RECENT ADVANCES IN IMMUNOLOGY RECENT ADVANCES IN IMMUNOLOGY Edited by Asuman U. Miiftiioglu CerrahpO§a Medical Faculty of University of Istanbul Istanbul, Turkey and Nefise Barlas Admiral Bristol Hospital Istanbul, Turkey PLENUM PRESS • NEW YORK AND LONDON Library of Congress Cataloging in Publication Data Main entry under title: Recent advances in immunology. "Proceedings of the fifth European Immunology Meeting, held June 1982 in Istan bul, Turkey"-P. Includes bibliographical references and index. I. Immunology - Congresses. 2. Immunopathology - Congresses. I. Miiftiioglu, Asuman D. II. Barlas, Nefise. III. European Immunology Meeting (5th: 1982: Istan bul, Turkey) [DNLM: 1. Allergy and immunology-Congresses. W3 EU882 5th 1982r/QW 504 E89 1982r) QR1BO.3.R43 1984 616.07'9 83-24494 ISBN-13: 978-1-4684-4651-7 e-ISBN-13: 978-1-4684-4649-4 DOl: 10.1007/978-1-4684-4649-4 Proceedings of the fifth European Immunology Meeting, held June 1982 in Istanbul, Turkey © 1984 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1984 A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher PREFACE The aim of this publication is to present the up-to-date views of the many eminent immunologists who contributed to the scientific program of the 5th European Immunology Meeting held in Istanbul in June 1982. Recent Advances in Immunology is intended for immunol ogists both in the basic sciences and in clinical medicine. It provides under one cover an assemblage of information about funda mental problems in immunology and clinical applications. The book opens with Prof. E.A. Kabat's review of the problems in understanding the structural basis of antibody complementarity. The succeeding four papers deal with the role of macrophages in the various stages of immune phenomena. The first of the two articles on T cells reports a product necessary for suppressor activity and the second describes an analysis of precursors of cytotoxic T lym phocytes. The articles dealing with immunogenetics start with the description of new loci in HLA by Prof. J.J. van Rood and co-workers followed by a paper describing the molecular cloning of H-2 class I genes. Prof. P.J. Lachmann begins the discussion on the genetics of the complement system. There are three stimulating articles on the chemistry and genetics of the complement components and their asso ciations with disease. After a review of artificial antigens and synthetic vaccines, papers on immunomodulation describe strategies for improving immunogenicity, immunomodulation in tumor systems and by xenobiotics. A report on the technical difficulties and improvements of the human-human hybridoma system links the first part of the book with the clinical immunology papers. The discussion of lymphocyte dys functions associated with enzyme defects is followed by three papers dealing with various forms of immunodeficiency. The section on auto immunity starts with the discussion of T cell regulation in auto immune diseases. A comprehensive paper by Prof. D. Doniach and G.F. Bottazzo describes the principles of early detection of autoimmune endocrine disorders. The role of autoimmune T lymphocytes in the pathogenesis of myasthenia gravis gives a good example of the coop eration between laboratory and clinical medicine. Finally some of the patho-physiological mechanisms of immediate type hypersensitivity v PREFACE are discussed in three papers: the properties and function of human IgG short term sensitizing anaphylactic antibody, leukotrienes and lipid factors and the regulation of imflammatory reactions by calmodulin. The contributors deserve all the credit that the meeting may have achieved in bringing into perspective much new knowledge in the various fields of immunology. Their cooperative efforts are much ap preciated. We are convinced that a book giving the highlights of the Istanbul Meeting is particulary timely and we hope that it will be well-received. Asuman U. MUftUo~lu, M.D. Nefise Barlas, M.D. CONTENTS Problems in Understanding the Generation of Antibody Complementarity....................... 