DOCSLIB.ORG

Complement and Antibody-Mediated Enhancement of Red Blood Cell Invasion by Plasmodium Falciparum

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Complement and Antibody-Mediated Enhancement of Red Blood Cell Invasion by Plasmodium Falciparum The Pennsylvania State University The Graduate School College of Medicine COMPLEMENT AND ANTIBODY-MEDIATED ENHANCEMENT OF RED BLOOD CELL INVASION BY PLASMODIUM FALCIPARUM A Dissertation in Microbiology and Immunology by Sergei Sergeievich Biryukov 2016 Sergei Sergeievich Biryukov Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2016 The dissertation of Sergei Sergeievich Biryukov was reviewed and approved* by the following: Jose Stoute Professor of Medicine, and Microbiology and Immunology Dissertation Advisor Chair of Committee David J. Spector Professor Emeritus of Microbiology and Immunology Todd Schell Associate Professor of Microbiology and Immunology Neil Christensen Professor of Pathology, and Microbiology and Immunology Channe Gowda Professor of Biochemistry and Molecular Biology Aron Lukacher Professor and Chair of Microbiology and Immunology *Signatures are on file in the Graduate School ii Abstract Plasmodium falciparum malaria is responsible for close to one million deaths worldwide each year. The Plasmodium life cycle involves invasion of hepatocytes and erythrocytes. The repeating cycle of erythrocyte invasion and destruction is the root cause of the morbidity and mortality brought about by the pathogen. Development of naturally acquired immunity against the parasite is an extremely slow process taking years to decades to develop, and it does not seem to result in sterile immunity. Attempts to develop a vaccine to block erythrocyte invasion have proven unsuccessful. Clinical data have demonstrated the development of a strong humoral immune response in vaccinated individuals. Although antibodies raised against vaccine antigens inhibit invasion in vitro in the presence of heat-inactivated (HI) serum, there is poor efficacy in vivo. The reasons for this discrepancy are unknown. A number of studies, in both humans and animal models, have shown that the complement cascade is activated during malaria infection. We hypothesize that complement activation and opsonization of merozoites enhances complement receptor 1 (CR1)-mediated invasion of erythrocytes. If we are correct, the parasite can hijack this arm of the innate immune response for its own benefit, avoiding or diminishing the efficacy of antibodies. We tested this hypothesis by studying the effect of mouse monoclonal anti-merozoite surface protein 1 (MSP-1) antibody 5.2 (mAb5.2) and antibodies from recipients of a merozoite vaccine (MSP142) for their ability to enhance or inhibit invasion in a complement-dependent manner. We carried out invasion assays with the above antibodies with appropriate controls in fresh or HI serum, or in complement-depleted or reconstituted serum. In addition, we tested iii the relevance of the CR1 pathway by inhibiting with sCR1. Invasion of erythrocytes was enhanced by fresh serum relative to 3 min, 5 min, or 30 min HI serum. Furthermore, addition of mAb5.2 to fresh serum increased the enhancement effect. Addition of C2 and Factor B to 3 min HI serum, but not to 30 min, rescued the enhancement of invasion in the presence of mAb5.2. Likewise, Compstatin, a C3 specific inhibitor, and sCR1 negated the enhancing affects of mAb5.2 in fresh serum but not that of fresh serum alone. Furthermore, soluble CR1 had invasion inhibitory activity in 3 min HI serum that was independent of antibody. Purified antibodies from MSP-1 vaccinees showed inhibitory activity in C3/C4 inactivated serum, but inhibition was drastically reduced in C3/C4 reconstituted serum. Passive transfer of anti-P. berghei antibodies into wild type mice enhanced parasitemia in an inverse dose-dependent manner. In addition, C3-deficient mice showed decreased parasite growth relative to wild type mice. In addition, we utilized erythrocytes from individuals with paroxysmal nocturnal hemoglobinuria (PNH), which results in the absence of glycosylphosphatidylinositol (GPI)-anchored receptors, in an effort to identify novel receptors utilized by the parasite for erythrocyte invasion. We found that PNH RBCs were invaded less effectively than wild type RBCs. Therefore, we carried out growth and invasion assays with anti-GPI erythrocyte receptor antibodies against six potential targets with appropriate controls in fresh or HI serum, or in complement-depleted or reconstituted serum. We identified Semaphorin-7A (SEMA7A) as a potential erythrocyte receptor that may interact with complement in promoting erythrocyte invasion by merozoites. iv Our results demonstrate that merozoites can highjack the complement system to their own advantage in a number of ways. Activation of the complement cascade via the classical pathway can allow merozoites to bind to CR1 and invade via this pathway. In addition, in the absence of antibodies, activation of the mannose binding lectin pathway by default may allow merozoites to bind to other complement receptors on the RBC that mediate invasion. Such mechanisms could explain or contribute to the low efficacy of vaccine-induced anti-merozoite antibodies to block invasion in vivo. These findings are of great importance to the efforts to develop a merozoite blocking vaccine. v Table of Contents List of Figures ................................................................................................................ viii Abbreviations .................................................................................................................. x Acknowledgments .......................................................................................................... xii Chapter I: Literature Review ............................................................................................ 