DOCSLIB.ORG

Mast Cells As Novel Effector Cells in the Pathogenesis of Chronic Graft-Versus-Host Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mast Cells As Novel Effector Cells in the Pathogenesis of Chronic Graft-Versus-Host Disease University of Kentucky UKnowledge Theses and Dissertations--Microbiology, Microbiology, Immunology, and Molecular Immunology, and Molecular Genetics Genetics 2020 MAST CELLS AS NOVEL EFFECTOR CELLS IN THE PATHOGENESIS OF CHRONIC GRAFT-VERSUS-HOST DISEASE Ethan Strattan University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0001-6905-0813 Digital Object Identifier: https://doi.org/10.13023/etd.2020.419 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Strattan, Ethan, "MAST CELLS AS NOVEL EFFECTOR CELLS IN THE PATHOGENESIS OF CHRONIC GRAFT- VERSUS-HOST DISEASE" (2020). Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics. 24. https://uknowledge.uky.edu/microbio_etds/24 This Doctoral Dissertation is brought to you for free and open access by the Microbiology, Immunology, and Molecular Genetics at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Ethan Strattan, Student Dr. Gerhard Carl Hildebrandt, Major Professor Dr. Carol Pickett, Director of Graduate Studies MAST CELLS AS NOVEL EFFECTOR CELLS IN THE PATHOGENESIS OF CHRONIC GRAFT-VERSUS-HOST DISEASE ________________________________________ DISSERTATION ________________________________________ A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Ethan Jesse Strattan Lexington, Kentucky Co-Directors: Dr. Gerhard Carl Hildebrandt, Professor of Medicine and Dr. Subbarao Bondada, Professor Lexington, Kentucky Copyright © Ethan Jesse Strattan 2020 https://orcid.org/0000-0001-6905-0813 ABSTRACT OF DISSERTATION MAST CELLS AS NOVEL EFFECTOR CELLS IN THE PATHOGENESIS OF CHRONIC GRAFT-VERSUS-HOST DISEASE Hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host-disease (GVHD), a condition wherein the donor cells recognize the patient tissues as non-self. GVHD can manifest anywhere from weeks to decades post-transplant and is classified as either acute or chronic GVHD, both of which are significant causes of transplant-related morbidity and mortality. However, GVHD is a complex, multifactorial, and enigmatic disease. The factors driving GVHD at the cellular and molecular level are incompletely understood. Immunosuppression targeting T-cells has not always been effective and increases the risk of relapse. Prophylactic immunosuppression can be particularly detrimental in the context of cGVHD, where symptoms can appear even decades after transplant. There is great need to further understand the mechanisms of GVHD pathogenesis in order to more effectively make use of HSCT. Mast cells are an arm of the immune system that are primarily known for their role in atopic disease. However, recent studies have demonstrated new paradigms for mast cell activity, showing that they can play important roles in tissue homeostasis and wound healing. Therefore, the purpose of this dissertation is to explore the role of mast cells in the onset of fibrotic chronic GVHD. We hypothesized that mast cells, through their interactions with tissue-resident and circulating GVHD effector cells, would be detrimental in chronic GVHD by exerting proinflammatory and profibrotic effects on the surrounding tissue. We examined mast cells in vitro in mono- and co-culture models, finding that they are significantly resistant to conditioning-induced cell death, as well as capable of inducing proliferation of fibroblasts. We further tested our hypothesis in vivo in murine models of allogeneic transplant using both wild type and mast cell-deficient mice. Compared to wild type recipients, mast cell-deficient recipients had significant reductions in GVHD symptomology and skin manifestations, as well as in chemokine levels and immune cell recruitment in the skin. We show that mast cell chemokine production is blocked by drugs currently used clinically to treat chronic GVHD, and that skin from GVHD patients is enriched in mast cells. Lastly, we show that recipient-derived mast cells are capable of surviving after transplant. Taken together, these data demonstrate a role for mast cells in the onset of dermal chronic GVHD. We therefore outline methods and pathways by which mast cells could be targeted for therapeutic inhibition and discuss future studies that would further clarify the function of mast cells in chronic GVHD pathogenesis. KEYWORDS: GVHD, mast cells, transplant, immunology Ethan Jesse Strattan 08/28/2020 MAST CELLS AS NOVEL EFFECTOR CELLS IN THE PATHOGENESIS OF CHRONIC GRAFT-VERSUS-HOST DISEASE By Ethan Jesse Strattan Dr. Gerhard Carl Hildebrandt Co-director of Dissertation Dr. Subbarao Bondada Co-director of Dissertation Dr. Carol Pickett Director of Graduate Studies 08/28/2020 Date To my wife, Lydia, who has been an endless source of support and love (and tea) throughout graduate school. You kept me sane, grounded, encouraged, and entertained, and I could not have done this without