MOLECULAR GENETICS OF IMMUNOGLOBULIN New Comprehensive Biochemistry Volume 17 Generml Editors A NEUBERGER London L.L.M van DEENEN Utreclzt ELSEVIER Amsterdam New York * Oxford Molecular Genetics of Immunoglobulin Edifors F CALABI and M.S NEUBERGER Medical Research Council Ltihoratory of Molecular Biology, Hills Road, Combridge C B 2 Q H , U K 1987 ELSEVIER Amsterdam New York Oxford 1987, Elsevier Science Publishers B.V (Biomcdical Division) All rights reserved No part of this publication may hc rcprocluced stored i n a retrieval system, or transmitted i n any form or by any means, electronic mechanical photocopying recording or otherwise, without the prior written permission of the Publisher Elsevicr Science Publishers B.V (Biomedical Division) P O Box 1527, 1000 BM Amsterdam The Nethcrlands No responsihility is assumed hy the Publisher for any injury and/or damage to persons or property as a matter of products liahility negligence o r otherwise or frcm any use or operation of any methods products, instructions or ideas contained in the material herein Because of the rapid advances in the medical sciences, the Publisher recommends that independent verification o f diagnoses and drug dosages should be made S p e d rc7guluriotz.s f i i r reciders i i i rlic U S A This publication has been registered with the Copyright Clearance Center Inc (CCC) Salem, Massachusetts Information can he obtained from the CCC about conditions under which the photocopying o f parts of this publication may he madc in the USA All other copyright questions including photocopving outside of the USA should be referred to the Publisher ISBN 0-444-XO915-5 (volume) ISBN 0-434-80.303-3 (series) Published by: Elsevier Science Publishers B.V (Biomedical Division) P.O Box 211 1000 A E Amsterdam The Netherlands Sole distributors lor thc USA and C;ln;da: Elsevier Science Publishing Company Inc 51- Vandcrbilt Avenuc New York, NY 10017 USA Library of Congress Cataloging in publication Data Molecular genetics of inimunoglohulin (New comprehensive hiochcmistry ; v 17) Includes bibliographies and index 1, Immunoglobulins Genetics Gene exprcssion I Calahi, F (Franco) 11 Neuberger, M.S (Michael S.) 111 Series [DNLM: I Gene Expression Regulation Immunoglobulins genetics, WI NE372F v.17 / QW 601 M7181 QD4IS.N-IX ~ 571.19'2 s [616.07'9] 87-24302 (QR186.71 ISBN 0-444-80915-5 (U.S.) Printed in The Netherlands V Preface Immunoglobulin genes are not just of interest to immunologists An understanding of the way in which DNA rearrangement and somatic mutation contribute to antibody diversity is of importance to a wide range of biologists The cell-type specificity of immunoglobulin gene expression is of concern to many who are interested in gene expression in mammals Furthermore, the immunoglobulin superfamily itself presents important questions to those interested in evolution The analysis of immunoglobulins and of their genetics has advanced rapidly since the mid-l970s, mainly as a result of the application of recombinant DNA and monoclonal antibody technologies The essential features of the molecular anatomy of both antibodies and their genes have been largely identified; this has resulted in significant insights into the way antibody diversity is generated Clearly, much still remains to be elucidated in these areas, whilst studies both of regulation and of phylogeny are still in