DOCSLIB.ORG

Nasopharyngeal Infection by Streptococcus Pyogenes Requires Superantigen-Responsive Vβ-Specific T Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nasopharyngeal Infection by Streptococcus Pyogenes Requires Superantigen-Responsive Vβ-Specific T Cells Nasopharyngeal infection by Streptococcus pyogenes requires superantigen-responsive Vβ-specific T cells Joseph J. Zeppaa, Katherine J. Kaspera, Ivor Mohorovica, Delfina M. Mazzucaa, S. M. Mansour Haeryfara,b,c,d, and John K. McCormicka,c,d,1 aDepartment of Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada; bDepartment of Medicine, Division of Clinical Immunology & Allergy, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5A5, Canada; cCentre for Human Immunology, Western University, London, ON N6A 5C1, Canada; and dLawson Health Research Institute, London, ON N6C 2R5, Canada Edited by Philippa Marrack, Howard Hughes Medical Institute, National Jewish Health, Denver, CO, and approved July 14, 2017 (received for review January 18, 2017) The globally prominent pathogen Streptococcus pyogenes secretes context of invasive streptococcal disease is extremely dangerous, potent immunomodulatory proteins known as superantigens with a mortality rate of over 30% (10). (SAgs), which engage lateral surfaces of major histocompatibility The role of SAgs in severe human infections has been well class II molecules and T-cell receptor (TCR) β-chain variable domains established (5, 11, 12), and specific MHC-II haplotypes are known (Vβs). These interactions result in the activation of numerous Vβ- risk factors for the development of invasive streptococcal disease specific T cells, which is the defining activity of a SAg. Although (13), an outcome that has been directly linked to SAgs (14, 15). streptococcal SAgs are known virulence factors in scarlet fever However, how these exotoxins contribute to superficial disease and and toxic shock syndrome, mechanisms by how SAgs contribute colonization is less clear. Using experimental murine models estab- to the life cycle of S. pyogenes remain poorly understood. Herein, lished to mimic acute nasopharyngeal infection (16), the expression we demonstrate that passive immunization against the Vβ8-target- of HLAs and that of a specific SAg [i.e., streptococcal pyrogenic ing SAg streptococcal pyrogenic exotoxin A (SpeA), or active immu- exotoxin A (SpeA)], were absolutely required for productive in- nization with either wild-type or a nonfunctional SpeA mutant, fection (17). As the upper respiratory tract is a major niche for protects mice from nasopharyngeal infection; however, only passive S. pyogenes (18), this provided one explanation as to why this path- ogen produces SAgs. Immunization with an MHC-II binding site immunization, or vaccination with inactive SpeA, resulted in high-titer mutant of SpeA also provided initial evidence that anti-SAg anti- SpeA-specific antibodies in vivo. Mice vaccinated with wild-type β + bodies could mediate protection from nasopharyngeal infection (17). SpeA rendered V 8 T cells poorly responsive, which prevented Herein, we provide evidence that passive immunization, infection. This phenotype was reproduced with staphylococcal en- β + or vaccination with a further-attenuated SpeA toxoid, affords terotoxin B, a heterologous SAg that also targets V 8 T cells, antibody-mediated protection in a murine model of S. pyogenes and rendered mice resistant to infection. Furthermore, antibody- nasopharyngeal infection. Furthermore, our vaccination experiments mediated depletion of T cells prevented nasopharyngeal infection also uncovered an antibody-independent protection phenotype by S. pyogenes, but not by Streptococcus pneumoniae, a bacterium whereby vaccination with fully functional SAg induced Vβ-specific that does not produce SAgs. Remarkably, these observations sug- T-cell unresponsiveness. Remarkably, T cells were required for ef- gest that S. pyogenes uses SAgs to manipulate Vβ-specific T cells to ficient S. pyogenes infection. Productive infection resulted in a T-cell– establish nasopharyngeal infection. dependent proinflammatory cytokine microenvironment, which may be beneficial to S. pyogenes, although T-cell depletion did not impact superantigen | Streptococcus pyogenes | T cells | infection | nasopharynx the upper respiratory tract bacterial burden of a non-SAg secreting he globally prominent bacterial pathogen Streptococcus pyo- Significance Tgenes (also commonly referred to as the group A Strepto- coccus) exists primarily as a colonizer