisal support development Specialist Hospital and Research Center Editorial support Dr. Anas Abdel Rahman,King Faisal Specialist Hospital and Research Center Prof Andreas Lopata (AL), James Cook University Dr. Majed Aldasouki, King Faisal Specialist Hospital and Research Center Grant proposal Dr. Anas Abdel Rahman, King Faisal writing Specialist Hospital and Research Center Financial Research Department of Genetics, King Faisal Support Specialist Hospital and Research Center College of Public Health, Medical and Veterinary Sciences, James Cook University Conference HDRES Grant rounds-2018,James travel Cook University Dr. Majed Aldasouki, King Faisal Specialist Hospital and Research Center Dr. Anas Abdelrahman,King Faisal Specialist Hospital and Research Center Stipend James Cook University Postgraduate Research Scholarship Write up support Doctoral completion fund, Faculty of Medicine, Health and Molecular Sciences, James Cook University Data Collection Blood sample Dr.
    [Show full text]
  • DOCK8 Drives Src-Dependent NK Cell Effector Function Conor J
    DOCK8 Drives Src-Dependent NK Cell Effector Function Conor J. Kearney, Stephin J. Vervoort, Kelly M. Ramsbottom, Andrew J. Freeman, Jessica Michie, Jane This information is current as Peake, Jean-Laurent Casanova, Capucine Picard, Stuart G. of September 23, 2021. Tangye, Cindy S. Ma, Ricky W. Johnstone, Katrina L. Randall and Jane Oliaro J Immunol 2017; 199:2118-2127; Prepublished online 9 August 2017; Downloaded from doi: 10.4049/jimmunol.1700751 http://www.jimmunol.org/content/199/6/2118 Supplementary http://www.jimmunol.org/content/suppl/2017/08/09/jimmunol.170075 http://www.jimmunol.org/ Material 1.DCSupplemental References This article cites 38 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/199/6/2118.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology DOCK8 Drives Src-Dependent NK Cell Effector Function Conor J.
    [Show full text]