their infancy We felt nevertheless that it was a good time to draw together what we know about the molecular genetics of immunoglobulin We wish to thank the authors for contributing to this volume and the publisher for prompt publication Cambridge Franco Calabi Michael S Neuberger This Page Intentionally Left Blank Contents Preface List of abbreviations Chapter I Structure and function of antibodies D.R Burton (Sheffield, U K ) I Introduction Structure of IgG 2.1 General considerations 2.2 Domain structure 2.3 Structure of Fab 2.4 Antigen recognition 2.5 Structure of Fc 2.6 The hinge: IgG subclasses 2.7 Isotypes, allotypes and idiotypes Functions of IgG 3.1 Introduction 3.2 Interaction with protein A 3.3 Complement activation 3.4 Interaction with cellular 3.5 Other functions of IgG 3.6 Rheumatoid factors 3.7 Membrane or surface IgG 3.8 Structure-function relationships in IgG: domain hypothesis , , , , , , , , , Structure o f other immunoglobulins in relation t o IgG Structure and function of I g M 5.1 Structure of IgM 5.2 Functions of IgM 5.3 Membrane IgM Structure and function of IgA , 6.1 Structure of serum 6.2 Structure of secret 6.3 Functions of IgA v XII 1 3 6 11 21 21 22 24 26 27 27 28 36 37 39 39 39 41 41 VIII Structure and function of IgD X Structure and function of IgE X l Structure o f IgE Functions of IgE Summary 41 43 43 Acknowledgements References 46 47 Chapter Genes encoding the immunoglobulin constant regions M Briiggemann (Cambridge UK) 51 Introduction Chromosomal localization Organization of constant region genes 3.1 Mouse heavy chain genes 3.2 Mouse light chain genes Human heavy chain gencs 3.4 Human light chain genes 3.5 Other species 3.6 Switch regions 3.7 Membrane exons J chain constant region genes 4.1 Heavy chain genes 4.2 4.3 4.4 4.5 4.6 Light chain genes Polymorphism Pseudogenes Evolution Aberrations and malignancies 52 52 53 54 55 55 58 61 62 62 64 64 67 68 69 70 72 Acknowledgements References 75 75 Chapter Genes encoding the immunoglobulin variable regions P.H Brodeur (Boston MA USA) 81 Introduction V gene structure Gene families 3.1 Mouse VI, families 3.2 Human V,, families 3.3 Mouse V, families 3.4 Human V, families 3.5 Mouse V, families 3.6 Human V, families 86 87 88 89 89 IX Genenumber 4.1 Number of mouse V genes 4.2 Number of human V genes ., , , ,., , , , , Chromosome assignment Gene organization 6.1 Igh locus organization , , , , , , , , , 6.2 I g K locus organization 6.3 Igh locus organization Polymorphism Conclusions Acknowledgements , , , , , , , References 90 90 02 94 95 95 99 101 101 105 105 106 Chapter Assembly of immunoglobulin vuriuble region gene segmeitls M Reth and L Leclercq (Cologne, FRG and Paris, France) 111 Introduction mechanism 2.1 Joining signals , , , , , , , , , 2.2 Joining models , 2.3 Control of joining , , , , , , , Order of rearrangement events during B cell tlcvelopment 3.1, Rearrangements at the IgH locus 3.2 Rearrangements at the light chain loci , Allelic exclusion of immunoglobulin gcne expression 111 112 112 I14 129 Acknowledgements , , , Kefcrences 13 Chapter Immunoglobulin heavy chain cluss switching U Krawinkel and A Radbruch (Cologne, FRG) I17 131 135 Introduction 135 , 139 , , , , , , 142 145 3.2 Isotype commitment Molecular analysis , 4.2 4.3 4.4 4.5 Long transcripts , Class switch recombination Switch sequences Switch recombination sites .,, 140 146 232 J