DOCSLIB.ORG

Antigen Mimicry-Recognizing Paratope

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antigen Mimicry-Recognizing Paratope Structural Evaluation of a Mimicry-Recognizing Paratope: Plasticity in Antigen−Antibody Interactions Manifests in Molecular Mimicry This information is current as of September 28, 2021. Suman Tapryal, Vineet Gaur, Kanwal J. Kaur and Dinakar M. Salunke J Immunol published online 3 June 2013 http://www.jimmunol.org/content/early/2013/06/01/jimmun ol.1203260 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 3, 2013, doi:10.4049/jimmunol.1203260 The Journal of Immunology Structural Evaluation of a Mimicry-Recognizing Paratope: Plasticity in Antigen–Antibody Interactions Manifests in Molecular Mimicry Suman Tapryal,*,1 Vineet Gaur,*,1 Kanwal J. Kaur,* and Dinakar M. Salunke*,† Molecular mimicry manifests antagonistically with respect to the specificity of immune recognition. However, it often occurs because different Ags share surface topologies in terms of shape or chemical nature. It also occurs when a flexible paratope accommodates dissimilar Ags by adjusting structural features according to the antigenic epitopes or differential positioning in the Ag combining site. Toward deciphering the structural basis of molecular mimicry, mAb 2D10 was isolated from a maturing immune response elicited against methyl a-D-mannopyranoside and also bound equivalently to a dodecapeptide. The physicochemical evidence of this carbohydrate– peptide mimicry in the case of mAb 2D10 had been established earlier. These studies had strongly suggested direct involvement of Downloaded from a flexible paratope in the observed mimicry. Surprisingly, comparison of the Ag-free structure of single-chain variable fragment 2D10 with those bound to sugar and peptide Ags revealed a conformationally invariant state of the Ab while binding to chemically and structurally disparate Ags. This equivalent binding of the two dissimilar Ags was through mutually independent interactions, dem- onstrating functional equivalence in the absence of structural correlation. Thus, existence of a multispecific, mature Ab in the secondary immune response was evident, as was the plasticity in the interactions while accommodating topologically diverse Ags. Although our data highlight the structural basis of receptor multispecificity, they also illustrate mechanisms adopted by the immune http://www.jimmunol.org/ system to neutralize the escape mutants generated during pathogenic insult. The Journal of Immunology, 2013, 191: 000–000. pecific molecular recognition involves receptor and ligand mimicry has also been exploited as a conceptual tool for rational surfaces to complement each other in terms of shape and drug design to identify inhibitors as the substrate mimics of var- S charge to achieve physiologically meaningful interactions. It ious therapeutic target proteins and enzymes (15, 16). is not uncommon, however, that completely unrelated molecules Methyl a-D-mannopyranoside and a dodecapeptide (DVFYPY- share common receptors, possibly through similar structural and/or PYASGS) known to bind Con A with comparable affinities have chemical features involved in recognition and binding, resulting in been studied extensively as a model system to address molecular molecular mimicry (1–3). Molecular mimicry often occurs by de- mimicry in the humoral immune response (17–19). Polyclonal sera by guest on September 28, 2021 sign and manifests as a control during various regulatory mecha- generated against methyl a-D-mannopyranoside cross-recognize the nisms (4). It also occurs as an accidental encounter of structural dodecapeptide, and correspondingly antipeptide sera cross-react resemblances, particularly in the immune system, sometimes with the mannopyranoside (20). Additionally, dodecapeptide was culminating in pathological conditions such as autoimmune dis- observed to cross-boost the antisugar response in mice (21). The orders (5–8). The molecular mimicry between self and viral or structure of dodecapeptide in complex with Con A was determined. bacterial peptides generally leads to the activation of self-reactive Comparison of sugar and peptide structures bound to Con A T cells resulting in autoimmune pathologies, for example, multi- revealed that although peptide displayed structural and functional ple sclerosis, autoimmune hepatitis, and myocarditis (9–11). The mimicry