197,99 €
Mehr erfahren.
- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Human Blood Groups is a comprehensive and fully referenced text covering both the scientific and clinical aspects of red cell surface antigens, including: serology, inheritance, biochemistry, molecular genetics, biological functions and clinical significance in transfusion medicine.
Since the last edition, seven new blood group systems and over 60 new blood group antigens have been identified. All of the genes representing those systems have now been cloned and sequenced.
This essential new information has made the launch of a third edition of Human Blood Groups, now in four colour, particularly timely.
This book continues to be an essential reference source for all those who require clinical information on blood groups and antibodies in transfusion medicine and blood banking.
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 1728
Veröffentlichungsjahr: 2013
Ähnliche
Table of Contents
Title page
Copyright page
Foreword to 1st edition
Preface to the third edition
Some abbreviations used
1 Human Blood Groups: Introduction
1.1 Introduction
1.2 Blood group terminology
1.3 Chromosomal location of blood group genes
1.4 DNA analysis for blood group testing
1.5 Structures and functions of blood group antigens
2 ABO, H, and Lewis Systems
Part 1: History and introduction
Part 2: Biochemistry, inheritance, and biosynthesis of the ABH and Lewis antigens
2.2 Structure of ABH, Lewis, and related antigens
2.3 Biosynthesis, inheritance, and molecular genetics
Part 3: ABO, H, and secretor
2.4 A1 and A2
2.5 ABO phenotype and gene frequencies
2.6 Secretion of ABO and H antigens
2.7 Subgroups of A
2.8 Subgroups of B
2.9 Amos and Bmos
2.10 A and B gene interaction
2.11 Overlapping specificities of A- and B-transferases (GTA and GTB)
2.12 H-deficient phenotypes
2.13 Acquired alterations of A, B, and H antigens on red cells
2.14 ABH antibodies and lectins
Part 4: Lewis system
2.15 Lea and Leb antigens and phenotypes
2.16 Antigen, phenotype, and gene frequencies
2.17 Lewis antibodies
2.18 Other antigens associated with Lewis
Part 5: Tissue distribution, disease associations, and functional aspects
2.19 Expression of ABH and Lewis antigens on other blood cells and in other tissues
2.20 Associations with disease
2.21 Functional aspects
3 MNS Blood Group System
3.1 History and introduction
3.2 Biochemistry and molecular genetics
3.3 MN and Ss polymorphisms
3.4 Effects of enzyme treatment on the MNSs antigens
3.5 The rare glycophorin A-deficient phenotypes En(a−) and MK
3.6 U antigen and the GPB-deficient phenotypes S– s– U− and S– s– U+var
3.7 M and N variants representing amino acid substitutions within the N-terminal region of GPA and GPB
3.8 The Miltenberger series
3.9 Hybrid glycophorins and the low frequency antigens associated with them
3.10 GP(A–B) variants
3.11 GP(B–A–B) variants
3.12 GP(A–B–A) variants
3.13 Further details on Hil, TSEN, MINY, Mur, and Mia; antigens associated with hybrid glycophorins
3.14 GP(B–A)-associated variants
3.15 Antigens associated with GPA amino acid substitutions proximal to the membrane and with abnormal expression of Wrb
3.16 Other low frequency antigens of the MNS system
3.17 Antigens associated with atypical glycophorin glycosylation
3.18 M, N, S, s, and U antibodies
3.19 GYPA mutation assay
3.20 Association with Rh
3.21 Glycophorins as receptors for pathogens
3.22 Development and distribution of MNS antigens
3.23 Function and evolution of glycophorins
4 P1PK, Globoside, and FORS Blood Group Systems, plus Some Other Related Blood Groups