1 Introduction to malaria .......................................................................................... 1 Malaria a Severe Public Health Problem ................................................... 1 Malaria and Plasmodium falciparum Lifecycle ........................................... 2 Plasmodium falciparum Erythrocyte Invasion Pathways ...................................... 5 Invasion Ligands Utilized by Merozoites ............................................................... 7 The Merozoite Surface Proteins ................................................................ 7 The P. falciparum Erythrocyte Binding Antigens and the P. falciparum Reticulocyte Binding Protein Homologues ................................................. 9 Characterization of Humoral Immune Response to Plasmodium Erythrocytic Stages ................................................................................................................ 12 Naturally acquired immunity ..................................................................... 12 Conflicting Data Between in vitro vs. in vivo Blood-stage Studies ........... 20 Common in vitro Testing Methods and Antibody Functions ..................... 23 The complement system .................................................................................... 25 Complement Activation and Malaria ........................................................ 27 Role of Complement in Cerebral Malaria ................................................. 32 Role of Complement in Placental Malaria ................................................ 36 Role of Complement in Severe Malarial Anemia ..................................... 40 Paroxysmal Nocturnal Hemoglobinuria Erythrocyte Invasion by P. falciparum .. 45 Merozoite-specific Thrombospondin-related Anonymous Protein and Semaphorin 7A ........................................................................................ 47 Concluding remarks ............................................................................................ 48 Chapter II: Materials and Methods ................................................................................ 51 Chapter III: Complement and Antibody-mediated Enhancement of Red Cell Invasion and Growth of Plasmodium falciparum .......................................................................... 63 Abstract: ............................................................................................................. 63 Significance: ....................................................................................................... 64 vi Introduction: ........................................................................................................ 65 Results: .............................................................................................................. 67 Discussion: ......................................................................................................... 73 Acknowledgments: ............................................................................................. 78 Figure Legends: .................................................................................................. 79 Figures: .............................................................................................................. 84 Chapter IV: Inhibition of erythrocyte invasion by Plasmodium falciparum due to Semaphorin 7A and complement interaction ................................................................. 98 Introduction: ........................................................................................................ 98 Results: ............................................................................................................ 100 Discussion: ....................................................................................................... 106
Load more

Recommended publications
  • (CD147) Is Induced by C/Ebpβ and Is Differentially Expressed in ALK+
    Laboratory Investigation (2017) 97, 1095–1102 © 2017 USCAP, Inc All rights reserved 0023-6837/17 EMMPRIN (CD147) is induced by C/EBPβ and is differentially expressed in ALK+ and ALK − anaplastic large-cell lymphoma Janine Schmidt1, Irina Bonzheim1, Julia Steinhilber1, Ivonne A Montes-Mojarro1, Carlos Ortiz-Hidalgo2, Wolfram Klapper3, Falko Fend1 and Leticia Quintanilla-Martínez1 Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPβ, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPβ for the unusual phenotype of ALK+ ALCL cells, C/EBPβ was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK − cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPβ knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK − ALCL cases showed a weaker CD147 expression.