to sugar, it did not bind at the carbohydrate binding site of humoral immune system has also been shown to produce auto- Con A, but adjacent to it (22, 23). Thus, although these data sug- reactive Abs, some of which are also associated with cancers (12, gested functional quasi-equivalence between the dodecapeptide and 13). In case of the anti–U1-70 kDa autoimmunity, the host protein the carbohydrate moiety, the precise topological correlation be- shares T cell epitopes with 13 fungal proteins (14). Molecular tween the two molecules was elusive. Although the mimicry between the sugar and peptide molecules was functionally elucidated during the onset as well as the *National Institute of Immunology, New Delhi 110067, India; and †Regional Centre progression of the humoral immune response, further analyses at for Biotechnology, Gurgaon 122016, India the molecular level were considered best addressed using rel- 1 S.T. and V.G. contributed equally to this work. evant mAbs. Indeed, the mAb 2D10 generated against the man- Received for publication November 27, 2012. Accepted for publication May 3, 2013. nopyranoside moiety bound both the methyl a-D-mannopyranoside This work was supported by a grant from the Department of Biotechnology, Gov- and the dodecapeptide (DVFYPYPYASGS) with equivalent af- ernment of India and by a J.C. Bose fellowship. finity (24), providing an elegant model for structural and func- The sequences presented in this article have been submitted to the Research Collaboratory tional investigations. Thermodynamic and in silico studies had for Structural Bioinformatics Protein Data Bank (http://www.rcsb.org) under accession codes 4H0G, 4H0I, and 4H0H. suggested a flexible Ag combining site as a basis for the promis- Address correspondence and reprint requests to Dr. Dinakar M. Salunke, Regional cuous recognition of these otherwise chemically distinct molecules Centre for Biotechnology, 180 Udyog Vihar Phase I, Gurgaon 122016, India. E-mail (25). Because 2D10-Fab could not be crystallized, a shorter re- address: [email protected] combinant single-chain variable fragment (scFv; single-chain Ab) Abbreviations used in this article: rmsd, root-mean-square deviation; scFv, single- molecule 2D10 was constructed that facilitated application of crys- chain variable fragment. tallographic methods to understand functional mimicry involving the Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 mannopyranoside and the dodecapeptide (26). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1203260 2 PLASTICITY IN Ag–Ab INTERACTIONS In this study we present crystal structures of scFv of the mAb used for model building. Throughout the procedure, Rwork and Rfree (30) 2D10 in an Ag-free state as well as in complex with the sugar, methyl were used to monitor the progress of the refinement by omitting 10% of the data, chosen randomly, for calculation of R values. Once the model for a-D-mannopyranoside, and the dodecapeptide. Superimposition of free the scFv 2D10 molecules had been completed, density visible at the Ag these structures revealed that the CDRs of the Ab had a predefined binding site could be interpreted as methyl a-D-mannopyranoside mole- invariant conformation in all the three forms, implying that the Ag cule in case of the scFv–sugar complex. In the case of the scFv–peptide combining site may have a rigid structure. Analysis of the inter- complex, connected density at the Ag combining site allowed residues P3– actions between the paratope and the respective Ags revealed a P9 of the peptide to be fitted in electron density map. The model of peptide was fitted by visualizing 2Fo-Fc map at a s cutoff of 0.7 and Fo-Fc map at unique mechanism for the manifestation of carbohydrate–peptide a s cutoff of 1.6. The quality of the model was controlled with MolProbity mimicry with respect to their recognition by the immune receptors. (32). Superimpositions of the entire proteins and their various submolecular components were carried out using superpose (33) from the CCP4 program suite as well as from PyMol. The Ag and Ab interface interactions were Materials and Methods determined using Contact (CCP4 program suite) and PISA (34). The epitope– Ag molecules paratope interactions and the buried surface areas for each Ag-bound scFv structure were calculated using PISA. The methyl a-D-mannopyranoside was procured from Sigma-Aldrich,
Load more