4.1 Introduction
4.2 Biochemistry, biosynthesis, and genetics
4.3 P1 (P1PK1) and anti-P1
4.4 Pk phenotype, Pk (P1PK3) antigen, and anti-Pk
4.5 NOR (PIPK4) antigen and polyagglutination
4.6 P (GLOB1) antigen and anti-P
4.7 FORS1 and the Forssman glycolipid
4.8 LKE and anti-LKE
4.9 Sialosylparagloboside and PX2 antigen
4.10 p Phenotype and anti-PP1Pk
4.11 Other P antibodies
4.12 P antigens as receptors for pathogenic micro-organisms
4.13 The association of P antibodies with early abortion
5 Rh and RHAG Blood Group Systems
5.1 Introduction
5.2 History
5.3 Notation and genetic models
5.4 Haplotypes, genotypes, and phenotypes
5.5 Biochemistry and molecular genetics of the Rh polypeptides
5.6 D and variants of D
5.7 Predicting D phenotype from DNA
5.8 C and c
5.9 E and e
5.10 Compound CE antigens
5.11 G (RH12)
5.12 Cw, Cx, and MAR
5.13 VS (RH20) and V (RH10)
5.14 Variants with abnormal Cc and Ee antigens
5.15 Haplotypes producing neither E nor e; D– – and related phenotypes
5.16 Rh-deficiency phenotypes: Rhnull and Rhmod
5.17 Low frequency Rh antigens and the antibodies that define them
5.18 Rh antibodies
5.19 Rh mosaics and acquired phenotype changes
5.20 The RHAG blood group system
5.21 Development and distribution of Rh antigens and RhAG
5.22 Functional aspects of the Rh and RhAG proteins
5.23 Evolutionary aspects
6 Lutheran Blood Group System
6.1 Introduction
6.2 The Lutheran glycoproteins and the gene that encodes them
6.3 Lua and Lub (LU1 and LU2)
6.4 Other Lutheran antigens and antibodies
6.5 Recombinant Lutheran antigens
6.6 Effects of enzymes and reducing agents on Lutheran antigens
6.7 Lunull and anti-Lu3 (LU3)
6.8 Lumod : the In(Lu) phenotype
6.9 Acquired Lu(a−b−) phenotypes
6.10 Distribution, functions, and disease associations
7 Kell and Kx Blood Group Systems
7.1 Introduction
7.2 The Kell glycoprotein and the gene that encodes it
7.3 K and k (KEL1 and KEL2)
7.4 Kpa, Kpb, and Kpc (KEL3, KEL4, and KEL21)
7.5 Jsa and Jsb (KEL6 and KEL7)
7.6 Other Kell-system antigens
7.7 The Kell-null and Kell-mod phenotypes and anti-Ku (-KEL5)
7.8 Kell depression in Gerbich-negative phenotypes
7.9 Acquired and transient depressed Kell phenotypes
7.10 Effects of enzymes and reducing agents on Kell antigens
7.11 Kell antigens on other cells and in other species
7.12 Functional aspects
7.13 The Kx blood group system
8 Duffy Blood Group System
8.1 Introduction
8.2 DARC, the Duffy glycoprotein, and the gene that encodes it
8.3 Fya and Fyb (FY1 and FY2)
8.4 Fy(a–b–) phenotype; Fy3, Fy5, and Fy6 antigens
8.5 Duffy genotype determination
8.6 Site density, development, and distribution of Duffy antigens
8.7 The Duffy glycoprotein is a chemokine receptor
8.8 Duffy antigens and malaria
8.9 Other disease associations
9 Kidd Blood Group System
9.1 Introduction
9.2 The Kidd glycoprotein and the gene that encodes it
9.3 Jka and Jkb (JK1 and JK2)
9.4 Jk(a–b–) phenotype and Jk3 antigen
9.5 The Kidd glycoprotein is the red cell urea transporter UT-B
10 Diego Blood Group System
10.1 Introduction
10.2 Band 3, the red cell anion exchanger (AE1), and the gene that encodes it
10.3 Dia and Dib (DI1 and DI2)
10.4 Wright antigens
10.5 Other Diego antigens, DI5 to DI22
10.6 Band 3 deficiency
10.7 Functional aspects and band 3 membrane complexes
10.8 Tissue distribution
10.9 South-East Asian ovalocytosis (SAO)
11 Yt Blood Group System
11.1 Introduction
11.2 Yt antigens and red cell acetylcholinesterase
11.3 Yta and Ytb
11.4 Anti-Yta and -Ytb
11.5 Transient Yt(a–b–) phenotype, anti-Ytab, and red cell AChE deficiency
12 Xg Blood Group System
12.1 Introduction