CD4 poly-lg receptor Thy-1 MRC OX-2 MHC molecules CD1 molecules T cell receptors Immunoglobulins IgG FcR I B-gP NCAM MAGiNcp Fig 12 Hypothetical evolutionary tree o l the immunoglobulin superfamily Round symbols, genes or gene segments; square symbols polypeptide units: tilled symbols V units: empty symbols; C units See text for details sulted from the fusion of multiple copies of a smaller building block [202]; (2) derivation of the C unit, which presumably greatly favoured chain-chain association, whilst allowing greater flexibility in the structure of the V domain; (3) splitting of the exon encoding the V domain which dramatically increased the potential for variability The evolutionary relatedness found amongst members of the immunoglobulin superfamily suggests that the diversity of present day functions constitutes an adaptation, under different selective pressures of the same primordial function The biological role of those members whose function has yet to be determined can also be expected to be related to this primordial function Since primordial functions are phylogenetically conserved, the investigation of structurally and/or functionally related systems in lower organisms can provide clues in the quest for the function of the primordial immunoglobulin system The study of the fusibility gene locus in Botryllus, a colonial tunicate, as well as of self-incompatibility systems in plants, has led to the suggestion that the vertebrate major histocompatibility complex, and thus perhaps the whole immunoglobulin superfamily, has derived from self-nonself recognition systems evolved to prevent self-fertilization in hermaphrodite organisms [203,204] 233 However, an alternative hypothesis is that the function of the primordial V unit derived from its propensity to self-associate [ 1871 Thus, the immunoglobulin superfamily may have evolved as a primitive, like-like recognition system Such a function is still clearly recognizable in the homophilic binding of NCAM, which is both documented in early embryogenesis and is conserved in phylogenesis, as well as in the interactions between immunoglobulin and immunoglobulin-like cellular receptors The interactions 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Lindsten T Okaniura, M., Cohen D.I and Davis, M.M (1984) Nature 312, 31-35 208 Chien Y.-h Gascoigne N.R.J Kavaler J Lee N.E and Davis, M.M (1984) Nature 309 322-326 239 209 Tunnacliffe A, Kefford, R Milstein C Forster, A and Rabbitts T.H (1985) Proc Natl Acad Sci USA 82, 5068-5072 210 Gascoigne N.R.J., Chien, Y.-h Becker D.M., Kavaler J and Davis M.M (1984) Nature 310, 387-391 211 Lefranc M.-P., Forster, A and Rabbitts T H (1986) Proc Natl Acad Sci USA 83 9596-9600 212 Lawrence, S.K., Smith C.L., Srivastava R., Cantor, C.R and Weissman S.M (1987) Science 235, 1387-1390 213 Klein J and Figueroa, F (1986) Immunol Today 7, 41-44 214 Klein, J and Figueroa, F (1986) Immunol Today 7, 78-81 215 Kimura, N., Toyonaga, B., Yoshikai, Y Du R.-P and Mak T.W (1987) Eur J Immunol 17 375-383 216 Chien, Y.