Recommended publications
  • Citrullinated Protein Antibody Paratope Drives Epitope Spreading and Polyreactivity in Rheumatoid Arthritis
    Arthritis & Rheumatology Vol. 0, No. 0, Month 2019, pp 1–11 DOI 10.1002/art.40760 © 2019, American College of Rheumatology Affinity Maturation of the Anti–Citrullinated Protein Antibody Paratope Drives Epitope Spreading and Polyreactivity in Rheumatoid Arthritis Sarah Kongpachith, Nithya Lingampalli, Chia-Hsin Ju, Lisa K. Blum, Daniel R. Lu, Serra E. Elliott, Rong Mao and William H. Robinson Objective. Anti–citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). While epitope spreading of the serum ACPA response is believed to contribute to RA pathogenesis, little is understood regarding how this phenomenon occurs. This study was undertaken to analyze the antibody repertoires of individuals with RA to gain insight into the mechanisms leading to epitope spreading of the serum ACPA response in RA. Methods. Plasmablasts from the blood of 6 RA patients were stained with citrullinated peptide tetramers to identify ACPA- producing B cells by flow cytometry. Plasmablasts were single-cell sorted and sequenced to obtain antibody repertoires. Sixty-nine antibodies were recombinantly expressed, and their anticitrulline reactivities were characterized using a cyclic citrullinated peptide enzyme- linked immuosorbent assay and synovial antigen arrays. Thirty- six mutated antibodies designed either to represent ancestral antibodies or to test paratope residues critical for binding, as determined from molecular modeling studies, were also tested for anticitrulline reactivities. Results. Clonally related monoclonal ACPAs and their shared ancestral antibodies each exhibited differential re- activity against citrullinated antigens. Molecular modeling identified residues within the complementarity-determining region loops and framework regions predicted to be important for citrullinated antigen binding. Affinity maturation re- sulted in mutations of these key residues, which conferred binding to different citrullinated epitopes and/or increased polyreactivity to citrullinated epitopes.
    [Show full text]
  • Molecular Mimicry Between Anoctamin 2 and Epstein-Barr Virus Nuclear Antigen 1 Associates with Multiple Sclerosis Risk
    Molecular mimicry between Anoctamin 2 and Epstein- Barr virus nuclear antigen 1 associates with multiple sclerosis risk Katarina Tengvalla,b,1, Jesse Huanga,b, Cecilia Hellströmc, Patrick Kammerd, Martin Biströme, Burcu Ayogluf, Izaura Lima Bomfima,b,PernillaStridha,b, Julia Buttd,NicoleBrennerd,AngelikaMicheld, Karin Lundbergb,g, Leonid Padyukovb,g, Ingrid E. Lundbergb,g, Elisabet Svenungssong, Ingemar Ernbergh, Sigurgeir Olafssoni, Alexander T. Diltheyj,k, Jan Hillerta, Lars Alfredssonl,m, Peter Sundströme, Peter Nilssonc,2, Tim Waterboerd,2, Tomas Olssona,b,2, and Ingrid Kockuma,b,2 aNeuroimmunology Unit, The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience, Karolinska Institute, 171 76 Stockholm, Sweden; bCentrum for Molecular Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden; cDivision of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH - Royal Institute of Technology, 171 21, Solna, Sweden; dInfections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; eDepartment of Pharmacology and Clinical Neuroscience, Umeå University, 901 85 Umeå, Sweden; fDivision of Cellular and Clinical Proteomics, Department of Protein Science, SciLifeLab, KTH - Royal Institute of Technology, 171 21, Solna, Sweden; gDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, 171 76 Stockholm, Sweden; hDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institute,
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,796,427 B2 Spee Et Al
    USOO8796427B2 (12) United States Patent (10) Patent No.: US 8,796,427 B2 Spee et al. (45) Date of Patent: Aug. 5, 2014 (54) HUMANIZED ANTI-HUMAN NKG2A EP 1036327 A2 9, 2000 MONOCLONAL ANTIBODY JP O3112485 A 5, 1991 JP O3112486 A 5, 1991 (75) Inventors: Petrus Johannes Louis Spee, Allerød E. 2025. A 3.28. (DK); Jianhe Chen, Beijing (CN); JP O3112484 U. 8, 2005 Soren Berg Padkjaer, Vaerlose (DK); WO 99.28748 A2 6, 1999 Jing Su, Beijing (CN); Jinchao Zhang, W 94.9. A2 258 Beijing (CN); Jiujiu Yu, Zhejiang (CN) WO O3,OO8449 A1 1, 2003 WO O3,O95965 A2 11/2003 (73) Assignee: Novo Nordisk A/S, Bagsvaerd (DK) WO 2004.?003.019 A2 1/2004 WO WO-2004/056312 T 2004 (*) Notice: Subject to any disclaimer, the term of this WO WO 2006/070286 12, 2004 patent is extended or adjusted under 35 W. 3:39:23, A. i58. U.S.C. 154(b) by 153 days. WO WO 2006O70286 A2 * T 2006 WO 2007042573 A2 4/2007 (21) Appl. No.: 12/811,990 WO WO 2007042573 A2 * 4, 2007 WO WO 2008/OO9545 1, 2008 (22) PCT Filed: Jan. 23, 2009 WO 2009/092805 A1 T 2009 (86). PCT No.: PCT/EP2009/050795 OTHER PUBLICATIONS S371 (c)(1), Petrie, E. J., et al. (2008), J. Exp. Med. 205: 725-735.