you. To my friends, who accommodated my busy schedule when we could meet up, and when we could not, let me live vicariously through them. To my parents and siblings, who did their best not to let their eyes glaze over when I talked about science. ACKNOWLEDGMENTS First and foremost, I would like to thank my mentor, Dr. Gerhard Hildebrandt. He has always believed in me and pushed me to do the best possible science. At the same time, he has been aware of the sometimes-difficult realities of graduate school and has been willing to compromise and adjust to my schedule when needed. Altogether, those traits have made him an excellent mentor during these four years, and I am very grateful to have been in his lab. I could not have done this without the aid and support of my lab-mates, Drs. Senthil Palaniyandi and Reena Kumari. They have helped me through countless experiments and I will always be thankful for their willingness to assist. I hope I have returned even a fraction of the kindness, patience, and support both of you have shown me. I also want to thank my graduate committee as well as the many faculty and staff who have given their time and expertise to mentor me. Dr. Jamie Sturgill was always available for feedback or support and she shared her love of mast cells with me, for which I will forever be grateful. Drs. Joe McGillis, Sarah D’Orazio, John Yannelli, and Charlie Snow have all offered a listening ear when I needed career guidance, experimental advice, or just wanted to chat. And to the staff of the flow cytometry core: thanks for putting up with me constantly running behind. A final thanks to my fellow MIMG graduate students, especially Gabby Keb and Beth Oates, without whom I would have gone much crazier. iii TABLE OF CONTENTS ACKNOWLEDGMENTS ............................................................................................................ iii LIST OF TABLES ...................................................................................................................... viii LIST OF FIGURES .......................................................................................................................ix CHAPTER 1. INTRODUCTION AND BACKGROUND ........................................................... 1 1.1 Introduction ........................................................................................................................ 1 1.2 Skin – Structure and function ............................................................................................. 2 1.3 Hematopoietic stem cell transplantation ............................................................................. 4 1.3.1 Procedure .................................................................................................................
Load more

Recommended publications
  • Differentiating Between Anxiety, Syncope & Anaphylaxis
    Differentiating between anxiety, syncope & anaphylaxis Dr. Réka Gustafson Medical Health Officer Vancouver Coastal Health Introduction Anaphylaxis is a rare but much feared side-effect of vaccination. Most vaccine providers will never see a case of true anaphylaxis due to vaccination, but need to be prepared to diagnose and respond to this medical emergency. Since anaphylaxis is so rare, most of us rely on guidelines to assist us in assessment and response. Due to the highly variable presentation, and absence of clinical trials, guidelines are by necessity often vague and very conservative. Guidelines are no substitute for good clinical judgment. Anaphylaxis Guidelines • “Anaphylaxis is a potentially life-threatening IgE mediated allergic reaction” – How many people die or have died from anaphylaxis after immunization? Can we predict who is likely to die from anaphylaxis? • “Anaphylaxis is one of the rarer events reported in the post-marketing surveillance” – How rare? Will I or my colleagues ever see a case? • “Changes develop over several minutes” – What is “several”? 1, 2, 10, 20 minutes? • “Even when there are mild symptoms initially, there is a potential for progression to a severe and even irreversible outcome” – Do I park my clinical judgment at the door? What do I look for in my clinical assessment? • “Fatalities during anaphylaxis usually result from delayed administration of epinephrine and from severe cardiac and respiratory complications. “ – What is delayed? How much time do I have? What is anaphylaxis? •an acute, potentially
    [Show full text]
  • Elements of Immunoglobulin E Network Associate with Aortic Valve Area in Patients with Acquired Aortic Stenosis