within the human upper Superantigen toxins were defined over 25 years ago for their respiratory tract and skin, but is also capable of causing some of ability to activate T cells in a T-cell receptor β-chain variable the most aggressive and invasive infections known. Indeed, up to domain-dependent manner. This “Vβ-specific” T-cell activation 12% of some adolescent populations may be colonized asymp- is the hallmark feature of the superantigen, and although tomatically by S. pyogenes (1); yet, this pathogen remains re- these toxins can mediate dangerous human disease such as sponsible for over 700 million superficial infections, and at least toxic shock syndrome, mechanisms that explain why bacteria 500,000 deaths, primarily due to invasive infections and acquired produce superantigens have remained enigmatic. Herein, we autoimmune manifestations in resource-poor settings (2). De- provide evidence that Streptococcus pyogenes utilizes super- β spite this enormous impact on human populations, there are antigens to target functional, V -specific T cells to promote a currently no vaccines available against this pathogen (3). state of colonization providing a mechanism that helps explain S. pyogenes encodes an impressive repertoire of virulence why bacteria produce toxins that specifically activate T cells of factors that primarily function to disrupt multiple facets of the the adaptive immune system. This work also implicates the host innate immune response (4). However, one family of toxins superantigen exotoxins as potential vaccine candidates against secreted by this organism, known as superantigens (SAgs) (5), this globally important, human-specific pathogen. + + function to specifically target and activate both CD4 and CD8 Author contributions: J.J.Z., K.J.K., S.M.M.H., and J.K.M. designed research; J.J.Z., K.J.K., T cells of the adaptive immune system (6). SAgs function by I.M., and D.M.M. performed research; J.J.Z., K.J.K., and S.M.M.H. contributed new re- bridging lateral surfaces of the MHC class II (MHC-II) molecule agents/analytic tools; J.J.Z., K.J.K., S.M.M.H., and J.K.M. analyzed data; and J.J.Z. and on antigen-presenting cells with the T-cell receptor (TCR) on J.K.M. wrote the paper. T cells, in a TCR variable β-chain (Vβ)-dependent manner. In- The authors declare no conflict of interest. deed, Vβ-specific T-cell activation is the defining feature of the This article is a PNAS Direct Submission. SAg (7) and these unconventional interactions explain how SAgs See Commentary on page 10000. can activate such a large percentage of the total T-cell pop- 1To whom correspondence should be addressed. Email: [email protected]. ulation (8). In rare cases, systemic T-cell activation by SAgs can This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. lead to the streptococcal toxic shock syndrome (9), which in the 1073/pnas.1700858114/-/DCSupplemental. 10226–10231 | PNAS | September 19, 2017 | vol. 114 | no. 38 www.pnas.org/cgi/doi/10.1073/pnas.1700858114 Downloaded by guest on September 27, 2021 organism, Streptococcus pneumoniae. This work supports the use of have been used in vaccination studies (20, 21). Consistent with toxoid SAgs as potential vaccine candidates against S. pyogenes na- this, a model of SpeA in complex with HLA-DQ8 predicted Tyr100 SEE COMMENTARY sopharyngeal infection and indicates that SAgs specifically target and would hydrogen bond with the conserved MHC-II α-chain Lys39 manipulate Vβ-specific T-cell subsets to promote the initiation (Fig. 2A), while the SpeA side chains of Leu41 and Leu42 were of infection. predicted to extend into a pocket formed by the MHC-II α1- domain (Fig. S1). Based on this analysis, we generated a triple Results mutant containing alanine substitutions at all three positions Passive Immunization with SAg-Neutralizing Antibodies Protects Mice (SpeAL41A/L42A/Y100A), henceforth known as SpeATRI (Fig. 2B). from S. pyogenes Nasopharyngeal Infection. The human upper re- SpeATRI was attenuated at all concentrations tested for activating spiratory tract represents the major ecological niche for many B6HLA mouse splenocytes compared with wild-type SpeA (Fig. strains of S. pyogenes (18), and intranasal inoculation of mice has 2C). Next, we used SpeATRI in our vaccination regimen (Fig. 2D) been used to model this environment (16, 19). Previously, we in parallel with wild-type SpeA, or a vehicle (sham) control. In- demonstrated that mouse expression of HLA class II molecules terestingly, mice vaccinated with wild-type SpeA and SpeATRI were both protected from nasopharyngeal infection compared (referred to as B6HLA mice), and S. pyogenes MGAS8232 ex- pression of SpeA, were critical host and bacterial factors, re- with sham-vaccinated mice (Fig. 2E); however, only SpeATRI- spectively, that enhanced nasopharyngeal infection by up to four vaccinated mice generated significant anti-SpeA IgG antibody ti- F orders of magnitude (17). It was also demonstrated that vacci- ters (Fig. 2 ). Low levels of anti-SpeA IgM were only detected in the SpeA -vaccinated mice, while anti-SpeA IgA were not de- nation of these mice with a SpeA MHC-II binding mutant TRI tectable from any group