* (2), (4) Date: Nov. 19, 2010 Bagot et al., “Functional Inhibitory Receptors Expressed by a Cuta neous T-Cell Lymphoma-Specific Cytolytic Clonal T-Cell Popula (87) PCT Pub. No.: WO2009/0928.05 tion.” Journal ofInvestigative Dermatology, 2000, vol.
    [Show full text]
  • Neural Message Passing for Joint Paratope-Epitope Prediction
    Neural message passing for joint paratope-epitope prediction Alice Del Vecchio 1 Andreea Deac 2 3 4 Pietro Lio` 1 Petar Velickoviˇ c´ 4 Abstract Hence, both the antibody and the antigen may be viewed as sequences of amino acid residues. Their binding site Antibodies are proteins in the immune system consists of two regions: the paratope on the antibody, and which bind to antigens to detect and neutralise the epitope on its corresponding antigen. Predicting them them. The binding sites in an antibody-antigen can therefore be posed as a binary classification problem: interaction are known as the paratope and epitope, for each amino acid residue in the antibody and antigen, respectively, and the prediction of these regions respectively, do they participate in the binding? is key to vaccine and synthetic antibody develop- ment. Contrary to prior art, we argue that paratope However, proteins can also be considered as graphs with its and epitope predictors require asymmetric treat- residues as nodes, with two nodes sharing an edge if their ment, and propose distinct neural message passing residues are spatially close. Recently, such contact graphs architectures that are geared towards the specific have been directly leveraged for protein function prediction aspects of paratope and epitope prediction, re- by Gligorijevic et al.(2020). spectively. We obtain significant improvements The advantage of considering a sequence based approach on both tasks, setting the new state-of-the-art and over a graph-based approach is that structural information recovering favourable qualitative predictions on is much harder to obtain. However, recent advancements antigens of relevance to COVID-19.
    [Show full text]
  • 030710 Molecular Mimicry in Multiple Sclerosis
    The new england journal of medicine clinical implications of basic research Molecular Mimicry in Multiple Sclerosis Hartmut Wekerle, M.D., and Reinhard Hohlfeld, M.D. Most experts believe that multiple sclerosis is an senting cells expressed only the relevant HLA-DR2 autoimmune disease in which T cells recognize and restriction molecules. Normally, in HLA-DR2–pos- attack components of the axonal myelin sheath and itive persons, antigen-presenting cells (which in- other features of the central nervous system, de- clude dendritic cells, macrophages, and B cells) ex- stroying myelin and the underlying axon. Although self-reactive T cells are present in the immune sys- tem of people with multiple sclerosis, they are also found in a quiescent state in perfectly healthy peo- ple. Their pathogenic potential is realized only on acute activation, which can occur through different mechanisms. Recent work by Lang and colleagues focused on molecular mimicry, one of the presumed 1 T-cell receptor triggers of autoimmunity. Hy.2E11 Lang and coworkers investigated the antigen- specific T-cell receptor of a particular T-cell clone Epstein–Barr Myelin basic (Hy.2E11), originally isolated from the blood of a virus peptide protein peptide patient with multiple sclerosis. The clone was se- lected for its reactivity to a self antigen — the mye- lin basic protein (MBP) — but it was later found to cross-react with a peptide analogous to part of a viral antigen, the polymerase of the Epstein–Barr virus (EBV).2 The new work shows that this dual response is more complex than anticipated. The mimicry is not simply explained by the structural similarity of the two peptides, as posited by the original model of autoimmune mimicry,3 in which a foreign antigen HLA-DR2a HLA-DR2b is sufficiently similar to a self antigen to trigger an autoimmune response.