1 E.A. Kabat Natural Immunity and Macrophages - Introductory Remarks .....................•........ 15 M.L. Lohmann-Matthes Role of Macrophages in T Cell Activation •••••••••••••••• 17 P. Erb, G. Rami 1 a , A. Stern, and I. Sklenar Antigen Presentation by Dendritic Cells ••••••••••••••.•• 23 G.H. Sunshine, A.A. Czitrom, S. Edwards, M. Feldmann, and D.R. Katz The Macrophage as a Cytotoxic Effector Cell in Mice and Humans ....•...........•.......... 29 M.L. Lohmann-Matthes, H. Lang, D. Krumwieh, and D. Sun A Cell-Free Product Secreted by Ly-2+ Cells Can Induce a Molecule Required for Ly2 Suppressor Cell It...... Activity .•...•............................. 39 P.M. Flood, D. Louie, and R.K. Gershon Frequency-Analysis of Precursors of Cytotoxic T Lymphocytes in Radiation Chimeras: Enumeration of Antigenspecific CTL-P Restricted to Thymic MHC- and Bone Marrow-MHC-Determinants •.....•......•............. 51 K. Pfizenmaier, H. Stockinger, M. Krenke, P. Scheurich, C. Hardt, M. Rellinghoff, and H. Wagner New Loci in HLA ....••.......••..••••......•. " ....•....•. 61 J.J. van Rood, A. van Leeuwen, and A. Termijtelen vii viii CONTENTS Molecu~ar Clonin~ of H-2 Class I Genes 1..0 the H-2 Haplotype """"""""""""""""""""""""""""" 69 A.L. Mellor, L. Golden, E. Weiss, H. Bullman, H. Bud, J. Hurst, R. Flavell, R.F.L. James, E. Simpson, A.R.M. Townsend, P.M. Taylor, J. Ferluga, L. Leben, M. Santamaria, G. Atfield, and H. Festenstein Why Study Complement Genetics? •••••••••••••••••••••••••• 77 P. Lachmann The Family of Proteins Having Internal Thiolester 87 Bonds """"""""""""""""""""""""",,""""""""""""""""""" R.A. Harrison Structural Analysis of Cloned Mouse and Human DNA Sequences Specifying C3, the Third Component of Complement ••••••••••••••••• 101 G. Fey, K. Wiebauer, H. Domdey, M. Kazmaier, C. Southgate, and V. Muller HLA Encoded Genes and Their Associations with Disease " " .. " " " " " " " " .......... " " .... " " " " .... " .. " .. " " " " " " .. " 107 G. Hauptmann Artificial Antigens and Synthetic Vaccines - A Review " " " " " " " " " " " " " " " .. " " "" " .. " " " " " "" "" " " " " " .. " " " " 113 R. Arnon Strategies for Improving Immunogenicity: The Deliberate Association of MHC (HLA) Antigens with Other Molecules •••••••••••.••.•••••• 119 A.R. Sanderson / Immunomodu1ation in Tumor Systems •••••••••.••••••••••••• 125 A. Matter Immunomodu1ation by Xenobiotics: Introductory Remarks to Immunotoxico10gy ••••••••.••.•..•..•••••.••••..• 137 F. Spreafico, A. Vecchi, M. Sironi, W. Luini, E. Pasqualetto, M. Romano, A. Merendino, and A. Canegrati Antibody Producing Human-Human Hybridomas .•••••••••••••• 147 L. Olsson Lymphocyte Dysfunctions Associated with Enzyme Defects " .. """ .. ,,"""""""""""",, .. ,,"""""""""""""" 151 B.J.M. Zegers, L.J.M. Spaapen, W. Kuis, J.J. Roord, G.T. Rijkers, and J.W. Stoop CONTENTS ix Immunologically Distinct Forms of Primary Hypogammaglobulinaemia: Studies Using Pokeweed Mitogen and Epstein-Barr Virus •..••••••.••••.•.•••.•••.•••••••• 163 T.A.E. Platts-Mills, R.S. Pereira, A.D.B. Webster, and S.R. Wilkins T Cell Subset Responses in Varied Immunodeficiency Syndromes .•••..••••.••••••.••.•.•• 167 F. Caballero, P. Kohler, and A.R. Hayward Immune Dysfunctions in Ataxia-Telangiectasia .•.•.•••••... 173 A.I. Berkel, F. Ersoy, O. Sanal, G. Ciliv, and O. Yegin Some Aspects of T Cell Regulation in Autoimmune Diseases .••.•.••.....•..•..•.•..•..•...•••.••.•.... 183 R.E. Ballieux and C.J. Heijnen Early Detection of Autoimmune Endocrine Disorders •..•.... 191 D. Doniach and G.F. Bottazzo Permanent Lines of T Lymphocytes Specific for Acetylcholine Receptors: A Clonal Approach to Study the Pathogenesis of Myasthenia Gravis 205 B.C.G. Schalke, R. Hohlfeld, I. Kalies, A. Ben-Nun, I.R. Cohen, and H. Wekerle Human IgG Short-Term Sensitizing Anaphylactic Antibody: Differences in Properties from Those of IgG4 •••.••. 211 W.E. Parish Leukotrienes and Lipid Factors: Mediators and Modulators of the Inflammatory Reactions ••.. .