Persistent Eosinophilia Is a Challenging Problem
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Four Diseases, PLAID, APLAID, FCAS3 and CVID and One Gene
Four diseases, PLAID, APLAID, FCAS3 and CVID and one gene (PHOSPHOLIPASE C, GAMMA-2; PLCG2 ) : striking clinical phenotypic overlap and difference Necil Kutukculer1, Ezgi Yilmaz1, Afig Berdeli1, Raziye Burcu G¨uven Bilgin1, Ayca Aykut1, Asude Durmaz1, Ozgur Cogulu1, G¨uzideAksu1, and Neslihan Karaca1 1Ege University Faculty of Medicine May 15, 2020 Abstract We suggest PLAID,APLAID and FCAS3 have to be considered as same diseases,because of our long-term clinical experiences and genetic results in six patients.Small proportion of CVID patients are also PLAID/APLAID/FCAS3 patients and all these have disease-causing-mutations in PLCG2-genes,so it may be better to define all of them as “PLCG2 deficiency”. Key Clinical Message: Germline mutations in PLCG2 gene cause PLAID,APLAID,FCAS3, and CVID.Clinical experiences in patients with PLCG2 mutations led us to consider that PLAID, APLAID and FCAS3 are same diseases.It may be better to define all of them as “PLCG2 deficiency”. INTRODUCTION The PLCG2 gene which is located on the 16th chromosome (16q23.3) encodes phospholipase Cg2 (PLCG2), a transmembrane signaling enzyme that catalyzes the production of second messenger molecules utilizing calcium as a cofactor and propagates downstream signals in several hematopoietic cells (1). Recently, het- erozygous germline mutations in human PLCG2 were linked to some clinical phenotypes with some overlap- ping features|PLCg2-associated antibody deficiency and immune dysregulation syndrome (PLAID) (OMIM 614878) and autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID) (OMIM 614878) (2-4) and familial cold autoinflammatory syndrome (FCAS3) (OMIM 614468) (5). All of them are autosomal dominant inherited diseases. -
My Beloved Neutrophil Dr Boxer 2014 Neutropenia Family Conference
The Beloved Neutrophil: Its Function in Health and Disease Stem Cell Multipotent Progenitor Myeloid Lymphoid CMP IL-3, SCF, GM-CSF CLP Committed Progenitor MEP GMP GM-CSF, IL-3, SCF EPO TPO G-CSF M-CSF IL-5 IL-3 SCF RBC Platelet Neutrophil Monocyte/ Basophil B-cells Macrophage Eosinophil T-Cells Mast cell NK cells Mature Cell Dendritic cells PRODUCTION AND KINETICS OF NEUTROPHILS CELLS % CELLS TIME Bone Marrow: Myeloblast 1 7 - 9 Mitotic Promyelocyte 4 Days Myelocyte 16 Maturation/ Metamyelocyte 22 3 – 7 Storage Band 30 Days Seg 21 Vascular: Peripheral Blood Seg 2 6 – 12 hours 3 Marginating Pool Apoptosis and ? Tissue clearance by 0 – 3 macrophages days PHAGOCYTOSIS 1. Mobilization 2. Chemotaxis 3. Recognition (Opsonization) 4. Ingestion 5. Degranulation 6. Peroxidation 7. Killing and Digestion 8. Net formation Adhesion: β 2 Integrins ▪ Heterodimer of a and b chain ▪ Tight adhesion, migration, ingestion, co- stimulation of other PMN responses LFA-1 Mac-1 (CR3) p150,95 a2b2 a CD11a CD11b CD11c CD11d b CD18 CD18 CD18 CD18 Cells All PMN, Dendritic Mac, mono, leukocytes mono/mac, PMN, T cell LGL Ligands ICAMs ICAM-1 C3bi, ICAM-3, C3bi other other Fibrinogen other GRANULOCYTE CHEMOATTRACTANTS Chemoattractants Source Activators Lipids PAF Neutrophils C5a, LPS, FMLP Endothelium LTB4 Neutrophils FMLP, C5a, LPS Chemokines (a) IL-8 Monocytes, endothelium LPS, IL-1, TNF, IL-3 other cells Gro a, b, g Monocytes, endothelium IL-1, TNF other cells NAP-2 Activated platelets Platelet activation Others FMLP Bacteria C5a Activation of complement Other Important Receptors on PMNs ñ Pattern recognition receptors – Detect microbes - Toll receptor family - Mannose receptor - bGlucan receptor – fungal cell walls ñ Cytokine receptors – enhance PMN function - G-CSF, GM-CSF - TNF Receptor ñ Opsonin receptors – trigger phagocytosis - FcgRI, II, III - Complement receptors – ñ Mac1/CR3 (CD11b/CD18) – C3bi ñ CR-1 – C3b, C4b, C3bi, C1q, Mannose binding protein From JG Hirsch, J Exp Med 116:827, 1962, with permission. -
Abstract: Age-Related Immune Dysregulation and Increases In