    [Show full text]
  • Review Article Infectious Diseases and Autoimmunity
    Review Article Infectious diseases and autoimmunity Lucia G. Delogu1, Silvia Deidda2, Giuseppe Delitala2, Roberto Manetti2 1Department of Drug Science, University of Sassari, Italy 2Department of Clinical, Experimental and Oncological Medicine, University of Sassari, Italy Abstract Introduction: Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. Methodology: We searched PubMed, Cochrane, and Scopus without time limits for relevant articles. Results: In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity. Conclusions: Besides genetic predisposition to autoimmunity, viral and bacterial infections are known to be involved in the initiation and promotion of autoimmune diseases. These studies suggest that pathogens can trigger autoimmunity through molecular mimicry and their adjuvant effects during initiation of disease, and can promote autoimmune responses through bystander activation or epitope spreading via inflammation and/or superantigens. Key words: viral infection; bacterial infection; autoreactive lymphocyte; molecular mimicry; bystander activation; epitope spreading; autoimmune disease J Infect Dev Ctries 2011; 5(10):679-687. (Received 03 May 2011 – Accepted 29 June 2011) Copyright © 2011 Delogu et al. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    [Show full text]
  • The Role of Herpes Simplex Virus Type 1 Infection in Demyelination of the Central Nervous System
    International Journal of Molecular Sciences Review The Role of Herpes Simplex Virus Type 1 Infection in Demyelination of the Central Nervous System Raquel Bello-Morales 1,2,* , Sabina Andreu 1,2 and José Antonio López-Guerrero 1,2 1 Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain; [email protected] (S.A.); [email protected] (J.A.L.-G.) 2 Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Cantoblanco, 28049 Madrid, Spain * Correspondence: [email protected] Received: 30 June 2020; Accepted: 15 July 2020; Published: 16 July 2020 Abstract: Herpes simplex type 1 (HSV-1) is a neurotropic virus that infects the peripheral and central nervous systems. After primary infection in epithelial cells, HSV-1 spreads retrogradely to the peripheral nervous system (PNS), where it establishes a latent infection in the trigeminal ganglia (TG). The virus can reactivate from the latent state, traveling anterogradely along the axon and replicating in the local surrounding tissue. Occasionally, HSV-1 may spread trans-synaptically from the TG to the brainstem, from where it may disseminate to higher areas of the central nervous system (CNS). It is not completely understood how HSV-1 reaches the CNS, although the most accepted idea is retrograde transport through the trigeminal or olfactory tracts. Once in the CNS, HSV-1 may induce demyelination, either as a direct trigger or as a risk factor, modulating processes such as remyelination, regulation of endogenous retroviruses, or molecular mimicry. In this review, we describe the current knowledge about the involvement of HSV-1 in demyelination, describing the pathways used by this herpesvirus to spread throughout the CNS and discussing the data that suggest its implication in demyelinating processes.