    [Show full text]
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • Role of C5ar1 and C5L2 Receptors in Ischemia-Reperfusion Injury
    Journal of Clinical Medicine Article Role of C5aR1 and C5L2 Receptors in Ischemia-Reperfusion Injury Carlos Arias-Cabrales 1,* , Eva Rodriguez-Garcia 1, Javier Gimeno 2, David Benito 3, María José Pérez-Sáez 1, Dolores Redondo-Pachón 1, Anna Buxeda 1, Carla Burballa 1, Marta Crespo 1, Marta Riera 3,* and Julio Pascual 1,* 1 Department of Nephrology, Parc de Salut Mar, 08003 Barcelona, Spain; [email protected] (E.R.-G.); [email protected] (M.J.P.-S.); [email protected] (D.R.-P.); [email protected] (A.B.); [email protected] (C.B.); [email protected] (M.C.) 2 Department of Pathology, Parc de Salut Mar, 08003 Barcelona, Spain; [email protected] 3 Kidney Research Group, Hospital del Mar Medical Research Institute, IMIM, 08003 Barcelona, Spain; [email protected] * Correspondence: [email protected] (C.A.-C.); [email protected] (M.R.); [email protected] (J.P.) Abstract: The role of C5a receptors (C5aR1 and C5L2) in renal ischemia-reperfusion injury (IRI) is uncertain. We generated an in vitro model of hypoxia/reoxygenation with human proximal tubule epithelial cells to mimic some IRI events. C5aR1, membrane attack complex (MAC) and factor H (FH) deposits were evaluated with immunofluorescence. Quantitative polymerase chain reaction evaluated the expression of C5aR1, C5L2 genes as well as genes related to tubular injury, inflammation, and profibrotic pathways. Additionally, C5aR1 and C5L2 deposits were evaluated in kidney graft biopsies (KB) from transplant patients with delayed graft function (DGF, n = 12) and compared with Citation: Arias-Cabrales, C.; a control group (n = 8). We observed higher immunofluorescence expression of C5aR1, MAC and FH Rodriguez-Garcia, E.; Gimeno, J.; as higher expression of genes related to tubular injury, inflammatory and profibrotic pathways and Benito, D.; Pérez-Sáez, M.J.; of C5aR1 in the hypoxic cells; whereas, C5L2 gene expression was unaffected by the hypoxic stimulus.
    [Show full text]
  • The Membrane Complement Regulatory Protein CD59 and Its Association with Rheumatoid Arthritis and Systemic Lupus Erythematosus
    Current Medicine Research and Practice 9 (2019) 182e188 Contents lists available at ScienceDirect Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp Review Article The membrane complement regulatory protein CD59 and its association with rheumatoid arthritis and systemic lupus erythematosus * Nibhriti Das a, Devyani Anand a, Bintili Biswas b, Deepa Kumari c, Monika Gandhi c, a Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India b Department of Zoology, Ramjas College, University of Delhi, India c University School of Biotechnology, Guru Gobind Singh Indraprastha University, India article info abstract Article history: The complement cascade consisting of about 50 soluble and cell surface proteins is activated in auto- Received 8 May 2019 immune inflammatory disorders. This contributes to the pathological manifestations in these diseases. In Accepted 30 July 2019 normal health, the soluble and membrane complement regulatory proteins protect the host against Available online 5 August 2019 complement-mediated self-tissue injury by controlling the extent of complement activation within the desired limits for the host's benefit. CD59 is a membrane complement regulatory protein that inhibits the Keywords: formation of the terminal complement complex or membrane attack complex (C5b6789n) which is CD59 generated on complement activation by any of the three pathways, namely, the classical, alternative, and RA SLE the mannose-binding lectin pathway. Animal experiments and human studies have suggested impor- Pathophysiology tance of membrane complement proteins including CD59 in the pathophysiology of rheumatoid arthritis Disease marker (RA) and systemic lupus erythematosus (SLE). Here is a brief review on CD59 and its distribution, structure, functions, and association with RA and SLE starting with a brief introduction on the com- plement system, its activation, the biological functions, and relations of membrane complement regu- latory proteins, especially CD59, with RA and SLE.