12.2 Xga frequencies
12.3 Xga inheritance
12.4 Xga antigen
12.5 Anti-Xga
12.6 CD99, a quantitative polymorphism related to Xg
12.7 X-chromosome inactivation and the pseudoautosomal region
12.8 CD99 and XG genes
12.9 A model for explaining the association between the Xg and CD99 polymorphisms
12.10 XX males and sex chromosome aneuploidy
12.11 Functional aspects and association with disease
12.12 Xga and CD99 in animals
13 Scianna Blood Group System
13.1 Introduction
13.2 ERMAP, the Scianna glycoprotein, and the gene that encodes it
13.3 Scianna antigens
14 Dombrock Blood Group System
14.1 Introduction
14.2 The Dombrock glycoprotein, ART4, and the gene that encodes it
14.3 Dombrock antigens
14.4 Dombrock system antibodies
15 Colton Blood Group System
15.1 Introduction
15.2 The Colton glycoprotein, aquaporin-1, and the gene that encodes it
15.3 Coa and Cob (CO1 and CO2)
15.4 Co3 and the Conull and Comod phenotypes
15.5 Co4 and the Co(a−b−) Co:3 phenotype
15.6 Colton antigens and monosomy 7
15.7 Colton antibodies
15.8 Functional aspects
16 LW Blood Group System
16.1 Introduction and history
16.2 The LW glycoprotein (ICAM-4) and the gene that encodes it
16.3 LWa and LWb (LW5 and LW7)
16.4 LW(a–b–) and LWab (LW6)
16.5 LW expression and effects of enzymes and reducing agents
16.6 Acquired LW-negative phenotypes and transient anti-LW
16.7 LW antibodies
16.8 Functional aspects and disease association
16.9 LW antigens in animals
17 Chido/Rodgers Blood Group System
17.1 Introduction
17.2 Basic serology
17.3 Ch and Rg antigens are located on C4
17.4 Further complexities of C4
17.5 Further complexities of Chido and Rodgers
17.6 Chido/Rodgers antibodies: clinical significance
17.7 Associations with disease
18 Gerbich Blood Group System
18.1 Introduction
18.2 Glycophorin C (GPC) and glycophorin D (GPD), and GYPC, the gene that encodes them
18.3 The high frequency antigens Ge2, Ge3, and Ge4, and the Gerbich-negative phenotypes
18.4 Other Gerbich antigens
18.5 Gerbich antibodies
18.6 Development and distribution of Gerbich antigens
18.7 Functional aspects: association of GPC and GPD with the membrane skeleton
18.8 Malaria
19 Cromer Blood Group System
19.1 Introduction
19.2 Decay-accelerating factor (DAF) and the Cromer system
19.3 Inab, the Cromer-null phenotype, and anti-IFC (-CROM7)
19.4 Cromer system antigens and antibodies
19.5 Functional aspects DAF and CD59: GPI-linked complement-regulatory proteins
19.6 DAF as a receptor for pathogenic microorganisms
20 Knops Blood Group System and the Cost Antigens
20.1 Introduction
20.2 Complement receptor 1 (CR1) and the Knops system
20.3 Helgeson, a mod phenotype in the Knops system
20.4 Antigens of the Knops system
20.5 Knops system antibodies
20.6 Functional aspects of CR1, a complement-regulating protein
20.7 CR1 associations with malaria and other pathogens
20.8 The Cost collection: Csa and Csb (COST1 and COST2)
21 Indian Blood Group System and the AnWj Antigen
21.1 Introduction
21.2 CD44 and the Indian antigens
21.3 Indian antigens
21.4 Effects of In(Lu) on CD44 and Indian antigens
21.5 Indian antibodies
21.6 Functional aspects of CD44
21.7 AnWj (901009)
22 Ok Blood Group System
22.1 Introduction
22.2 Basigin, the Ok glycoprotein
22.3 OK antigens and antibodies
22.4 Tissue distribution and function of basigin
22.5 Basigin and malaria
23 Raph Blood Group System
23.1 Introduction
23.2 CD151 and the tetraspanin superfamily
23.3 CD151 is the Raph glycoprotein
23.4 MER2 (RAPH1) antigen and anti-MER2
23.5 Disease associations and functional aspects
23.6 Tetraspanin CD82 is also present on red cells