    biomedicines Communication Elements of Immunoglobulin E Network Associate with Aortic Valve Area in Patients with Acquired Aortic Stenosis Daniel P. Potaczek 1,2,† , Aleksandra Przytulska-Szczerbik 2,†, Stanisława Bazan-Socha 3 , Artur Jurczyszyn 4, Ko Okumura 5, Chiharu Nishiyama 6, Anetta Undas 2,7,‡ and Ewa Wypasek 2,8,*,‡ 1 Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Philipps University Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center, 35043 Marburg, Germany; [email protected] 2 Krakow Center for Medical Research and Technology, John Paul II Hospital, 31-202 Krakow, Poland; [email protected] (A.P.-S.); [email protected] (A.U.) 3 Department of Internal Medicine, Jagiellonian University Medical College, 31-066 Krakow, Poland; [email protected] 4 Department of Hematology, Jagiellonian University Medical College, 31-501 Krakow, Poland; [email protected] 5 Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan; [email protected] 6 Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585, Japan; [email protected] 7 Institute of Cardiology, Jagiellonian University Medical College, 31-202 Krakow, Poland 8 Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, 30-705 Krakow, Poland * Correspondence: [email protected]; Tel.: +48-12-614-31-35 † These first authors contributed equally to this work. ‡ These last authors contributed equally to this work. Abstract: Allergic mechanisms are likely involved in atherosclerosis and its clinical presentations, Citation: Potaczek, D.P.; Przytulska-Szczerbik, A.; Bazan-Socha, such as coronary artery disease (CAD).
    [Show full text]
  • An Avoidable Cause of Thymoglobulin Anaphylaxis S
    Brabant et al. Allergy Asthma Clin Immunol (2017) 13:13 Allergy, Asthma & Clinical Immunology DOI 10.1186/s13223-017-0186-9 CASE REPORT Open Access An avoidable cause of thymoglobulin anaphylaxis S. Brabant1*, A. Facon2, F. Provôt3, M. Labalette1, B. Wallaert4 and C. Chenivesse4 Abstract Background: Thymoglobulin® (anti-thymocyte globulin [rabbit]) is a purified pasteurised, gamma immune globulin obtained by immunisation of rabbits with human thymocytes. Anaphylactic allergic reactions to a first injection of thymoglobulin are rare. Case presentation: We report a case of serious anaphylactic reaction occurring after a first intraoperative injection of thymoglobulin during renal transplantation in a patient with undiagnosed respiratory allergy to rabbit allergens. Conclusions: This case report reinforces the importance of identifying rabbit allergy by a simple combination of clini- cal interview followed by confirmatory skin testing or blood tests of all patients prior to injection of thymoglobulin, which is formally contraindicated in patients with a history of hypersensitivity to rabbit proteins. Keywords: Thymoglobulin, Anaphylactic allergic reaction, Rabbit proteins Background [7]. Cases of serious anaphylactic reactions to thymo- Thymoglobulin is an IgG fraction purified from the globulin due to rabbit protein allergy are very rare, and serum of rabbits immunised against human thymocytes. consequently, specific tests for rabbit allergy are not The preparation consists of polyclonal antilymphocyte usually performed as part of the pre-transplant assess- IgG directed against T lymphocyte surface antigens, and ment. We report a case of serious anaphylactic reaction induction of profound lymphocyte depletion is though due to rabbit protein allergy following a first injection of to be the main mechanism of thymoglobulin-mediated thymoglobulin.
    [Show full text]
  • Microarray Analysis of Novel Genes Involved in HSV- 2 Infection
    Microarray analysis of novel genes involved in HSV- 2 infection Hao Zhang Nanjing University of Chinese Medicine Tao Liu ( [email protected] ) Nanjing University of Chinese Medicine https://orcid.org/0000-0002-7654-2995 Research Article Keywords: HSV-2 infection,Microarray analysis,Histospecic gene expression Posted Date: May 12th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-517057/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/19 Abstract Background: Herpes simplex virus type 2 infects the body and becomes an incurable and recurring disease. The pathogenesis of HSV-2 infection is not completely clear. Methods: We analyze the GSE18527 dataset in the GEO database in this paper to obtain distinctively displayed genes(DDGs)in the total sequential RNA of the biopsies of normal and lesioned skin groups, healed skin and lesioned skin groups of genital herpes patients, respectively.The related data of 3 cases of normal skin group, 4 cases of lesioned group and 6 cases of healed group were analyzed.The histospecic gene analysis , functional enrichment and protein interaction network analysis of the differential genes were also performed, and the critical components were selected. Results: 40 up-regulated genes and 43 down-regulated genes were isolated by differential performance assay. Histospecic gene analysis of DDGs suggested that the most abundant system for gene expression was the skin, immune system and the nervous system.Through the construction of core gene combinations, protein interaction network analysis and selection of histospecic distribution genes, 17 associated genes were selected CXCL10,MX1,ISG15,IFIT1,IFIT3,IFIT2,OASL,ISG20,RSAD2,GBP1,IFI44L,DDX58,USP18,CXCL11,GBP5,GBP4 and CXCL9.The above genes are mainly located in the skin, immune system, nervous system and reproductive system.
