Molecular Aspects of Innate and Adaptive Immunity

311 Pages·2008·11.56 MB·English

by  Kenneth B. M. Reid

Molecular Aspects of Innate and Adaptive Immunity
Dedication
ThisbookisdedicatedtoallformermembersoftheMedicalResearchCouncil
ImmunochemistryUnit,1967–2008,andespeciallyinremembranceofthestaff
members Rod Porter, Rachel Fruchter, Lawrence Mole, Alan Williams, Tony
Gascoyne, Audrey Richards, and visiting scientists Marion Koshland, Metta
Strand, Walter Palm and Gordon Ross.
Molecular Aspects of Innate
and Adaptive Immunity
Edited by
Kenneth BM Reid and Robert B Sim
MRC Immunochemistry Unit, Department of Biochemistry, University of
Oxford, Oxford, UK
ISBN: 978-0-85404-698-0
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
rRoyalSocietyofChemistry,2008
Allrightsreserved
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Preface
This volume provides a survey of topics in the area of innate and adaptive
immunity, which have been researched within the MRC Immunochemistry
Unit, Oxford University, over a period of 40 years. The Unit was formed in
1967,withProfessorR.R.Porter(whowasawardedaNobelPrizein1972for
hisresearchonantibodystructure)asitsfirstDirector,withProfessorK.B.M.
Reid being Director from 1986 onwards.
Theextensionoftheresearchonantibodystructureintoastudyofoneofthe
body’s majordefence systems, thecomplementsystem(whichcanbetriggered
by many stimuli including antibody recognition of invading microbes) led to
the molecular characterization of many of the proteins of this important cas-
cade system. Particular attention was paid to the structure–function relation-
ships and genetics of the early components of the system, especially
components C1q, C1r, C1s, C2, factor B, factor D, the allotypes of C4, the
covalentbindingproperties ofactivatedC3 andC4,andalso theproteinsthat
regulate complement activation – such as C1inhibitor, factors H and I, C4b-
bindingproteinandproperdin. Studiesofcomplementreceptorspecificityand
structure were also undertaken, as well as a range of studies on complement
evolution and phylogeny.
Thedomainorganizationandfunctionsofhumanleukocyteintegrins(twoof
which are complement receptors), particularly with respect to heterodimer
formation and activation of integrins, analysis of their deficiency [leukocyte
adhesion deficiency (LAD)] and the involvement of these molecules in the
recognition and resolution of inflammation, was another long-term research
topic.
ThestudyofthemoleculargeneticsofcomplementcomponentC4ledonto
the analysis of a range of disease-susceptibility genes within the human major
histocompatibility complex (MHC) Class III region, and of associated novel
genes within the human MHC. These included heat shock protein (HSP) 70,
tumournecrosisfactor(TNF)alphaandcytochrome(Cyt)P450lociandtheir
association with immune-related diseases, a topic that has been a major
research interest within the Unit.
MolecularAspectsofInnateandAdaptiveImmunity
EditedByKennethBMReidandRobertBSim
rRoyalSocietyofChemistry,2008
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
v
vi Preface
Thecharacterizationofmembraneproteinsonleukocyteswasinitiatedinthe
early 1970s, and led to the concept that many of these molecules belong to an
immunoglobulinsuperfamily.ThisresearchwasinitiatedbyAlanF.Williams
intheImmunochemistryUnitandcontinued,from1978onwards,intheMRC
Cellular Immunology Unit.
Inmore recent years, structural andfunctionalstudiesofhyaluronan (HA)-
binding proteins and receptors, involved in extracellular matrix remodelling
and leukocyte migration during inflammation, formed a major research focus
intheUnit.HAisahighmolecularweightpolysaccharidefoundintissuesofall
vertebrates.TheinteractionofHA-bindingproteinswithHAhasacentralrole
in the formation and stability of extracellular matrix (e.g. in cartilage) and is
also important in immune-cell trafficking. The research has concentrated on
TSG-6(theproteinproductofTNF-stimulatedgene-6),anHA-bindingprotein
which is only expressed in adult tissues during inflammation, and the ubiqui-
tous HA-receptor CD44, which is involved in matrix assembly and leukocyte
migration.