24 JMH Blood Group System
24.1 Introduction
24.2 The JMH glycoprotein is semaphorin 7A (CD108)
24.3 JMH (JMH1)
24.4 JMH variants
24.5 Anti-JMH
24.6 Functional aspects
25 I and i Antigens, and Cold Agglutination
25.1 Introduction
25.2 I (I1) and i antigens
25.3 Biochemistry and molecular genetics
25.4 Adult i and other rare phenotypes
25.5 Distribution of Ii antigens
25.6 Ontogenesis and oncogenesis
25.7 I and i antibodies
25.8 I and i antigens and disease
25.9 Other cold agglutinins
26 Gill Blood Group System
26.1 Introduction
26.2 GIL (GIL1) and anti-GIL
26.3 Aquaporin-3 and GIL
26.4 Functional aspects
27 Junior and Langereis Blood Group Systems
27.1 Introduction
27.2 ATP-binding cassette (ABC) transporters
27.3 Junior system, Jra antigen, and ABCG2
27.4 Langereis system, Lan (LAN1) antigen, and ABCB6
28 Er Antigens
28.1 Introduction
28.2 Er antigens
28.3 Antibodies
29 Low Frequency Antigens
29.1 Antigens
29.2 Antibodies
29.3 Additional information on some of the antigens and antibodies
30 High Frequency Antigens, including Vel
30.1 Introduction
30.2 Vel (VEL1)
30.3 ABTI (VEL2)
30.4 Ata (August, 901003)
30.5 Emm (901008)
30.6 AnWj (901009)
30.7 PEL (901014)
30.8 MAM (901016)
31 Sid Antigen
31.1 Introduction
31.2 Sda and Cad
31.3 Sid antibodies and lectins
31.4 Biochemistry
31.5 Sda and gastrointestinal cancer
31.6 Malaria
32 HLA (Human Leucocyte-Associated) Class I Antigens on Red Cells
32.1 Bg antigens
32.2 Clinical significance of Bg antibodies
33 Polyagglutination and Cryptantigens
33.1 Introduction
33.2 Acquired polyagglutination and the cryptantigens involved
33.3 Inherited polyagglutination
33.4 Polyagglutination of undetermined status
Index
This edition first published 2013 © 1995, 2002, 2013 by Geoff Daniels
Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell.
Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK
The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
111 River Street, Hoboken, NJ 07030-5774, USA
For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell
The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.
Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.
The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.
Library of Congress Cataloging-in-Publication Data
Daniels, Geoff.
Human blood groups : Geoff Daniels ; foreword to first edition by Ruth Sanger. – 3rd ed.
p. ; cm.
Includes bibliographical references and index. ISBN 978-1-4443-3324-4 (hardback : alk. paper) – ISBN 978-1-118-49354-0(epub) – ISBN 978-1-118-49359-5 (obook) – ISBN 978-1-118-49361-8 (emobi) – ISBN 978-1-118-49362-5 (epdf)
I. Title.
[DNLM: 1. Blood Group Antigens. WH 420]
612.1'1825–dc23
2012040684
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover image (top right): Homology model of an Rh protein (RhD or RhCE) courtesy of Dr Nicholas Burton, University of Bristol, UK. Blood bag image: © iStockPhoto / pictorico
Cover design by Garth Stewart
Foreword to 1st Edition
It is a particular pleasure for me to welcome this new book on human blood groups, the more so since it emanates from the Medical Research Council’s Blood Group Unit. For 25 years this Unit devoted its energies to the search for new red cell antigens and the application of those already known to various problems, particularly to human genetics. During these years Rob Race and I produced six editions of Blood Groups in Man.
Dr Geoff Daniels joined the Unit in 1973 on Dr Race’s retirement; soon after, concurrently with the Unit’s move from the Lister Institute to University College, the scope of the Unit’s interest was broadened.