Load more

Recommended publications
  • The Ligands for Human Igg and Their Effector Functions
    antibodies Review The Ligands for Human IgG and Their Effector Functions Steven W. de Taeye 1,2,*, Theo Rispens 1 and Gestur Vidarsson 2 1 Sanquin Research, Dept Immunopathology and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; [email protected] 2 Sanquin Research, Dept Experimental Immunohematology and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; [email protected] * Correspondence: [email protected] Received: 26 March 2019; Accepted: 18 April 2019; Published: 25 April 2019 Abstract: Activation of the humoral immune system is initiated when antibodies recognize an antigen and trigger effector functions through the interaction with Fc engaging molecules. The most abundant immunoglobulin isotype in serum is Immunoglobulin G (IgG), which is involved in many humoral immune responses, strongly interacting with effector molecules. The IgG subclass, allotype, and glycosylation pattern, among other factors, determine the interaction strength of the IgG-Fc domain with these Fc engaging molecules, and thereby the potential strength of their effector potential. The molecules responsible for the effector phase include the classical IgG-Fc receptors (FcγR), the neonatal Fc-receptor (FcRn), the Tripartite motif-containing protein 21 (TRIM21), the first component of the classical complement cascade (C1), and possibly, the Fc-receptor-like receptors (FcRL4/5). Here we provide an overview of the interactions of IgG with effector molecules and discuss how natural variation on the antibody and effector molecule side shapes the biological activities of antibodies. The increasing knowledge on the Fc-mediated effector functions of antibodies drives the development of better therapeutic antibodies for cancer immunotherapy or treatment of autoimmune diseases.
    [Show full text]
  • The Food Poisoning Toxins of Bacillus Cereus
    toxins Review The Food Poisoning Toxins of Bacillus cereus Richard Dietrich 1,†, Nadja Jessberger 1,*,†, Monika Ehling-Schulz 2 , Erwin Märtlbauer 1 and Per Einar Granum 3 1 Department of Veterinary Sciences, Faculty of Veterinary Medicine, Ludwig Maximilian University of Munich, Schönleutnerstr. 8, 85764 Oberschleißheim, Germany; [email protected] (R.D.); [email protected] (E.M.) 2 Department of Pathobiology, Functional Microbiology, Institute of Microbiology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; [email protected] 3 Department of Food Safety and Infection Biology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. Box 5003 NMBU, 1432 Ås, Norway; [email protected] * Correspondence: [email protected] † These authors have contributed equally to this work. Abstract: Bacillus cereus is a ubiquitous soil bacterium responsible for two types of food-associated gastrointestinal diseases. While the emetic type, a food intoxication, manifests in nausea and vomiting, food infections with enteropathogenic strains cause diarrhea and abdominal pain. Causative toxins are the cyclic dodecadepsipeptide cereulide, and the proteinaceous enterotoxins hemolysin BL (Hbl), nonhemolytic enterotoxin (Nhe) and cytotoxin K (CytK), respectively. This review covers the current knowledge on distribution and genetic organization of the toxin genes, as well as mechanisms of enterotoxin gene regulation and toxin secretion. In this context, the exceptionally high variability of toxin production between single strains is highlighted. In addition, the mode of action of the pore-forming enterotoxins and their effect on target cells is described in detail. The main focus of this review are the two tripartite enterotoxin complexes Hbl and Nhe, but the latest findings on cereulide and CytK are also presented, as well as methods for toxin detection, and the contribution of further putative virulence factors to the diarrheal disease.