    [Show full text]
  • Butyrophilin, a Milk Protein, Modulates the Encephalitogenic T Cell Response to Myelin Oligodendrocyte Glycoprotein in Experimental Autoimmune Encephalomyelitis1
    Butyrophilin, a Milk Protein, Modulates the Encephalitogenic T Cell Response to Myelin Oligodendrocyte Glycoprotein in Experimental Autoimmune Encephalomyelitis1 Andreas Stefferl,2*† Anna Schubart,2* Maria Storch,2†‡ Aminullah Amini,§ Ian Mather,§ Hans Lassmann,† and Christopher Linington3* Experimental autoimmune encephalomyelitis (EAE) induced by sensitization with myelin oligodendrocyte glycoprotein (MOG) is a T cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis. We report that an encephalitogenic T cell response to MOG can be either induced or alternatively suppressed as a consequence of immunological cross-reactivity, or “molecular mimicry” with the extracellular IgV-like domain of the milk protein butyrophilin (BTN). In the Dark Agouti rat, active immunization with native BTN triggers an inflammatory response in the CNS characterized by the formation of scattered meningeal and perivascular infiltrates of T cells and macrophages. We demonstrate that this pathology is mediated by a MHC class II-restricted T cell response that cross-reacts with the MOG peptide sequence 76–87, IGEGKVALRIQN (identities underlined). Conversely, molecular mimicry with BTN can be exploited to suppress disease activity in MOG-induced EAE. We demonstrate that not only is EAE mediated by the adoptive transfer of MOG74–90 T cell lines markedly ameliorated by i.v. treatment with the homologous BTN peptide, BTN74–90, but that this protective effect is also seen in actively induced disease following transmucosal
    [Show full text]
  • IMMUNOCHEMICAL TECHNIQUES Antigens Antibodies
    Imunochemical Techniques IMMUNOCHEMICAL TECHNIQUES (by Lenka Fialová, translated by Jan Pláteník a Martin Vejražka) Antigens Antigens are macromolecules of natural or synthetic origin; chemically they consist of various polymers – proteins, polypeptides, polysaccharides or nucleoproteins. Antigens display two essential properties: first, they are able to evoke a specific immune response , either cellular or humoral type; and, second, they specifically interact with products of this immune response , i.e. antibodies or immunocompetent cells. A complete antigen – immunogen – consists of a macromolecule that bears antigenic determinants (epitopes) on its surface (Fig. 1). The antigenic determinant (epitope) is a certain group of atoms on the antigen surface that actually interacts with the binding site on the antibody or lymphocyte receptor for the antigen. Number of epitopes on the antigen surface determines its valency. Low-molecular-weight compound that cannot as such elicit production of antibodies, but is able to react specifically with the products of immune response, is called hapten (incomplete antigen) . antigen epitopes Fig. 1. Antigen and epitopes Antibodies Antibodies are produced by plasma cells that result from differentiation of B lymphocytes following stimulation with antigen. Antibodies are heterogeneous group of animal glycoproteins with electrophoretic mobility β - γ, and are also called immunoglobulins (Ig) . Every immunoglobulin molecule contains at least two light (L) and two heavy (H) chains connected with disulphidic bridges (Fig. 2). One antibody molecule contains only one type of light as well as heavy chain. There are two types of light chains - κ and λ - that determine type of immunoglobulin molecule; while heavy chains exist in 5 isotypes - γ, µ, α, δ, ε; and determine class of immunoglobulins - IgG, IgM, IgA, IgD and IgE .
    [Show full text]
  • Immunoglobulins.Pdf
    Immunoglobulins RAKESH SHARDA Department of Veterinary Microbiology NDVSU College of Veterinary Science & A.H., MHOW Structure and Functions Definition • Immunoglobulins are glycoprotein molecules belonging to γ-globulins class of plasma proteins produced in response to a non-self or an altered self immunogen and act as antibodies in humoral adaptive immune response. • Immunoglobulins are produced in vertebrates by plasma cells, which are the terminally differentiated B lymphocytes + - albumin globulins α α β γ Amount of protein of Amount 1 2 Immune serum Ag adsorbed serum Mobility Basic Immunoglobulin Structure • γ-globulin • glycoprotein • heterodimer • ‘Y’ shaped molecule • coded by immunoglobulin supergene family Basic Immunoglobulin Structure Disulfide bond Carbohydrate C V L L CH CH CH 2 3 V 1 Hinge Region H Immunoglobulin Structure – a monomer (H2L2) Disulfide bond • 2 Heavy & 2 Light chains Carbohydrate • Disulfide bonds CL – Inter-chain VL CH2 CH3 – Intra-chain CH1 Hinge Region VH Immunoglobulin Structure • Variable & Constant Disulfide bond regions in each chain – VL & CL Carbohydrate – VH & CH C • Forms globular loop L like structure called as VL CH2 CH3 domains CH1 Hinge Region • Hinge Region VH Basic Immunoglobulin Structure • A monomer (H2L2) of an immunoglobulin molecule is made up of: – 2 Light Chains (identical) ~25 KDa – 2 Heavy Chains (identical) ~50 KDa • Each light chain bound to heavy chain by disulfide bonds (H-L) • Each heavy chain bound to heavy chain by disulfide bonds (H-H) • The ¼ portion of each H chain and ½ of each L chain towards amino terminal are more variable (110 aa each - VH and VL) in amino acid composition as compared to the remaining portion towards carboxyl terminal (CH and CL) in each monomer, which has nearly constant composition in each domain of a given isotype.