-H., Iwashima M Kaplan K B Elliott, J.F and Davis M.M (1987) Nature 327, 677-682 This Page Intentionally Left Blank 24 Subject index a see IgA and IgH a , - B glycoproteins 227 228 Abelson lines, I 1, 138 147, 179,183 Acquired immune deficiency syndrome, 226 Adenovirus 158 I65 E3il9kDa glycoprotcins 231 Allelic exclusion 129 156 182 Allotypes 21 40 08 72 Alloreactivity 224 Alternative splicing 136, 140 144 227 231 Alu family 70 Anaphylaxis Antibody-dependent ccllular cytotoxicity 24 15 Antigen binding 37 181 Antigen presentation 220 Ars (/,-azophenylnrsonate) 104 184 187, 195 197 Avian B cells 136 /3,-microglobulin 221, 224 B cells 39 41 43 60 65 123 136 142 153 1.58 160 187 197, 220 H cell Iymphom;i 137 153 158 /I(./- alld h('l-2 74 BiP 130 Bovine IgH genes 56 Bursa of Fabricius 117 136 c-nzvc 73, 94, 144 Clq, 17 22 38 C D I , 219, 227 CD2 227 CD3 207, 212 215, 230 CD3 207 215 226, 231 CD8 207, 215, 226 Cell-type qxcificity 168 CG dinucleotide\, 225 Chi sequences 60 225 226 Chicken IgH genes 56 A genes 58 217 Chromatin 147 IS4 Chromosome localization, 51, 62, 94, 219 227 Chromosome translocations 73 115, 14.1 Class switch 57 135, 155, 192 commitment to 139, 143 frequency of 136 induction, 139 I43 in plasinacytoinas 144 long transcripts, 136 140 LPS activation 136 143 rccombination 142 I46 regulation I38 \econdary I37 sequences 145 Clonal selection theory I04 Clonal senescencc 196 Coin hi 11nt ori al diversity , I 78 I Complement 17 18 20 22 38 41 55 Coinplementaritv determining regions (CDR's) 5, 87 120 182 180 191 207, 212 214 217 Co-expression IgH gene\ 140 166 173 Constant (C) region 211 genes, 52, 213 Cytomegalovirus, 163 23 Cytotoxicity 215 antibody-dependent 715 we IgD and IgH Dcletional joining 16 Deletions of inimunoglohulin, 72 Diversity 115 177 210 220 224 Diversity ( D ) segments, 52 82, 95 OX, 116 119%178 1x3 210, 212 usage, 121 DJII replacements 122 transcripts 122 156 DNase in joining 117 DNase I sensitivity 118 145 154 Domains of immunoglobulin, , 27 see IgE and IgH 242 E l a protein of adenovirus 158 E3ilYkDa glycoprotein of adenovirus type 2, 231 En h‘i nce r IgH 125 159, 168 K 163 polyoma 160 s v 160 Exonuclease in joining, 115 Fab and F(ab’), fragments 3, 32 207 Fc and pFc’ fragments, I , 11 25 26 Fc receptors 18 24, 39 41 44 46, 141, 215 228 Flexibility of immunoglobulin 18 Framework regions 82 Fusibility gene locus 232 y si’c IgG and IgH Gene conversion, 58 64 71 72 104 193, 225 Genomic footprinting, 161 Glycosylation 11 40 42 156 Hamster IgG genes 56 Haplotypes 69, 103 146 226 Heavy-chain binding protein 130 Heptamer 112, 124, 128, 180 Heptamerinonamer signals, 83 112, 209 Hinge region, 18, 64 HIV-I 163, 226 gpl 10 231 HLA-A 220 -B 220 -c.220 -DP 220 -DO 220 -DR 220 Human Fc receptors 25 hypervariable minisatellite regions 226 IgH enhancer, 159 IgH locus 54, 64 95 immunodeficiency virus, 163 226 light chain loci, 55 99, 101 V,, families, 86 V, families 87 V, families 89 Hybridomas, 86 138, 187 Hypervariable regions see Complementarity determining regions Hypodactyly, 94 Idiotype 21 IgA 230 (I gene structure, 64 allotypes 40 expression 141 functions, 39, 41 hinge homology to CD8 227 secretory form 41 serum form 39 sequence 29 structures, 39 41 IgD gene structure 64 expression, 155 166 sequence 29 function 43 receptors 43 structure 741 IgE binding lactors 45 E gene structure 66 expression 141, 166 function 44 receptor 45 sequence 29 structure 43 IgG binding factors, 26 clearance 26 complement activation 21 expression 1-11 Fc receptor binding, 24 functions 21 y gene structure 65 membrane form, 27 61 protein A binding 21 sequence 12 structure IgH-DEX idiotype 98 IgH genes bovine 56 chicken S6 chromosome localization 51 94 co-expression 140 166, 