    [Show full text]
  • The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections
    toxins Review The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections Patience Shumba 1, Srikanth Mairpady Shambat 2 and Nikolai Siemens 1,* 1 Center for Functional Genomics of Microbes, Department of Molecular Genetics and Infection Biology, University of Greifswald, D-17489 Greifswald, Germany; [email protected] 2 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland; [email protected] * Correspondence: [email protected]; Tel.: +49-3834-420-5711 Received: 20 May 2019; Accepted: 10 June 2019; Published: 11 June 2019 Abstract: Necrotizing soft tissue infections (NSTIs) are critical clinical conditions characterized by extensive necrosis of any layer of the soft tissue and systemic toxicity. Group A streptococci (GAS) and Staphylococcus aureus are two major pathogens associated with monomicrobial NSTIs. In the tissue environment, both Gram-positive bacteria secrete a variety of molecules, including pore-forming exotoxins, superantigens, and proteases with cytolytic and immunomodulatory functions. The present review summarizes the current knowledge about streptococcal and staphylococcal toxins in NSTIs with a special focus on their contribution to disease progression, tissue pathology, and immune evasion strategies. Keywords: Streptococcus pyogenes; group A streptococcus; Staphylococcus aureus; skin infections; necrotizing soft tissue infections; pore-forming toxins; superantigens; immunomodulatory proteases; immune responses Key Contribution: Group A streptococcal and Staphylococcus aureus toxins manipulate host physiological and immunological responses to promote disease severity and progression. 1. Introduction Necrotizing soft tissue infections (NSTIs) are rare and represent a more severe rapidly progressing form of soft tissue infections that account for significant morbidity and mortality [1].
    [Show full text]
  • How Do Pathogenic Microorganisms Develop Cross-Kingdom Host Jumps? Peter Van Baarlen1, Alex Van Belkum2, Richard C
    Molecular mechanisms of pathogenicity: how do pathogenic microorganisms develop cross-kingdom host jumps? Peter van Baarlen1, Alex van Belkum2, Richard C. Summerbell3, Pedro W. Crous3 & Bart P.H.J. Thomma1 1Laboratory of Phytopathology, Wageningen University, Wageningen, The Netherlands; 2Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands; and 3CBS Fungal Biodiversity Centre, Utrecht, The Netherlands Correspondence: Bart P.H.J. Thomma, Abstract Downloaded from https://academic.oup.com/femsre/article/31/3/239/2367343 by guest on 27 September 2021 Laboratory of Phytopathology, Wageningen University, Binnenhaven 5, 6709 PD It is common knowledge that pathogenic viruses can change hosts, with avian Wageningen, The Netherlands. Tel.: 10031 influenza, the HIV, and the causal agent of variant Creutzfeldt–Jacob encephalitis 317 484536; fax: 10031 317 483412; as well-known examples. Less well known, however, is that host jumps also occur e-mail: [email protected] with more complex pathogenic microorganisms such as bacteria and fungi. In extreme cases, these host jumps even cross kingdom of life barriers. A number of Received 3 July 2006; revised 22 December requirements need to be met to enable a microorganism to cross such kingdom 2006; accepted 23 December 2006. barriers. Potential cross-kingdom pathogenic microorganisms must be able to First published online 26 February 2007. come into close and frequent contact with potential hosts, and must be able to overcome or evade host defences. Reproduction on, in, or near the new host will DOI:10.1111/j.1574-6976.2007.00065.x ensure the transmission or release of successful genotypes.