    [Show full text]
  • Hypersensitivity Reactions (Types I, II, III, IV)
    Hypersensitivity Reactions (Types I, II, III, IV) April 15, 2009 Inflammatory response - local, eliminates antigen without extensively damaging the host’s tissue. Hypersensitivity - immune & inflammatory responses that are harmful to the host (von Pirquet, 1906) - Type I Produce effector molecules Capable of ingesting foreign Particles Association with parasite infection Modified from Abbas, Lichtman & Pillai, Table 19-1 Type I hypersensitivity response IgE VH V L Cε1 CL Binds to mast cell Normal serum level = 0.0003 mg/ml Binds Fc region of IgE Link Intracellular signal trans. Initiation of degranulation Larche et al. Nat. Rev. Immunol 6:761-771, 2006 Abbas, Lichtman & Pillai,19-8 Factors in the development of allergic diseases • Geographical distribution • Environmental factors - climate, air pollution, socioeconomic status • Genetic risk factors • “Hygiene hypothesis” – Older siblings, day care – Exposure to certain foods, farm animals – Exposure to antibiotics during infancy • Cytokine milieu Adapted from Bach, JF. N Engl J Med 347:911, 2002. Upham & Holt. Curr Opin Allergy Clin Immunol 5:167, 2005 Also: Papadopoulos and Kalobatsou. Curr Op Allergy Clin Immunol 7:91-95, 2007 IgE-mediated diseases in humans • Systemic (anaphylactic shock) •Asthma – Classification by immunopathological phenotype can be used to determine management strategies • Hay fever (allergic rhinitis) • Allergic conjunctivitis • Skin reactions • Food allergies Diseases in Humans (I) • Systemic anaphylaxis - potentially fatal - due to food ingestion (eggs, shellfish,
    [Show full text]
  • Anaphylaxis Following Administration of Extracorporeal Photopheresis for Cutaneous T Cell Lymphoma
    Volume 26 Number 9| September 2020| Dermatology Online Journal || Letter 26(9):18 Anaphylaxis following administration of extracorporeal photopheresis for cutaneous T cell lymphoma Jessica Tran1,2, Lisa Morris3, Alan Vu4, Sampreet Reddy1, Madeleine Duvic1 Affiliations: 1Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, 2Baylor College of Medicine, Houston, Texas, USA, 3University of Missouri Columbia School of Medicine, Columbia, Missouri , USA, 4University of Texas McGovern Medical School, Houston, Texas, USA Corresponding Author: Madeleine Duvic MD, Department of Dermatology, The University of Texas MD Anderson Cancer Center, Unit 1452, 1515 Holcombe Boulevard, Houston, TX 77030, Tel: 713-792-6800, Email: [email protected] peripheral blood from a patient, (ii) separating the Abstract white blood cells from whole blood by Extracorporeal photopheresis is a non-invasive centrifugation, (iii) adding psoralen, a therapy used for the treatment of a range of T cell photosensitizing agent, to the white blood cells, (iv) disorders, including cutaneous T cell lymphoma. exposing the white blood cells to ultraviolet A (UVA) During extracorporeal photopheresis, peripheral radiation, and (v) re-infusing the treated white blood blood is removed from the patient and the white blood cells are separated from whole blood via cells to the patient [3]. The re-infusion of apoptotic centrifugation. The white blood cells are exposed to leukocytes triggers an immune response resulting in psoralen (a photosensitizing agent) and ultraviolet A production of CD8+ tumor suppressor cells in CTCL radiation, causing cell apoptosis. The apoptotic [3]. Extracorporeal photopheresis is generally leukocytes are subsequently re-infused into the regarded as safe with few side effects [3].