Having been divorced from blood groups and otherwise occupied in 12 years of retirement, I am delighted and astonished at the rapid advances made in recent years. The number of blood group loci have increased to 23 and all except one have found their chromosomal home. The biochemical backgrounds of most of the corresponding antigens are defined and hence several high and low incidence antigens gathered into systems. The molecular basis of many red cell antigens has provided an explanation for some confusing serological relationships which were observed many years before.
Dr Daniels is to be congratulated on his stamina in producing a comprehensive text and reference book on human blood groups, for which many scientists will be grateful.
Ruth SangerDecember 1994
Preface to the third edition
The primary purpose of this book, like the first two editions, is to describe human blood group antigens and their inheritance, the antibodies that define them, the structure and functions of the red cell membrane macromolecules that carry them, and the genes that encode them or control their biosynthesis. In addition, this book provides information on the clinical relevance of blood groups and on the importance of blood group antibodies in transfusion medicine in particular.
The second edition of Human Blood Groups was published in 2002; this new edition will appear 11 years later. There have been many new findings in the blood group world over those years. In order to prevent the book from becoming too cumbersome, my goal has been to produce a third edition roughly the same size as the first two. I have tried to do this without eliminating anything too important, although this has not been easy, with so much new material to include. Since 2002, about 69 new blood group antigens and seven new blood group systems have been identified, and all of the 38 genes representing those systems have been cloned and sequenced.
In the preface of the sixth edition of Blood Groups in Man, the predecessor of Human Blood Groups, Race and Sanger wrote, ‘Here is the last edition of this book: the subject has grown to need more than our two pencils’. Well, here is the last edition of Human Blood Groups; the subject is rapidly growing too vast to be contained in a textbook. In the previous two editions I strove to include all fully validated blood group antigens and genetic changes associated with their expression or loss of expression. This has proved impossible and pointless in this edition so, although the genetic bases of all the important blood group polymorphisms are described, in many cases the reader is directed to web sites for a more complete list of mutations, particularly those responsible for null phenotypes. In the next few years, next-generation sequencing will become readily available and affordable, and the number of genetic variations associated with red cell change will increase exponentially.
I wish to thank again all the people who helped me produce the first two editions, in particular Patricia Tippett, Carole Green, David Anstee, and Joan Daniels. I would like to add my thanks to Dr Nicholas Burton at the University of Bristol who provided many of the protein models for this edition. Finally I would like to thank all the numerous colleagues from around the world who have provided so much of the information in this book, in published or unpublished form, over so many years.
Geoff Daniels
Some Abbreviations Used
ADP
Adenosine diphosphate
ATP
Adenosine triphosphate
AET
2-aminoethylisothiourunium bromide
AIHA
Autoimmune haemolytic anaemia
bp
Base-pair
CDA
Congenital dyserythropoietic anaemia
cDNA
Complimentary DNA
CFU-E
Colony-forming unit-erythroid
Da
Daltons
DAT
Direct antiglobulin test
DNA
Deoxyribonucleic acid
DTT
Dithiothreitol
Gal
Galactose
GalNAc
N
-acetylgalactosamine
GlcNAc
N
-acetylglucosamine
GDP
Guanosine diphosphate
GPI
Glycosylphosphatidylinositol
GSL
Glycosphingolipid
GTA
A-transferase
GTB
B-transferase
HCF
Hydatid cyst fluid
HDFN
Haemolytic disease of the fetus and newborn
HTR
Haemolytic transfusion reaction
IAT
Indirect antiglobulin test
ISBT
International Society of Blood Transfusion (may refer to ISBT terminology)
kb
Kilo-bases
kDa
Kilo-Daltons
MAIEA
Monoclonal antibody immobilisation of erythrocyte antigens
mRNA
Messenger ribonucleic acid
MW
Molecular weight
PCR
Polymerase chain reaction
RFLP
Restriction fragment-length polymorphism
RNA
Ribonucleic acid
SDS PAGE
Sodium dodecyl sulphate polyacrylamide gel electrophoresis
SNP
Single nucleotide polymorphism
1
Human Blood Groups: Introduction
1.1 Introduction
What is the definition of a blood group? Taken literally, any variation or polymorphism detected in the blood could be considered a blood group. However, the term blood group is usually restricted to blood cell surface antigens and generally to red cell surface antigens. This book focuses on the inherited variations in human red cell membrane proteins, glycoproteins, and glycolipids. These variations are detected by alloantibodies, which occur either ‘naturally’, due to immunisation by ubiquitous antigens present in the environment, or as a result of alloimmunisation by human red cells, usually introduced by blood transfusion or pregnancy. Although it is possible to detect polymorphism in red cell surface proteins by other methods such as DNA sequence analysis, such variants cannot be called blood groups unless they are defined by an antibody.