    [Show full text]
  • Biological Toxins As the Potential Tools for Bioterrorism
    International Journal of Molecular Sciences Review Biological Toxins as the Potential Tools for Bioterrorism Edyta Janik 1, Michal Ceremuga 2, Joanna Saluk-Bijak 1 and Michal Bijak 1,* 1 Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] (E.J.); [email protected] (J.S.-B.) 2 CBRN Reconnaissance and Decontamination Department, Military Institute of Chemistry and Radiometry, Antoniego Chrusciela “Montera” 105, 00-910 Warsaw, Poland; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +48-(0)426354336 Received: 3 February 2019; Accepted: 3 March 2019; Published: 8 March 2019 Abstract: Biological toxins are a heterogeneous group produced by living organisms. One dictionary defines them as “Chemicals produced by living organisms that have toxic properties for another organism”. Toxins are very attractive to terrorists for use in acts of bioterrorism. The first reason is that many biological toxins can be obtained very easily. Simple bacterial culturing systems and extraction equipment dedicated to plant toxins are cheap and easily available, and can even be constructed at home. Many toxins affect the nervous systems of mammals by interfering with the transmission of nerve impulses, which gives them their high potential in bioterrorist attacks. Others are responsible for blockage of main cellular metabolism, causing cellular death. Moreover, most toxins act very quickly and are lethal in low doses (LD50 < 25 mg/kg), which are very often lower than chemical warfare agents. For these reasons we decided to prepare this review paper which main aim is to present the high potential of biological toxins as factors of bioterrorism describing the general characteristics, mechanisms of action and treatment of most potent biological toxins.
    [Show full text]
  • From Phagosome Into the Cytoplasm on Cytolysin, Listeriolysin O, After Evasion Listeria Monocytogenes in Macrophages by Dependen
    Dependency of Caspase-1 Activation Induced in Macrophages by Listeria monocytogenes on Cytolysin, Listeriolysin O, after Evasion from Phagosome into the Cytoplasm This information is current as of September 23, 2021. Hideki Hara, Kohsuke Tsuchiya, Takamasa Nomura, Ikuo Kawamura, Shereen Shoma and Masao Mitsuyama J Immunol 2008; 180:7859-7868; ; doi: 10.4049/jimmunol.180.12.7859 http://www.jimmunol.org/content/180/12/7859 Downloaded from References This article cites 50 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/180/12/7859.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 23, 2021 *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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dependency of Caspase-1 Activation Induced in Macrophages by Listeria monocytogenes on Cytolysin, Listeriolysin O, after Evasion from Phagosome into the Cytoplasm1 Hideki Hara, Kohsuke Tsuchiya, Takamasa Nomura, Ikuo Kawamura, Shereen Shoma, and Masao Mitsuyama2 Listeriolysin O (LLO), an hly-encoded cytolysin from Listeria monocytogenes, plays an essential role in the entry of this pathogen into the macrophage cytoplasm and is also a key factor in inducing the production of IFN-␥ during the innate immune stage of infection.
    [Show full text]
  • Medical Management of Biologic Casualties Handbook
    USAMRIID’s MEDICAL MANAGEMENT OF BIOLOGICAL CASUALTIES HANDBOOK Fourth Edition February 2001 U.S. ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES ¨ FORT DETRICK FREDERICK, MARYLAND 1 Sources of information: National Response Center 1-800-424-8802 or (for chem/bio hazards & terrorist events) 1-202-267-2675 National Domestic Preparedness Office: 1-202-324-9025 (for civilian use) Domestic Preparedness Chem/Bio Help line: 1-410-436-4484 or (Edgewood Ops Center - for military use) DSN 584-4484 USAMRIID Emergency Response Line: 1-888-872-7443 CDC'S Bioterrorism Preparedness and Response Center: 1-770-488-7100 John's Hopkins Center for Civilian Biodefense: 1-410-223-1667 (Civilian Biodefense Studies) An Adobe Acrobat Reader (pdf file) version and a Palm OS Electronic version of this Handbook can both be downloaded from the Internet at: http://www.usamriid.army.mil/education/bluebook.html 2 USAMRIID’s MEDICAL MANAGEMENT OF BIOLOGICAL CASUALTIES HANDBOOK Fourth Edition February 2001 Editors: LTC Mark Kortepeter LTC George Christopher COL Ted Cieslak CDR Randall Culpepper CDR Robert Darling MAJ Julie Pavlin LTC John Rowe COL Kelly McKee, Jr. COL Edward Eitzen, Jr. Comments and suggestions are appreciated and should be addressed to: Operational Medicine Department Attn: MCMR-UIM-O U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) Fort Detrick, Maryland 21702-5011 3 PREFACE TO THE FOURTH EDITION The Medical Management of Biological Casualties Handbook, which has become affectionately known as the "Blue Book," has been enormously successful - far beyond our expectations. Since the first edition in 1993, the awareness of biological weapons in the United States has increased dramatically.