    [Show full text]
  • More Than a Pore: Nonlytic Antimicrobial Functions of Downloaded from Complement and Bacterial Strategies for Evasion
    REVIEW More than a Pore: Nonlytic Antimicrobial Functions of Downloaded from Complement and Bacterial Strategies for Evasion Elisabet Bjanes,a Victor Nizeta,b aDivision of Host-Microbe Systems and Therapeutics, Department of Pediatrics, UC San Diego, La Jolla, California, USA bSkaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, California, USA http://mmbr.asm.org/ SUMMARY ........................................................................1 INTRODUCTION ...................................................................2 BY THE BOOK: CANONICAL COMPLEMENT CASCADES ...............................2 Off to the Races—Pathway Activation . 2 More and More—Amplification . 3 End of the Line—Termination . 3 Pump the Brakes—Inhibition . 5 Surviving MAC Attack—Evasion of Complement Lysis by Gram-Negative Bacteria . 6 NONLYTIC COMPLEMENT FUNCTIONS AND BACTERIAL EVASION MECHANISMS ......8 Special Considerations in Gram-Positive Bacteria . 8 on January 27, 2021 at UNIV OF CALIF SAN DIEGO Preparing the Meal—Complement Aids Opsonization and Phagocytosis . 8 Food for Thought—Complement Traffics to Autophagy . 10 Fueling the Fire—Complement Modulates Inflammatory Responses . 11 Casting a Wider NET—Complement and Neutrophil Synergy . 12 Inside Scoop—Novel Roles of Intracellular Complement . 13 Tying the Clot—Complement and Coagulation Cross Talk . 15 Bridging the Gap—Complement Instructs Adaptive Immunity . 17 REFRAMING SCIENTIFIC PARADIGMS AND THERAPEUTIC APPROACHES TO ENCOMPASS COMPLEMENT ..................................................18
    [Show full text]
  • An Anticomplement Agent That Homes to the Damaged Brain and Promotes Recovery After Traumatic Brain Injury in Mice
    An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice Marieta M. Rusevaa,1,2, Valeria Ramagliab,1, B. Paul Morgana, and Claire L. Harrisa,3 aInstitute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; and bDepartment of Genome Analysis, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands Edited by Douglas T. Fearon, Cornell University, Cambridge, United Kingdom, and approved September 29, 2015 (received for review July 15, 2015) Activation of complement is a key determinant of neuropathology to rapidly and specifically inhibit MAC at sites of complement and disability after traumatic brain injury (TBI), and inhibition is activation, and test its therapeutic potential in experimental TBI. neuroprotective. However, systemic complement is essential to The construct, termed CD59-2a-CRIg, comprises CD59a linked fight infections, a critical complication of TBI. We describe a to CRIg via the murine IgG2a hinge. CD59a prevents assembly targeted complement inhibitor, comprising complement receptor of MAC in cell membranes (16), whereas CRIg binds C3b/iC3b of the Ig superfamily (CRIg) fused with complement regulator CD59a, deposited at sites of complement activation (17). The IgG2a designed to inhibit membrane attack complex (MAC) assembly at hinge promotes dimerization to increase ligand avidity. CD59- sites of C3b/iC3b deposition. CRIg and CD59a were linked via the 2a-CRIg protected in the TBI model, demonstrating that site- IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b targeted anti-MAC therapeutics may be effective in prevention binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited of secondary neuropathology and improve neurologic recovery MAC formation and prevented complement-mediated lysis in vitro.