173 deletions 71 enhancer, 125, IS9 hamster, 56 haplotypes 69 103 146 human 54 64 86 89 95 hypermethylation 130 243 mouse 52 64, 85, 89 95 rabbit rat 56 rearrangcment I19 R N A processing 170 shark, 57 sterile transcripts, 118 155 IS6 X laevis 57 IgH locus organization 96 Ig,-Efl and Ig,-Ef2, 99 IgM 230 complemcnt activation, 38 expression 141 164, 167 170 Fc receptor binding, 39 functions 36 membrane lorm 39, h l 164, 170 p gene structure 64 wcreted form 164 170 sequence 29 structure, 36 Immune precipitation 27 Immunological memory 196 Immunoglobulin carbohydrate chains 6, I I , 40 42 complementarity determing regions ( C D R s ) 82 120 182 189, 191 constant (C) region doinains 27 62 gene evolution 70 chromosomal localization 51 61 94 heavy chain isotypes 21 135 light chain hoinology unit 203 in the star lish 55 superfamily 68 71 variable ( V ) regions Influenza haemagglutinin 1x8 195 lntcrleukin (IL-4), 139, 143 147 lntcrvening sequence-mediated transfer, 72 Inversional joining, 116 127 lsotypc, 21, x4 135 a t the TcRV, locu\ 117 210 control of 11X D to D 184 210 D to Jll 116 119, 210 111 B cell development 126 replacement, 118 wcondary 120 179, 21 5ignals 83 112 128 209 V,,to DJ,, 118 122 I23 V I It o V ~ ~ DI IJX ,~ 124 ~ , V, t o J, 116 127 V, to J, 128 Junctional diversity, 182 K K genes chroinosome localization I , 94 227 human 55 67 88 99 227 mouse, 5.1, 67, X7 09 227 rabbit 57 rat, 57, 68 rcarrangemcnt 114 126 locus organization 99 A genes chicken 58 67 217 chromosome localization 52, 94 enhancer, I59 isotypcs 55 67 human -55 67 8Y 101 mouse, 53 07 89 101 rabbit 58 67 rat 57 rearrangement 126 I28 A locus organization 101 Leader sequence 83 Long terminal repeats (LTRs) 69 LPS cultures 136 139 142 LPS induction 163 Lyb-5 B cells 197 Ly-l B cells 198 Lyt-2.3, 94 Lysozyme w see IgH and IgM J chain 36 62 156 I68 Joining ( J ) segments 52 82 95 98 100 127, 178 210 217 usage 119 127 211 Joining 112, 179 192 accessibility model 118 M,icrophage 220 Mast cells, 45 Major histocompatiblllty complex (MHC) 101 193.219 232 class molecules 2lY 228 231 class I1 molecules 219 227 228 244 haplotypes 226 molecule, 233 binding to short peptides, 224 diversity, 220, 224 framework regions 22 I hypervariable regions 221 223, 225 intracellular transport, 224, 231 structure, 221 polymorphism 220 225 recombination 226 hotspots 226 restriction, 207, 212, 213 224 Membrane immunoglobulin 27 38 61, 155 164 170 Memory cells 136 137, 196 Messenger RNA turnover 167 170 Methylation, 130 140 145 154 Mouse /fill locus, 52, 95 light chain loci, 53 99 1 V,, families 85 V, families, 87 C - I T Z ~ C 74 94 144 MRC OX-2, 228 Myelin associated glycoprotein (see alro Neu ronal cytoplasmic protein), 227, 228 231 Myeloid cells 156 N segments 58 114 117, 182 210 218 Natural killcr cells, 25, 215 Neuronal cell-adhesion molccule, 227, 228 229 230 233 Neuronal cytoplasmic protein (see crl.ro Myelin associated glycoprotein) 227, 228 231 NF-AI and NF-A2 I NF-KB, 163 NF-pE1 163 NF-pE3 I63 Nonanier 112 NP (4-hydroxy-3-nitrophenylacetyl) 8, 104 1x7 196, 197 Octanuclcotide motif 83 158 Ox (2-phenyl-5-oxazolone) 189, 195 197 Phagocytosis, 24 Phosphoinositide, 229, 230 PC (phosphorylcholine), 104, 187 Plasmrrblasts 135 148 Plasma cells, 137, 153, 157, 169 Plasniacytoma 137, 144, 1.53 169 Poly-immunoglobulin receptor 41, 227, 228, 230 Polyadenylation 154 165 170 signals 65 151 