    [Show full text]
  • A Case Report of Nephrotic Syndrome While Undergoing Quinine Therapy
    Open Access Case Report DOI: 10.7759/cureus.2283 A Case Report of Nephrotic Syndrome While Undergoing Quinine Therapy Brittany Albrecht 1 , Shelley Giebel 2 , Michelle McCarron 3 , Bhanu Prasad 2 1. College of Medicine, University of Saskatchewan 2. Department of Nephrology, Regina General Hospital 3. Research and Performance Support, Saskatchewan Health Authority Corresponding author: Brittany Albrecht, [email protected] Abstract We summarize the case of an 81-year-old Caucasian female who presented to her family physician with signs and symptoms of nephrotic syndrome following a brief exposure to quinine. Prior to that visit, she was clinically well with no chronic medical ailments and met with her family physician for annual physical assessments. She had taken 11 tablets of quinine for nocturnal leg cramps over the course of 28 days before starting to notice mild peripheral edema, which subsequently progressed, leading to a family physician review. Her initial serum albumin level was 12 g/L, and a 24-hour urine protein output was quantified at 8.14 g/day; she was diagnosed as having nephrotic syndrome. A kidney biopsy confirmed the diagnosis of minimal change disease (MCD). Quinine therapy was stopped, and she was initiated on a tapering regime of prednisone with concurrent cyclosporine therapy. Within a fortnight of starting therapy, she went into remission and her immunosuppressive medications were rapidly tapered and discontinued. This paper reports an association between the use of quinine and subsequent MCD. This case report proposes that the use of quinine has an association with, and may be causal for, the development of minimal change disease.
    [Show full text]
  • 4 Antibodies from Other Species Melissa L
    85 4 Antibodies from Other Species Melissa L. Vadnais1, Michael F. Criscitiello2, and Vaughn V. Smider1 1Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA 2Texas A&M University, College of Veterinary Medicine and Biomedical Sciences, Department of Veterinary Pathobiology, 400 Raymond Stotzer Parkway, College Station, TX 77843, USA 4.1 Introduction Immunoglobulins are the molecular basis of humoral immunity. Across different species, these macromolecules maintain a common quaternary structure, which is typically comprised of two identical heavy chains with covalently attached oligosaccharide groups and two identical non-glycosylated, light chains. These glycoprotein molecules recognize and bind a particular antigen in a highly complex and exceedingly specific immune response. Antibodies are the primary protective molecules elicited by most vaccines, and recombinant antibodies are now a major class of therapeutics for multiple diseases. The earliest antibody therapeutics were derived from serum of nonhuman species. In particular, horse serum served as anti-venom yet had substantial toxicity (serum sickness) due totheimmuneresponseagainstthenonhumanantibodyprotein[1,2].Other antibody preparations such as anti-thymocyte globulin produced in rabbit had therapeutic benefit but also had significant toxicity. The use of alternative species for these therapeutic preparations was largely due to ease of production, as they were developed prior to the advent of modern molecular biology techniques, which have enabled rapid discovery and engineering of recombinant antibodies. Thus, most current approaches for producing recombinant antibodies rely on humanizing antibodies derived from other species, usually mice, or beginning with human scaffolds engineered into libraries or transgenic “humanized” mice. Recently, however, novel features of antibodies derived from other species have sparked interest in developing antibodies that may have particular unique features in binding certain antigens or epitopes [3–7].
    [Show full text]