Abstract: Age-related immune dysregulation and increases in inflammation, termed inflammaging, have been consistently implicated in most common age-related diseases, but the precise etiology of inter- individual differences in inflammaging are unknown. Changes in immunity and inflammation occur throughout the life course, but research on these processes among non-elderly populations has been limited. This is important because identifying sources of biological aging and inflammation before individuals reach older age may help identify points for intervention. The composition of the gut microbiota has been shown in animal models to have profound influence over, and interactions with, the immune system. Findings from germ-free mice suggest that commensal gut microbes are a key cause of inflammaging, but this hypothesis has not been well explored in humans. There are currently very few data examining how the microbiome relates to the fundamental aspects of aging biology, specifically inflammatory phenotypes and genomic markers of biological age. We propose to fill gaps in current microbiome research on aging, through the collection and analysis of oral and gut microbiome data in The National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative longitudinal cohort of adults with extensive social environment data and existing or ongoing analyses of genomic and phenotypic markers of inflammation and aging. The specific aims include the: 1) Collection of tongue and stool specimens with which to characterize the oral and gut microbiome in a nationally-representative sample (N ~10,155) of Add Health participants (mean age ~40); 2) Testing the association between the microbiome and biomarkers of aging and inflammation, and the creation of a novel “microbiome age clock”; 3) Examination of the relationships between life course exposures and microbiome species related to biomarkers of aging and inflammation as an adult; 4) Documentation and dissemination of data generated from this project. -
Hyperleukocytosis (Re)Visited- Is It Case Series Always Leukaemia: a Report of Two Pathology Section Cases and Review of Literature Short Communication
Review Article Clinician’s corner Original Article Images in Medicine Experimental Research Miscellaneous Letter to Editor DOI: 10.7860/JCDR/2020/40556.13409 Case Report Postgraduate Education Hyperleukocytosis (Re)Visited- Is it Case Series always Leukaemia: A Report of Two Pathology Section Cases and Review of Literature Short Communication ASHUTOSH RATH1, RICHA GUPTA2 ABSTRACT Hyperleukocytosis is defined as total leukocyte count of more than 100×109/L. Commonly seen in leukaemic conditions, non- leukaemic causes are usually not encountered and thought of. We report two such non-malignant cases of hyperleukocytosis. A six-year old girl presented with fever, cough and respiratory distress with a leukocyte count of 125.97×109/L. Another case is of a two-month old female infant, who presented with fever and respiratory distress and a leukocyte count of 112.27×109/L. The present case thrives to highlight various possible causes of hyperleukocytosis with an emphasis on non-malignant causes. Also, important complications and management of hyperleukocytosis are discussed. Keywords: Benign, Leukocytosis, Leukostasis CASE REPORT 1 for methicillin-resistant Staphylococcus aureus and was started A six-year-old girl was admitted with complaints of fever, non- on intravenous Vancomycin along with supportive care. Serial productive cough for one week and severe respiratory distress for monitoring of TLC revealed a gradual reduction and it returned to the the past one day. There was no other significant history. On physical baseline of 15×109/L after eight days. The patient was discharged examination, the patient had mild pallor. Respiratory examination after 10 days of hospital stay. -
Harnessing the Immune System to Overcome Cytokine Storm And
Khadke et al. Virol J (2020) 17:154 https://doi.org/10.1186/s12985-020-01415-w REVIEW Open Access Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents Sumanth Khadke1, Nayla Ahmed2, Nausheen Ahmed3, Ryan Ratts2,4, Shine Raju5, Molly Gallogly6, Marcos de Lima6 and Muhammad Rizwan Sohail7* Abstract Background: Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. Discussion: We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It efectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. -
Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency
Practice parameter Practice parameter for the diagnosis and management of primary immunodeficiency Francisco A. Bonilla, MD, PhD, David A. Khan, MD, Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD, David I. Bernstein, MD, Joann Blessing-Moore, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Chief Editor: Francisco A. Bonilla, MD, PhD Co-Editor: David A. Khan, MD Members of the Joint Task Force on Practice Parameters: David I. Bernstein, MD, Joann Blessing-Moore, MD, David Khan, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Primary Immunodeficiency Workgroup: Chairman: Francisco A. Bonilla, MD, PhD Members: Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD GlaxoSmithKline, Merck, and Aerocrine; has received payment for lectures from Genentech/ These parameters were developed by the Joint Task Force on Practice Parameters, representing Novartis, GlaxoSmithKline, and Merck; and has received research support from Genentech/ the American Academy of Allergy, Asthma & Immunology; the American College of Novartis and Merck. -