Polymorphism, 68 1 , 220 225 Polyoma cnhanccr, 160 Post-translational regulation, 167 Post-transcriptional regulation 164 170 Pre-B cells 1 121 136 140 153 158 178, 190 192 Primary ostcoarthritis 17 Promoter, 157 164 Promoter upstream clement, 157 Protein A 17 21 Pseudogencs 52, 54 69, 124 129, 217 pv1- I , 74 Rabbit lgH genes 55 K genes 57 A genes 58 Rat IgH genes, 56 K genes 57 68 A genes, 57 Rearrange men t sce J oining Recombination, 146 193 225 226 hotspots, 226 Restriction fragmcnt length polymorphism 55 69 97 99 I04 rheumatoid arthritis 17 27 factors 27 RNA processing, p1,,and p,, 170 splicing 166, 170 turnover 167 RS (rearranging sequence) 126, 128 Secreted immunoglobulin, 61, 165 Secretory component, 39 41, 61, 230 Self-incompatibility systems, 232 Serine protease inhibitors, 225 Serum levels of immunoglobulins, 45 Severe combined immune deficiency, 114 Shark, 57,71, 114 Signal sequence, 83 Somatic mutation 57, 58 177 186 at TcR loci, 212 218 245 Splicing, see R N A Sterile transcripts 118 140 155 SV40 enhancer 160 163 Switch, see Class switch Switch (S) regions, 58, 69 70 144 145 Tcells 43 117 119, 123 139, 156, 158, 162 169 197 212 cytotoxic, 214, 220 helper 214 T cell activating protein (TAP), 229 T cell receptor 100, 114, 116 122 206, 220 223 233 LY chain gene inversic~n/translocation,75 I 17 a/P, 207, 214 226 C region 212 glycosylation 12 hypervariable regions 207 212, 214 interchain disulphide bond 212 somatic mutation, 212 thymic selection, 212 214 V gene segments 210 V regions 209 V segment replacement, 218 /3 chain gene inversional joining, 116 117 retrovirus transduced, 23 I yl6, 215 expression, 215 in ontogeny, 215 and MHC restriction 215, 218 y chain, 216 connecting peptide, 216 glycosylation 216 hypervariahle regions 217 loci, 57 216 somatic mutation, 218 V gene segments, 217 V segment usage, 218 V segment replacement, 218 chain, 216 genes, chromosomal location, 52, 94 T cell repertoire 220 TATA box 83 157 Terminal trransferase 114 117, 182 211 Termination of transcription, 164 Thy- I , 228, 229 230 in squid brain 229 231 T L antigens 219 Tolerance, 196 1-opographical determinant Transcript ion at the TcR (Y locus 210 initiation, 157 polyadenylation 165 170 termination I64 ( b e ulso RNA Transgenic mice 130 161, 168 Translation, I67 Unequal crossing-over, 57, 72 140, 22.5 V genes, 83, 209 families 84 210 223 numbers 90, 178 polymorphism 101 rearrangement 112 179, 192, 209 structure, 81 V segments 82, 123, 178 210, 217 replacement 124 180, 211 218 usage, 123, 125, 180, 218 Variability, Variable (V) region(s), evolution, 209 isotypes, 84 subgroups 84 V , , genes, X4, 123 V,, transcripts, 123 130, 157 V, gencs, 53, 55 XI, 127 V, genes, 53 54 89, 128 V, transcripts, 157 Z-DNA 64 226 This Page Intentionally Left Blank .. .MOLECULAR GENETICS OF IMMUNOGLOBULIN New Comprehensive Biochemistry Volume 17 Generml Editors A NEUBERGER London L.L.M van DEENEN Utreclzt ELSEVIER Amsterdam New York * Oxford Molecular Genetics. .. New York, NY 10017 USA Library of Congress Cataloging in publication Data Molecular genetics of inimunoglohulin (New comprehensive hiochcmistry ; v 17) Includes bibliographies and index 1, Immunoglobulins... from papain digestion of immunoglobulin antigen binding fragment from pepsin digestion of immunoglobulin crystallizable fragment from papain digestion of immunoglobulin immunoglobulin Fc receptor