Another major interest within the Immunochemistry Unit has involved the
family of collectin molecules – which contain distinct globular carbohydrate-
binding domains linked to collagen-like regions – and play important roles in
innate immunity in the lungs and bloodstream by immediate recognition and
clearanceofmicrobialpathogens.Thiswasmostrecentlyextendedtoincludethe
ficolins, which have structural and functional similarities to the collectins. The
serum collectin mannan-binding lectin (MBL) and ficolins recognize arrays of
neutral sugars or acetylated compounds on microorganisms as being foreign
and, after binding to them, stimulate activation of MBL-associated serine
proteases(MASPs),whichresultinactivationoftheserumcomplementsystem–
thusrecruitingoneofthemajordefencesystemsinthebody.Collectinsfoundin
lung surfactant (surfactant proteins A and D (SP-A and SP-D)) also recognize
and clear microorganisms, but without involvement of complement activation.
Thecollectinsandficolins,inadditiontotheirinteractionswithmicroorganisms,
can resolve inflammation by binding to and promoting clearance of apoptotic
cellsandDNA–andbymodulatingthemannerinwhichallergensareprocessed
by dendritic cells. Recombinant forms of the collectins and ficolins are con-
sidered as candidates for new therapeutics for the treatment of infection and
inflammation.
Each chapter in the volume gives a brief historical background to a topic,
with some emphasis on work carried out within the Immunochemistry Unit,
and then provides a survey of recent advances in the field. The main theme
running through most of the chapters is that of protein structure–function
relationships – good examples being the descriptions of quaternary structures
oflargeoligomericproteins,offactorHandC1qbindingtospecificligands,or
of the chemistry of the mechanism of catalysis of the covalent binding of
activated C3 and C4 proteins to nucleophilic groups on microbial surfaces.
Kenneth B. M. Reid
Robert B. Sim
Contents
Section 1 Antibodies
Chapter 1 R. R. Porter and the Structure of Antibodies
Lisa A. Steiner and Julian B. Fleischman
1.1 Introduction 3
1.2 The Papain Fragments 4
1.3 The Four-chain Model 7
1.4 V and C Regions of Immunoglobulin Chains 8
References 9
Chapter 2 Chemical Engineering of Therapeutic Antibodies
George T. Stevenson and Weng Leong
2.1 Introduction 11
2.1.1 Structure of IgG 11
2.1.2 Availability of SH Groups 13
2.1.3 Enzymic Dissections 13
2.2 Useful Chemistry of SH Groups and SS Bonds 14
2.2.1 SS Interchange 15
2.2.2 Alkylation of SH Groups by Maleimides 17
2.3 Engineering IgG Modules 18
2.3.1 Attaching the PDM Linker to Fcg 19
2.3.2 Attaching the PDM Linker to Fab0g 20
2.3.3 Examples of Therapeutic Constructs 21
Acknowledgements 23
References 23
MolecularAspectsofInnateandAdaptiveImmunity
EditedByKennethBMReidandRobertBSim
rRoyalSocietyofChemistry,2008
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
vii
viii Contents
Section 2 The Complement System
Chapter 3 The Evolution of Complement Systems
Alister W. Dodds
3.1 Phylogeny in the MRC Immunochemistry Unit 27
3.2 Evolution of Immune Systems 28
3.3 Evolution of the Complement System 30
3.3.1 The Complement Pathways 30
3.3.2 Loss and Gain of Complement Components
in Some Evolutionary Lines 31
3.4 Phylogeny of the Complement System 33
3.4.1 Recognition Molecules; Ficolins, MBL and
C1q 34
3.4.2 Initiation Enzymes; Factor D, MASPs, C1r
and C1s 37
3.4.3 Thioester Proteins: C3, C4, C5, a2M, CD109