Primary Immunodeficiency Disorders
ALLERGY AND IMMUNOLOGY 00954543 /98 $8.00 + .OO PRIMARY IMMUNODEFICIENCY DISORDERS Robert J. Mamlok, MD Immunodeficiency is a common thought among both patients and physicians when confronted with what is perceived as an excessive num- ber, duration, or severity of infections. Because of this, the starting point for evaluating patients for suspected immunodeficiency is based on what constitutes ”too many infections.” It generally is agreed that children with normal immune systems may have an average of 6 to 8 respiratory tract infections per year for the first decade of life. Even after a pattern of ab- normal infection is established, questions of secondary immunodeficiency should first be raised. The relatively uncommon primary immunodefi- ciency diseases are statistically dwarfed by secondary causes of recurrent infection, such as malnutrition, respiratory allergy, chronic cardiovascular, pulmonary, and renal disease, and environmental factors. On the other hand, a dizzying spiral of progress in our understanding of the genetics and immunology of primary immunodeficiency disease has resulted in improved diagnostic and therapeutic tools. Twenty-five newly recognized immunologic disease genes have been cloned in the last 5 ~ears.2~It has become arguably more important than ever for us to recognize the clinical and laboratory features of these relatively uncommon, but increasingly treatable, disorders. CLASSIFICATION The immune system has been classically divided into four separate arms: The B-cell system responsible for antibody formation, the T-cell sys- From the Division of Pediatric Allergy and Immunology, Texas Tech University Health Sci- ences Center, Lubbock, Texas PRIMARY CARE VOLUME 25 NUMBER 4 DECEMBER 1998 739 740 MAMLOK tem responsible for immune cellular regulation, the phagocytic (poly- morphonuclear and mononuclear) system and the complement (opsonic) system. -
Immune Dysfunction and Neuroinflammation in Autism
Review Acta Neurobiol Exp 2016, 76: 257–268 Immune dysfunction and neuroinflammation in autism spectrum disorder Geir Bjørklund1*, Khaled Saad2, Salvatore Chirumbolo3, Janet K. Kern4, David A. Geier4, Mark R. Geier4, and Mauricio A. Urbina5 1 Council for Nutritional and Environmental Medicine, Mo i Rana, Norway, 2 Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt, 3 Department of Neurological and Movement Science, University of Verona, Verona, Italy, 4 Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA, 5 Departamento de Zoología, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción, Chile, * Email: [email protected] Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder with a complex pathogenesis. Many studies over the last four decades have recognized altered immune responses among individuals diagnosed with ASD. The purpose of this critical and comprehensive review is to examine the hypothesis that immune dysfunction is frequently present in those with ASD. It was found that often individuals diagnosed with ASD have alterations in immune cells such as T cells, B cells, monocytes, natural killer cells, and dendritic cells. Also, many individuals diagnosed with ASD have alterations in immunoglobulins and increased autoantibodies. Finally, a significant portion of individuals diagnosed with ASD have elevated peripheral cytokines and chemokines and associated neuroinflammation. In conclusion, immune dysregulation and inflammation are important components in the diagnosis and treatment of ASD. Key words: autism, cytokines, innate immunity, neuroinflammation INTRODUCTION a fundamental role in ASD development, despite some concern about whether it causes ASD onset or regulates Autism spectrum disorder (ASD) is considered ASD pathogenesis and symptomatology. -
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, -
Reptile Clinical Pathology Vickie Joseph, DVM, DABVP (Avian)