Blood groups were discovered at the beginning of the twentieth century when Landsteiner [1,2] noticed that plasma from some individuals agglutinated the red cells from others. For the next 45 years, only those antibodies that directly agglutinate red cells could be studied. With the development of the antiglobulin test by Coombs, Mourant, and Race [3,4] in 1945, non-agglutinating antibodies could be detected and the science of blood group serology blossomed. There are now 339 authenticated blood group antigens, 297 of which fall into one of 33 blood group systems, genetically discrete groups of antigens controlled by a single gene or cluster of two or three closely linked homologous genes (Table 1.1).
Table 1.1 Blood group systems.
Most blood group antigens are synthesised by the red cell, but the antigens of the Lewis and Chido/Rodgers systems are adsorbed onto the red cell membrane from the plasma. Some blood group antigens are detected only on red cells; others are found throughout the body and are often called histo-blood group antigens.
Biochemical analysis of blood group antigens has shown that they fall into two main types:
Some antigens are defined by the amino acid sequence of a glycoprotein, but are dependent on the presence of carbohydrate for their recognition serologically. In this book the three-letter code for amino acids is mainly used, though the single-letter code is often employed in long sequences and in some figures. The code is provided in Table 1.2.
Table 1.2 The 20 common amino acids: one- and three-letter codes.
A
Ala
Alanine
C
Cys
Cysteine
D
Asp
Aspartic acid
E
Glu
Glutamic acid
F
Phe
Phenylalanine
G
Gly
Glycine
H
His
Histidine
I
Ile
Isoleucine
K
Lys
Lysine
L
Leu
Leucine
M
Met
Methionine
N
Asn
Asparagine
P
Pro
Proline
Q
Gln
Glutamine
R
Arg
Arginine
S
Ser
Serine
T
Thr
Threonine
V
Val
Valine
W
Trp
Tryptophan
Y
Tyr
Tyrosine
In recent years, molecular genetical techniques have been introduced into the study of human blood groups and now most of the genes governing blood group systems have been cloned and sequenced (Table 1.1). Many serological complexities of blood groups are now explained at the gene level by a variety of mechanisms, including point mutation, unequal crossing-over, gene conversion, and alternative RNA splicing.
Discovery of the ABO blood groups first made blood transfusion feasible and disclosure of the Rh antigens led to the understanding, and subsequent prevention, of haemolytic disease of the fetus and newborn (HDFN). Although ABO and Rh are the most important systems in transfusion medicine, many other blood group antibodies are capable of causing a haemolytic transfusion reaction (HTR) or HDFN. Red cell groups have been important tools in forensic science, although this role was diminished with the introduction of HLA testing and has recently been displaced by DNA ‘fingerprinting’. For many years blood groups were the best human genetic markers and played a major part in the mapping of the human genome.
Blood groups still have much to teach us. Because red cells are readily available and haemagglutination tests relatively easy to perform, the structure and genetics of the red cell membrane proteins and lipids are understood in great detail. With the unravelling of the complexities of blood group systems by molecular genetical techniques, much has been learnt about the mechanisms responsible for the diversification of protein structures and the nature of the human immune response to proteins of different shapes resulting from variations in amino acid sequence.
1.2 Blood Group Terminology
The problem of providing a logical and universally agreed nomenclature has dogged blood group serologists almost since the discovery of the ABO system. Before going any further, it is important to understand how blood groups are named and how they are categorised into systems, collections, and series.