    [Show full text]
  • GATA2 Regulates Mast Cell Identity and Responsiveness to Antigenic Stimulation by Promoting Chromatin Remodeling at Super- Enhancers
    ARTICLE https://doi.org/10.1038/s41467-020-20766-0 OPEN GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super- enhancers Yapeng Li1, Junfeng Gao 1, Mohammad Kamran1, Laura Harmacek2, Thomas Danhorn 2, Sonia M. Leach1,2, ✉ Brian P. O’Connor2, James R. Hagman 1,3 & Hua Huang 1,3 1234567890():,; Mast cells are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the mast cell lineage-determining factors. However, it is unclear whether these lineage- determining factors regulate chromatin accessibility at mast cell enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of mast cell identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We find that the number and densities of GATA2- but not MITF-bound sites at the super-enhancers are several folds higher than that at the typical enhancers. Our studies reveal that GATA2 promotes robust gene transcription to maintain mast cell identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key mast cell genes. 1 Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206, USA. 2 Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA. 3 Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, ✉ CO 80045, USA. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:494 | https://doi.org/10.1038/s41467-020-20766-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20766-0 ast cells (MCs) are critical effectors in immunity that at key MC genes.
    [Show full text]
  • How to Recognise and Manage Mild to Moderate Allergic Reactions in Children Information for Parents and Carers Contents Page What Is an Allergic Reaction? 2
    Children’s Allergy Clinic How to recognise and manage mild to moderate allergic reactions in children Information for parents and carers Contents Page What is an allergic reaction? 2 What can cause allergic reactions? 3 How to avoid contact with allergens 4 Signs and symptoms 6 Action plan 7 Nurseries, child-minders, schools/activity groups 9 Further information 11 What is an allergic reaction? An allergic reaction happens when the body’s immune system over-reacts to contact with normally harmless substances. An allergic person’s immune system treats certain substances as threats and releases substances such as histamines to defend the body against them. The release of histamine can cause the body to produce a range of mild to severe symptoms. An allergic response can develop after touching, swallowing, tasting, eating or breathing-in a particular substance. page 2 What can cause allergic reactions? Foods For example: • nuts (especially peanuts) • fish and shellfish • eggs and milk. Most allergic reactions to food occur immediately after swallowing, although some can occur up to several hours afterwards. Food allergies are more common in families who have other allergic conditions such as asthma, eczema and hay fever. Rarely, people have an allergic reaction to fruit, vegetables and legumes. Legumes include pulses, beans, peas and lentils. Peanuts are also part of the legume family. Insect stings • Reaction to an insect sting is immediate (within 30 minutes). Natural rubber latex Some common sources of latex are: • balloons • rubber bands • carpet backing • furniture filling • medical or dental items such as catheters, gloves, disposable items. Medicines Medication rarely causes a severe allergic reaction in children.
    [Show full text]
  • COVID-19 Vaccine and Allergy
    COVID Vaccine and Allergy Stephanie Leonard, MD Associate Clinical Professor Department of Pediatric Allergy & Immunology January 20, 2020 Safe and Impactful • Proper Screening COVID Vaccine • Monitoring Administration • Clinical Assessment • Vaccine Adverse Event Reporting System (VAERS) detected 21 cases of anaphylaxis after administration of a reported 1,893,360 first doses of the Pfizer-BioNTech COVID-19 vaccine • 11.1 cases per million doses (0.001%) • 1.3 cases per million for flu vaccines • 71% occurred within 15 min of vaccination, 86% within 30 minutes • Range = 2–150 minutes • Of 20 with follow-up info, all had recovered or been discharged home. • 17 (81%) with h/o allergies to food, vaccine, medication, venom, contrast, or pets. • 4 with no h/o any allergies • 7 with h/o anaphylaxis • Rabies vaccine • Flu vaccine • 19 (90%) diffuse rash or generalized hives Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020. MMWR Morb Mortal Wkly Rep 2021;70:46–51. Early Signs of Anaphylaxis • Respiratory: sensation of throat closing*, stridor, shortness of breath, wheeze, cough • Gastrointestinal: nausea*, vomiting, diarrhea, abdominal pain • Cardiovascular: dizziness*, fainting, tachycardia, hypotension • Skin/mucosal: generalized hives, itching, or swelling of lips, face, throat *these can be subjective and overlap with anxiety or vasovagal syndrome Labs that can help assess for anaphylaxis • Tryptase, serum (red top tube) • C5b-9 terminal complement complex Level, serum (SC5B9) (lavender top EDTA tube) Emergency Supplies Management of anaphylaxis at a COVID-19 vaccination site • If anaphylaxis is suspected, take the following steps: • Rapidly assess airway, breathing, circulation, and mentation (mental activity).