    [Show full text]
  • Flow Reagents Single Color Antibodies CD Chart
    CD CHART CD N° Alternative Name CD N° Alternative Name CD N° Alternative Name Beckman Coulter Clone Beckman Coulter Clone Beckman Coulter Clone T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells CD1a T6, R4, HTA1 Act p n n p n n S l CD99 MIC2 gene product, E2 p p p CD223 LAG-3 (Lymphocyte activation gene 3) Act n Act p n CD1b R1 Act p n n p n n S CD99R restricted CD99 p p CD224 GGT (γ-glutamyl transferase) p p p p p p CD1c R7, M241 Act S n n p n n S l CD100 SEMA4D (semaphorin 4D) p Low p p p n n CD225 Leu13, interferon induced transmembrane protein 1 (IFITM1). p p p p p CD1d R3 Act S n n Low n n S Intest CD101 V7, P126 Act n p n p n n p CD226 DNAM-1, PTA-1 Act n Act Act Act n p n CD1e R2 n n n n S CD102 ICAM-2 (intercellular adhesion molecule-2) p p n p Folli p CD227 MUC1, mucin 1, episialin, PUM, PEM, EMA, DF3, H23 Act p CD2 T11; Tp50; sheep red blood cell (SRBC) receptor; LFA-2 p S n p n n l CD103 HML-1 (human mucosal lymphocytes antigen 1), integrin aE chain S n n n n n n n l CD228 Melanotransferrin (MT), p97 p p CD3 T3, CD3 complex p n n n n n n n n n l CD104 integrin b4 chain; TSP-1180 n n n n n n n p p CD229 Ly9, T-lymphocyte surface antigen p p n p n
    [Show full text]
  • Quantitation of the Number of Molecules of Glycophorins C and D on Normal Red Blood Cells Using Radioiodinatedfab Fragments of Monoclonal Antibodies
    Quantitation of the Number of Molecules of Glycophorins C and D on Normal Red Blood Cells Using RadioiodinatedFab Fragments of Monoclonal Antibodies By Jon Smythe, Brigitte Gardner, andDavid J. Anstee Two rat monoclonal antibodies (BRAC 1 and BRAC 1 1 ) cytes. Fabfragments of BRAC 1 1 and ERIC 10 gave values have been produced. BRAC 1 recognizes an epitope com- of 143,000 molecules GPC per red blood cell (RBC). Fab mon to the human erythrocyte membrane glycoproteins fragments of BRAC1 gave 225,000 molecules of GPC and glycophorin C (GPC) and glycophorin D (GPD). BRAC 11 GPD per RBC. These results indicate that GPC and GPD is specific for GPC. Fabfragments of these antibodies and together are sufficiently abundantto provide membrane at- BRlC 10, a murine monoclonal anti-GPC,were radioiodin- tachment sites for all ofthe protein 4.1 in normal RBCs. ated and used in quantitative binding assays to measure 0 1994 by The American Societyof Hematology. the number of GPC and GPD molecules on normal erythro- HE SHAPE AND deformability of the mature human (200,000)" and those reported for GPC (50,000).7 This nu- Downloaded from http://ashpublications.org/blood/article-pdf/83/6/1668/612763/1668.pdf by guest on 24 September 2021 T erythrocyte is controlled by a flexible two-dimensional merical differencehas led to the suggestion that a significant lattice of proteins, which together comprise the membrane proportion of protein 4.1 in normal erythrocyte membranes skeleton.' The major components of the skeleton are spec- must be bound to sites other than GPC and GPD.3 The trin, actin, ankyrin, and protein 4.1.
    [Show full text]
  • Immuno 2014 No. 1
    Journal of Blood Group Serology and Molecular Genetics VOLUME 30, N UMBER 1, 2014 Immunohematology Journal of Blood Group Serology and Molecular Genetics Volume 30, Number 1, 2014 CONTENTS R EPORT 1 Indirect antiglobulin test-crossmatch using low-ionic-strength saline–albumin enhancement medium and reduced incubation time: effectiveness in the detection of most clinically significant antibodies and impact on blood utilization C.L. Dinardo, S.L. Bonifácio, and A. Mendrone, Jr. R EV I EW 6 Raph blood group system M. Hayes R EPORT 11 I-int phenotype among three individuals of a Parsi community from Mumbai, India S.R. Joshi C A SE R EPORT 14 Evans syndrome in a pediatric liver transplant recipient with an autoantibody with apparent specificity for the KEL4 (Kpb) antigen S.A. Koepsell, K. Burright-Hittner, and J.D. Landmark R EV I EW 18 JMH blood group system: a review S.T. Johnson R EPORT 24 Demonstration of IgG subclass (IgG1 and IgG3) in patients with positive direct antiglobulin tests A. Singh, A. Solanki, and R. Chaudhary I N M EMOR ia M 28 George Garratty, 1935–2014 Patricia A. Arndt and Regina M. Leger 30 A NNOUNCEMENTS 34 A DVERT I SEMENTS 39 I NSTRUCT I ONS FOR A UTHORS E D I TOR - I N -C H I EF E D I TOR ia L B OA RD Sandra Nance, MS, MT(ASCP)SBB Philadelphia, Pennsylvania Patricia Arndt, MT(ASCP)SBB Paul M. Ness, MD Pomona, California Baltimore, Maryland M A N AG I NG E D I TOR James P.