•.••.• 219 W. Konig, K.D. Bremm, K. Theobald, Ph. Pfeiffer, B. Szperalski, A. Bohn, P. Borgeat, B. Spur, A.E.G. Crea, and G. Falsone Calmodulin and Human Inflammatory Reactions 225 G. Marone, M. Columbo, S. Poto, P. Bianco, and M. Condorelli Contributors •••..•••••••..•..•..••.••.•......•.••.•.•••.. 231 Index .................................................... 239 PROBLEMS IN UNDERSTANDING THE GENERATION OF ANTIBODY COMPLEMENTARITY Elvin A. Kabat The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, and the Departments of Microbiology, Human Genetics and Development, and Neurology, and the Cancer Center/Institute for Cancer Research, Columbia University College of Physicians and Surgeons, New York, U.S.A. A major problem of the present decade is the elucidation of the structural basis of antibody complementarity, or, in other words, what do antibody combining sites of a given specificity look like and how do the various amino acid side chains make for different kinds of combining sites (1-3). Intimately related to this is the question of how the capacity to make these sites is maintained in the germ line. The genetic basis for the formation of antibody com bining sites differs from that of all other proteins with specific receptor sites such as enzymes, hormones and lectins in that anti body combining sites are formed by two chains whereas other receptor sites are essentially built of a single chain. It was generally es timated that mammals could form about 106 antibody combining sites but since the development of the hybridoma technique (4) this esti mate must clearly be low by several orders of magnitude since to date no two hybridomas making antibody combining sites to a single antigenic determinant such as al+6 dextran have been found to be identical (5-7). Let us consider what we know about the structure of antibody combining sites. As the amino acid sequences of light and of heavy chains of immunoglobulins were being determined, it became clear that both the light and heavy chains had a domain structure each domain having a disulfide bond with a loop of about 55-70 amino acids and that the antibody combining site was associated with the N-terminal domain of each chain termed the VL and VH domains (V=variable) respectively (Figure 1). The earliest sequence studies were carried out on human Bence Jones proteins shown by Edelman and 2 E.A.KABAT Fig. 1. Schematic view of four-chain structure of human IgG mole K cule. Numbers on right side denote actual residues of pro tein Eu (8,9). Numbers of Fab fragments on the left side are aligned for maximum homology; light chains are numbered according to Wu and Kabat (10,11). Heavy chains of Eu have residue 52A and 82A, B, C and lack residues termed 100A, B, C, D, E, F, G, Hand 35A, B. Thus residue 100 (end of vari able region) is 114 in actual sequence. Hypervariable re gions and complementarity-determining segments or regions are shown by heavier lines. VL and VH denote light- and heavy-chain variable regions; CHI, CH2, and CH3 are domains of constant region of heavy chain; CL is constant region of light chain. The hinge region in which two heavy chains are linked by disulfide bonds is indicated approximately. At tachment of carbohydrate is at residue 297. Arrows at resi dues 107 and 110 denote transition from variable to constant regions. Sites of action of papain and pepsin and locations of a number of genetic factors are given. (Reproduced with the kind permission of Academic Press). GaIly (11) to be the light chains of immunoglobulin; no two human Bence Jones proteins were found to have identical amino acid sequ ences in their amino terminal first domains and this led to their being termed variable regions. The antigenic specificity of Bence Jones proteins had permitted them to be classified into two classes, K and A and these were ascribable predominantly to amino acid dif ferences in the second or C domain (Figure 1); all K light chains,