    [Show full text]
  • Acute Immune Thrombocytopenic Purpura in Children
    Turk J Hematol 2007; 24:41-51 REVIEW ARTICLE © Turkish Society of Hematology Acute immune thrombocytopenic purpura in children Abdul Rehman Sadiq Public School, Bahawalpur, Pakistan [email protected] Received: Sep 12, 2006 • Accepted: Mar 21, 2007 ABSTRACT Immune thrombocytopenic purpura (ITP) in children is usually a benign and self-limiting disorder. It may follow a viral infection or immunization and is caused by an inappropriate response of the immune system. The diagnosis relies on the exclusion of other causes of thrombocytopenia. This paper discusses the differential diagnoses and investigations, especially the importance of bone marrow aspiration. The course of the disease and incidence of intracranial hemorrhage are also discussed. There is substantial discrepancy between published guidelines and between clinicians who like to over-treat. The treatment of the disease ranges from observation to drugs like intrave- nous immunoglobulin, steroids and anti-D to splenectomy. The different modes of treatment are evaluated. The best treatment seems to be observation except in severe cases. Key Words: Thrombocytopenic purpura, bone marrow aspiration, Intravenous immunoglobulin therapy, steroids, anti-D immunoglobulins 41 Rehman A INTRODUCTION There is evidence that enhanced T-helper cell/ Immune thrombocytopenic purpura (ITP) in APC interactions in patients with ITP may play an children is usually a self-limiting disorder. The integral role in IgG antiplatelet autoantibody pro- American Society of Hematology (ASH) in 1996 duction
    [Show full text]
  • Mast Cell Involvement in Fibrosis in Chronic Graft-Versus-Host Disease
    International Journal of Molecular Sciences Review Mast Cell Involvement in Fibrosis in Chronic Graft-Versus-Host Disease Ethan Strattan and Gerhard Carl Hildebrandt * Division of Hematology and Blood & Marrow Transplant, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; [email protected] * Correspondence: [email protected] Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host disease (GVHD), classified as either acute or chronic GVHD. While the pathology of acute GVHD is better understood, factors driving GVHD at the cellular and molecular level are less clear. Mast cells are an arm of the immune system that are known for atopic disease. However, studies have demonstrated that they can play important roles in tissue homeostasis and wound healing, and mast cell dysregulation can lead to fibrotic disease. Interestingly, in chronic GVHD, aberrant wound healing mechanisms lead to pathological fibrosis, but the cellular etiology driving this is not well-understood, although some studies have implicated mast cells. Given this novel role, we here review the literature for studies of mast cell involvement in the context of chronic GVHD. While there are few publications on this topic, the papers excellently characterized a niche for mast cells in chronic GVHD. These findings may be extended to other fibrosing diseases in order to better target mast cells or their mediators for treatment of fibrotic disease. Citation: Strattan, E.; Hildebrandt, Keywords: mast cells; GVHD; fibrosis; transplant; autoimmune; pathogenesis G.C.
    [Show full text]
  • Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management
    Journal of Clinical Medicine Review Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management Senthil Sukumar 1 , Bernhard Lämmle 2,3,4 and Spero R. Cataland 1,* 1 Division of Hematology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA; [email protected] 2 Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH 3010 Bern, Switzerland; [email protected] 3 Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany 4 Haemostasis Research Unit, University College London, London WC1E 6BT, UK * Correspondence: [email protected] Abstract: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy charac- terized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and im- munosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies Citation: Sukumar, S.; Lämmle, B.; with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial ther- Cataland, S.R.
    [Show full text]