    [Show full text]
  • Introduction to Bacteriology and Bacterial Structure/Function
    INTRODUCTION TO BACTERIOLOGY AND BACTERIAL STRUCTURE/FUNCTION LEARNING OBJECTIVES To describe historical landmarks of medical microbiology To describe Koch’s Postulates To describe the characteristic structures and chemical nature of cellular constituents that distinguish eukaryotic and prokaryotic cells To describe chemical, structural, and functional components of the bacterial cytoplasmic and outer membranes, cell wall and surface appendages To name the general structures, and polymers that make up bacterial cell walls To explain the differences between gram negative and gram positive cells To describe the chemical composition, function and serological classification as H antigen of bacterial flagella and how they differ from flagella of eucaryotic cells To describe the chemical composition and function of pili To explain the unique chemical composition of bacterial spores To list medically relevant bacteria that form spores To explain the function of spores in terms of chemical and heat resistance To describe characteristics of different types of membrane transport To describe the exact cellular location and serological classification as O antigen of Lipopolysaccharide (LPS) To explain how the structure of LPS confers antigenic specificity and toxicity To describe the exact cellular location of Lipid A To explain the term endotoxin in terms of its chemical composition and location in bacterial cells INTRODUCTION TO BACTERIOLOGY 1. Two main threads in the history of bacteriology: 1) the natural history of bacteria and 2) the contagious nature of infectious diseases, were united in the latter half of the 19th century. During that period many of the bacteria that cause human disease were identified and characterized. 2. Individual bacteria were first observed microscopically by Antony van Leeuwenhoek at the end of the 17th century.
    [Show full text]
  • SARS-Cov-2 As a Superantigen in Multisystem Inflammatory Syndrome in Children (MIS-C)
    SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children (MIS-C) Theodore Kouo, Worarat Chaisawangwong J Clin Invest. 2021. https://doi.org/10.1172/JCI149327. Commentary In-Press Preview Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation, shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt, Paschold, and Rivas et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCR beta variable gene segments (TRBV) may identify patients at risk for severe MIS-C. Find the latest version: https://jci.me/149327/pdf SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children (MIS-C) Theodore Kouo1 and Worarat Chaisawangwong2 1Department of Pediatrics, Division of Emergency Medicine, 2Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Address correspondence to: Theodore Kouo Johns Hopkins Children’s Center 1800 Orleans Street, G1509 Phone: 410-955-6146 Email: [email protected] COI Statement: The authors declare that no conflict of interest exists. Abstract Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation, shock, and can lead to multiple organ failure if unrecognized.