and Insect Thioester Proteins 39
3.4.4 Amplification Enzymes; C2 and Factor B 40
3.4.5 Lytic Proteins; C6, C7, C8 and C9 41
3.4.6 Control Proteins and Receptors 41
3.4.7 Possible Origins of Complement 42
3.5 Summary 43
Acknowledgements 43
References 44
Chapter 4 Structure and Function of the C1 Complex: A Historical
Perspective
Ge´rard J. Arlaud
4.1 From the Antibody to the C1 Complex of
Complement 49
4.2 Biochemistry of C1q and Elucidation of its Primary
Structure 50
4.3 Biochemistry of C1r and C1s and the C1 Activation
Mechanism 53
4.3.1 Biochemistry of C1r and C1s 53
4.3.2 Insights into the C1 Activation Mechanism 53
4.3.3 The Primary Structure of C1r 54
4.4 From the Domain Structure of C1r and C1s
to a Model of C1 Architecture 55
4.4.1 The N-terminal Interaction Domains 55
4.4.2 The C-terminal Catalytic Domains 56
4.4.3 A Low-resolution C1 Model 57
Contents ix
4.5 The Era of Structural Biology 57
4.5.1 A Three-dimensional C1 Model 57
4.5.2 C1r Activation and the Triggering Signal 58
4.5.3 C1q:BindingVersatilityArisesfromModularity 60
4.6 Conclusions and Perspectives 61
References 61
Chapter 5 Complement Components C3 and C4
S. K. Alex Law
5.1 The Road to Oxford 65
5.2 The Autolytic Cleavage Reaction 67
5.3 Red Wine and the Isotypes of C4 69
5.4 LOO-3,theAnti-C4MonoclonalAntibodythatOnly
Worked for Us 70
5.5 How to Catch Up from Three Years Behind 72
5.6 C4K and C4Y 74
5.7 The Best Beer that I had Ever Tasted 76
5.8 Silence is Golden, but could be Painful 76
5.9 A Bet that I both Won, and Lost 77
5.10 Final Comments 79
Acknowledgements 80
References 81
Chapter 6 Complement Control Proteins and Receptors:
From FH to CR4
Robert B. Sim, Beryl E. Moffatt, Jacqueline M. Shaw and
Janez Ferluga
6.1 Introduction 84
6.2 Factor H 85
6.3 Factor I 93
6.4 C4b-Binding Protein and Properdin 95
6.5 Complement Receptors 96
6.6 Complement Research into its Third Century 98
Acknowledgements 98
References 99
Chapter 7 Biology and Genetics of Complement C4
Michael C. Carroll
7.1 Introduction 105
7.2 Early Days in Oxford 105
7.3 Linkage of Innate and Adaptive Immunity 108
7.4 C4 and Autoimmunity 109
x Contents
7.5 Anti-RNA Mouse Model 111
7.6 Models for C4 in B Cell Tolerance 113
7.7 Summary 114
References 114
Section 3 Collectins and Ficolins in Innate Immunity
Chapter 8 The Structure of Mannan-binding Lectin and its
Functional Relevance
Jinhua Lu and Steffen Thiel
8.1 Introduction 121
8.2 MBL was Purified as a ‘By-product’ 122
8.3 MBL Structure, Genetics and Heterogeneity in Size 123
8.4 Concluding Remarks 126
References 127
Chapter9 PersonalAccountsoftheDiscoveryofMASP-2anditsRole
in the MBL Pathway of Complement Activation
Thomas Vorup-Jensen and Jens Chr. Jensenius
9.1 Preamble 129
9.2 The Oxonian Connection 130
9.3 MASP and the Serine Proteases of the
Complement System 131
9.4 Gene Characterization in the Pre-genomic Age:
Discovering MASP-2 134
9.5 Beyond Finding MASP-2 140
9.6 MASP-3: One Gene, Two Enzymes 142
9.7 End Note 143
References 144
Chapter10 TheStructureandFunctionofFicolins,MBLsandMASPs
RussellWallis,AndersKrarup andUmakhanthVenkatraman
Girija
10.1 Introduction 147
10.2 MBL and Ficolins in the Innate Immune System 148
10.3 Genetics of MBLs and Ficolins 148
10.3.1 Genetics and Tissue Distributions of MBLs 148
10.3.2 Genetics and Tissue Distributions of
Ficolins 151
10.4 Structural Organization of MBLs and Ficolins 152
10.5 Target Recognition by MBLs and Ficolins 155
10.5.1 Sugar Recognition by MBLs 155
10.5.2 Ligand binding by Ficolins 155