Reptile Clinical Pathology Vickie Joseph, DVM, DABVP (Avian) Session #121 Affiliation: From the Bird & Pet Clinic of Roseville, 3985 Foothills Blvd. Roseville, CA 95747, USA and IDEXX Laboratories, 2825 KOVR Drive, West Sacramento, CA 95605, USA. Abstract: Hematology and chemistry values of the reptile may be influenced by extrinsic and intrinsic factors. Proper processing of the blood sample is imperative to preserve cell morphology and limit sample artifacts. Identifying the abnormal changes in the hemogram and biochemistries associated with anemia, hemoparasites, septicemias and neoplastic disorders will aid in the prognostic and therapeutic decisions. Introduction Evaluating the reptile hemogram is challenging. Extrinsic factors (season, temperature, habitat, diet, disease, stress, venipuncture site) and intrinsic factors (species, gender, age, physiologic status) will affect the hemogram numbers, distribution of the leukocytes and the reptile’s response to disease. Certain procedures should be ad- hered to when drawing and processing the blood sample to preserve cell morphology and limit sample artifact. The goal of this paper is to briefly review reptile red blood cell and white blood cell identification, normal cell morphology and terminology. A detailed explanation of abnormal changes seen in the hemogram and biochem- istries in response to anemia, hemoparasites, septicemias and neoplasia will be addressed. Hematology and Chemistries Blood collection and preparation Although it is not the scope of this paper to address sites of blood collection and sample preparation, a few im- portant points need to be explained. For best results to preserve cell morphology and decrease sample artifacts, hematologic testing should be performed as soon as possible following blood collection. -
Bronchopulmonary Aspergillosis
Thorax: first published as 10.1136/thx.44.11.919 on 1 November 1989. Downloaded from Thorax 1989;44:919-924 Pulmonary eosinophilia with and without allergic bronchopulmonary aspergillosis B J CHAPMAN, S CAPEWELL, R GIBSON, A P GREENING, G K CROMPTON From the Respiratory Unit, Northern General Hospital, Edinburgh ABSTRACT Sixty five patients with pulmonary eosinophilia attending one respiratory unit were reviewed. All had fleeting radiographic abnormalities and peripheral blood eosinophil counts greater than 500 x 106/1. Eighteen had a single episode and 47 recurrent episodes during a median follow up period of 14 years. Thirty three patients had allergic bronchopulmonary aspergillosis on the basis of a positive skin test response to Aspergillusfumigatus, serum precipitins, or culture ofAfumigatus from sputum, or a combination of these. All but seven patients had asthma, six of the seven being in the group who did not have allergic bronchopulmonary aspergillosis. The patients with allergic bronchopulmonary aspergillosis were more often male and had a greater incidence ofasthma and an earlier age of onset of asthma than those without aspergillosis. The patients with aspergillosis had lower mean blood eosinophil counts and more episodes of pulmonary eosinophilia and more commonly had radiographic shadowing that suggested fibrosis or bronchiectasis (20 v 7). Pulmonary eosinophilia associated with allergic bronchopulmonary aspergillosis appears to be a distinct clinical syndrome resulting in greater permanent radiographic abnormality despite lower peripheral blood eosinophil counts. copyright. Introduction ated from secondary and tertiary referral centres, which makes it difficult to estimate the relative The term pulmonary eosinophilia describes a group of frequency of the various underlying conditions. -
Social Change, Parasite Exposure, and Immune Dysregulation
SOCIAL CHANGE, PARASITE EXPOSURE, AND IMMUNE DYSREGULATION AMONG SHUAR FORAGER-HORTICULTURALISTS OF AMAZONIA: A BIOCULTURAL CASE-STUDY IN EVOLUTIONARY MEDICINE by TARA CEPON ROBINS A DISSERTATION Presented to the Department of Anthropology and the Graduate School of the University of Oregon in partial fulfillment of the requirements for the degree of Doctor of Philosophy June 2015 DISSERTATION APPROVAL PAGE Student: Tara Cepon Robins Title: Social Change, Parasite Exposure, and Immune Dysregulation among Shuar Forager-Horticulturalists of Amazonia: A Biocultural Case-Study in Evolutionary Medicine This dissertation has been accepted and approved in partial fulfillment of the requirements for the Doctor of Philosophy degree in the Department of Anthropology by: J. Josh Snodgrass Chairperson Lawrence S. Sugiyama Core Member Frances J. White Core Member Brendan J.M. Bohannan Institutional Representative and Scott L. Pratt Dean of the Graduate School Original approval signatures are on file with the University of Oregon Graduate School. Degree awarded June 2015 ii © 2015 Tara Cepon Robins iii DISSERTATION ABSTRACT Tara Cepon Robins Doctor of Philosophy Department of Anthropology June 2015 Title: Social Change, Parasite Exposure, and Immune Dysregulation among Shuar Forager-Horticulturalists of Amazonia: A Biocultural Case-Study in Evolutionary Medicine The Hygiene Hypothesis and Old Friends Hypothesis focus attention on the coevolutionary relationship between humans and pathogens, positing that reduced pathogen exposure in economically developed