    [Show full text]
  • Medical Management of Biological Casualties Handbook
    USAMRIID’s MEDICAL MANAGEMENT OF BIOLOGICAL CASUALTIES HANDBOOK Sixth Edition April 2005 U.S. ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES FORT DETRICK FREDERICK, MARYLAND Emergency Response Numbers National Response Center: 1-800-424-8802 or (for chem/bio hazards & terrorist events) 1-202-267-2675 National Domestic Preparedness Office: 1-202-324-9025 (for civilian use) Domestic Preparedness Chem/Bio Helpline: 1-410-436-4484 or (Edgewood Ops Center – for military use) DSN 584-4484 USAMRIID’s Emergency Response Line: 1-888-872-7443 CDC'S Emergency Response Line: 1-770-488-7100 Handbook Download Site An Adobe Acrobat Reader (pdf file) version of this handbook can be downloaded from the internet at the following url: http://www.usamriid.army.mil USAMRIID’s MEDICAL MANAGEMENT OF BIOLOGICAL CASUALTIES HANDBOOK Sixth Edition April 2005 Lead Editor Lt Col Jon B. Woods, MC, USAF Contributing Editors CAPT Robert G. Darling, MC, USN LTC Zygmunt F. Dembek, MS, USAR Lt Col Bridget K. Carr, MSC, USAF COL Ted J. Cieslak, MC, USA LCDR James V. Lawler, MC, USN MAJ Anthony C. Littrell, MC, USA LTC Mark G. Kortepeter, MC, USA LTC Nelson W. Rebert, MS, USA LTC Scott A. Stanek, MC, USA COL James W. Martin, MC, USA Comments and suggestions are appreciated and should be addressed to: Operational Medicine Department Attn: MCMR-UIM-O U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) Fort Detrick, Maryland 21702-5011 PREFACE TO THE SIXTH EDITION The Medical Management of Biological Casualties Handbook, which has become affectionately known as the "Blue Book," has been enormously successful - far beyond our expectations.
    [Show full text]
  • B Cell Checkpoints in Autoimmune Rheumatic Diseases
    REVIEWS B cell checkpoints in autoimmune rheumatic diseases Samuel J. S. Rubin1,2,3, Michelle S. Bloom1,2,3 and William H. Robinson1,2,3* Abstract | B cells have important functions in the pathogenesis of autoimmune diseases, including autoimmune rheumatic diseases. In addition to producing autoantibodies, B cells contribute to autoimmunity by serving as professional antigen- presenting cells (APCs), producing cytokines, and through additional mechanisms. B cell activation and effector functions are regulated by immune checkpoints, including both activating and inhibitory checkpoint receptors that contribute to the regulation of B cell tolerance, activation, antigen presentation, T cell help, class switching, antibody production and cytokine production. The various activating checkpoint receptors include B cell activating receptors that engage with cognate receptors on T cells or other cells, as well as Toll-like receptors that can provide dual stimulation to B cells via co- engagement with the B cell receptor. Furthermore, various inhibitory checkpoint receptors, including B cell inhibitory receptors, have important functions in regulating B cell development, activation and effector functions. Therapeutically targeting B cell checkpoints represents a promising strategy for the treatment of a variety of autoimmune rheumatic diseases. Antibody- dependent B cells are multifunctional lymphocytes that contribute that serve as precursors to and thereby give rise to acti- cell- mediated cytotoxicity to the pathogenesis of autoimmune diseases
    [Show full text]
  • The Adaptive Immune Response B-Cells
    The Adaptive Immune Response B-cells The innate immune system provides immediate protection. The adaptive response takes time to develop and is antigen specific. Activation of B and T lymphocytes Naive Plasma cells Naive ADAPTIVE IMMUNITY The adaptive immune system consists of lymphocytes and their products, including antibodies. The receptors of lymphocytes are much more diverse than those of the innate immune system, but lymphocytes are not inherently specific for microbes, and they are capable of recognizing a vast array of foreign substances. http://www.pathologystudent.com/wp- content/uploads/2010/07/normal-lymphs.jpg There are two types of adaptive Immunity Humoral immunity: mediated by B lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig) that protects against extracellular microbes and their toxins. Cellular immunity: mediated by T lymphocytes and is responsible for defense against intracellular microbes. content/uploads/2011/05/adoptive_immunity.gif - sheng.com/wp - http://yang Types of Adaptive Immune Reponses Lymphocytes Although lymphocytes appear morphologically unimpressive and similar to one another, they are actually remarkably heterogeneous and specialized in molecular properties and functions. Lymphocytes and other cells involved in immune responses are not fixed in particular tissues (as are cells in most of the organs of the body) but are capable of migrating among lymphoid and other tissues and the vascular and lymphatic circulations. This feature permits lymphocytes to home to any site of infection. In lymphoid organs, different classes of lymphocytes are anatomically segregated in such a way that they interact with one another only when stimulated to do so by encounter with antigens and other stimuli.
    [Show full text]