1.2.1 An Internationally Agreed Nomenclature
The International Society of Blood Transfusion (ISBT) Working Party on Red Cell Immunogenetics and Blood Group Terminology was set up in 1980 to establish a uniform nomenclature that is ‘both eye and machine readable’. Part of the brief of the Working Party was to produce a nomenclature ‘in keeping with the genetic basis of blood groups’ and so a terminology based primarily around the blood group systems was devised. First the systems and the antigens they contained were numbered, then the high and low frequency antigens received numbers, and then, in 1988, collections were introduced. Numbers are never recycled: when a number is no longer appropriate it becomes obsolete.
Blood group antigens are categorised into 33 systems, seven collections, and two series. The Working Party produced a monograph in 2004 to describe the terminology [5], which was most recently updated in 2011 [6]. Details can also be found on the ISBT web site [7].
1.2.2 Antigen, Phenotype, Gene and Genotype Symbols
Every authenticated blood group antigen is given a six-digit identification number. The first three digits represent the system (001 to 033), collection (205 to 213), or series (700 for low frequency, 901 for high frequency); the second three digits identify the antigen. For example, the Lutheran system is system 005 and Lua, the first antigen in that system, has the number 005001. Each system also has an alphabetical symbol: that for Lutheran is LU. So Lua is also LU001 or, because redundant sinistral zeros may be discarded, LU1. For phenotypes, the system symbol is followed by a colon and then by a list of antigens present, each separated by a comma. If an antigen is known to be absent, its number is preceded by a minus sign. For example, Lu(a−b+) becomes LU:−1,2.
Devising a modern terminology for blood group alleles is more complex. One antigen, the absence of an antigen, or the weakness or absence of all antigens of a system may be encoded by several or many alleles. Over the last few years the Working Party has been developing a new terminology for bloods group alleles. Unfortunately at the time of publication of this book, it was still incomplete, controversial, and in draft form. Consequently, it has only partially been used in this book. Basically, alleles have the system symbol followed by an asterisk followed in turn by a number or series of numbers, separated by full stops, representing the encoded antigen and the allele number. Alternatively, in some cases a letter can be used instead of a number. For example, Lua allele can be LU*01 or LU*A. Genotypes have the symbol followed by an asterisk followed by the two alleles separated by a stroke. For example, Lua/Lub becomes LU*01/02 or LU*A/B. The letters N and M represent null and mod. For example, one of the inactive Lub alleles responsible for a null phenotype is LU*02N.01, the 02 representing the Lub allele, even though no Lub antigen is expressed. Genes, alleles, and genotypes are italicised. For lists of blood group alleles in the ISBT and other terminologies see the ISBT and dbRBC web sites [7,8].
Symbols for all human genes are provided by the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC) [9]. These often differ from the ISBT symbols, as the HGNC symbols reflect the function of the gene product (Table 1.1). When referring to alleles defining blood group antigens, the ISBT gene symbol is preferred because the HGNC symbols often change with changes in the perceived functions of the gene product.
1.2.3 Blood Group Systems
A blood group system consists of one or more antigens, governed by a single gene or by a complex of two or more very closely linked homologous genes with virtually no recombination occurring between them. Each system is genetically discrete from every other blood group system. All of the genes representing blood group systems have been identified and sequenced.
In some systems the gene directly encodes the blood group determinant, whereas in others, where the antigen is carbohydrate in nature, the gene encodes a transferase enzyme that catalyses biosynthesis of the antigen. A, B, and H antigens, for example, may all be located on the same macromolecule, yet H-glycosyltransferase is produced by a gene on chromosome 19 while the A- and B-transferases, which require H antigen as an acceptor substrate, are products of a gene on chromosome 9. Hence H belongs to a separate blood group system from A and B (Chapter 2). Regulator genes may affect expression of antigens from more than one system: In(Lu) down-regulates expression of antigens from both Lutheran and P systems (Chapter 6); mutations in RHAG are responsible for Rhnull phenotype, but may also cause absence of U (MNS5) and Fy5 antigens (Chapter 5). So absence of an antigen from cells of a null-phenotype is never sufficient evidence for allocation to a system. Four systems consist of more than one gene locus: MNS has three loci; Rh, Xg, and Chido/Rodgers have two each.