    [Show full text]
  • Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis
    ORIGINAL RESEARCH published: 05 January 2021 doi: 10.3389/fimmu.2020.599647 Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis Andy Dernstedt 1, Jana Leidig 1, Anna Holm 2, Priscilla F. Kerkman 1, Jenny Mjösberg 3, Clas Ahlm 1, Johan Henriksson 4, Magnus Hultdin 5 and Mattias N. E. Forsell 1* 1 Department of Clinical Microbiology, Section of Infection and Immunology, Umeå University, Umeå, Sweden, 2 Department of Clinical Sciences, Division of Otorhinolaryngology, Umeå University, Umeå, Sweden, 3 Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, 4 Molecular Infection Medicine Sweden, Department of Molecular Biology, Umeå University, Umeå, Sweden, 5 Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Edited by: Accelerating Factor (DAF) blocks complement deposition on host cells and therefore Judith Fraussen, also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR University of Hasselt, Belgium lo Reviewed by: engagement and that T cell-dependent stimuli preferentially led to activation of DAF B lo Paolo Casali, cells. Consistent with this, a majority of light and dark zone GC B cells were DAF and University of Texas Health Science susceptible to complement-dependent phagocytosis, as compared with DAFhi GC B Center at San Antonio, United States hi Shengli Xu, cells. We could also show that the DAF GC B cell subset had increased expression of the Bioprocessing Technology Institute plasma cell marker Blimp-1.
    [Show full text]
  • LP Review Published.Pdf
    Molecular Immunology 56 (2013) 413–422 Contents lists available at SciVerse ScienceDirect Molecular Immunology jo urnal homepage: www.elsevier.com/locate/molimm Review Toward a structure-based comprehension of the lectin pathway of complement a a b,∗ Troels R. Kjaer , Steffen Thiel , Gregers R. Andersen a Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus, Denmark b Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus, Denmark a r t a b i c l e i n f o s t r a c t Article history: To initiate the lectin pathway of complement pattern recognition molecules bind to surface-linked car- Received 2 May 2013 bohydrates or acetyl groups on pathogens or damaged self-tissue. This leads to activation of the serine Accepted 14 May 2013 proteases MASP-1 and MASP-2 resulting in deposition of C4 on the activator and assembly of the C3 convertase. In addition MASP-3 and the non-catalytic MAp19 and MAp44 presumably play regulatory Keywords: functions, but the exact function of the MASP-3 protease remains to be established. Recent functional Complement system studies have significantly advanced our understanding of the molecular events occurring as activation Pattern recognition progresses from pattern recognition to convertase assembly. Furthermore, atomic structures derived MBL MASP by crystallography or solution scattering of most proteins acting in the lectin pathway and two key complexes have become available. Here we integrate the current functional and structural knowledge Protease activation C4 concerning the lectin pathway proteins and derive overall models for their glycan bound complexes.
    [Show full text]
  • Hereditary Angioedema: a Broad Review for Clinicians
    REVIEW ARTICLE Hereditary Angioedema A Broad Review for Clinicians Ugochukwu C. Nzeako, MD, MPH; Evangelo Frigas, MD; William J. Tremaine, MD ereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10000 to 1 in 150000 persons; HAE has been reported in all races, and no sex predomi- nance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known trig- Hgers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named “type 3” HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal sys- tems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corti- costeroids, antihistamines, and epinephrine can be useful adjuncts but typically are not effica- cious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents.
    [Show full text]