1.2.4 Collections
Collections were introduced into the terminology in 1988 to bring together genetically, biochemically, or serologically related sets of antigens that could not, at that time, achieve system status, usually because the gene identity was not known. Thirteen collections have been created, six of which have subsequently been declared obsolete (Table 1.3): the Gerbich (201), Cromer (202), and Indian (203) collections have now become systems; Auberger (204), Gregory (206), and Wright (211) have been incorporated into the Lutheran, Dombrock, and Diego systems, respectively.
Table 1.3 Blood group collections.
1.2.5 Low Frequency Antigens, the 700 Series
Red cell antigens that do not fit into any system or collection and have an incidence of less than 1% in most populations tested are given a 700 number (see Table 29.1). The 700 series currently consists of 18 antigens. Thirty-six 700 numbers are now obsolete as the corresponding antigens have found homes in systems or can no longer be defined owing to lack of reagents.
1.2.6 High Frequency Antigens, the 901 Series
Originally antigens with a frequency greater than 99% were placed in a holding file called the 900 series, equivalent to the 700 series for low frequency antigens. With the establishment of the collections, so many of these 900 numbers became obsolete that the whole series was abandoned and the remaining high frequency antigens were relocated in a new series, the 901 series, which now contains six antigens (see Table 30.1). The 901 series antigen Jra and Lan became systems 32 and 33 in 2012 when their genes were identified (Chapter 27).
1.2.7 Blood Group Terminology Used in This Book
The ISBT terminology provides a uniform nomenclature for blood groups that can be continuously updated and is suitable for storage of information on computer databases. The Terminology Working Party does not expect, or even desire, that the numerical terminology be used in all circumstances, although it is important that it should be understood so that the genetically based classification is understood. In this book, the alternative, ‘popular’ nomenclature, recommended by the Working Party [5], will generally be used. This does not reflect a lack of confidence in the numerical terminology, but is simply because most readers will not be well acquainted with blood group numbers and will find the contents of the book easier to digest if familiar names are used. The numerical terminology will be provided throughout the book in tables and often, in parentheses, in the text.
The order of the chapters of this book is based on the order of the blood group systems, collections, and series. There are, however, a few exceptions, the most notable of which are the ABO, H, and Lewis systems, which appear together in one mega-chapter (Chapter 2), because they are so closely related, biochemically.
1.3 Chromosomal Location of Blood Group Genes
Blood groups have played an important role as human gene markers. In 1951, when the Lutheran locus was shown to be genetically linked to the locus controlling ABH secretion, blood groups were involved in the first recognised human autosomal linkage and, consequently, the first demonstration of recombination resulting from crossing-over in humans [10,11]. When, in 1968, the Duffy blood group locus was shown to be linked to an inherited visible deformity of chromosome 1, it became the first human gene locus assigned to an autosome [12]. Since all blood group system genes have now been sequenced, all have been assigned to a chromosome (Table 1.1, Figure 1.1).
Figure 1.1 Human male chromosomes, showing location of blood group and related genes.
1.4 DNA Analysis for Blood Group Testing
Since the discovery of blood groups in 1900, most blood group testing has been carried out by serological means. With the application of gene cloning and sequencing of blood group genes at the end of the twentieth century, however, it became possible to predict blood group phenotypes from the DNA sequence. The molecular bases for almost all of the clinically significant blood group polymorphisms have been determined, so it is possible to carry out blood grouping by DNA analysis with a high degree of accuracy.
There are three main reasons for using molecular methods, rather than serological methods, for red cell blood grouping:
1.4.1 Clinical Applications of Molecular Blood Grouping
A very important application is determination of fetal blood group in order to assess the risk of HDFN. This is a non-invasive procedure carried out on cell-free fetal DNA in the maternal plasma, which represents 3–6% of the cell-free DNA in the plasma of a pregnant woman [13]. This technology is most commonly applied to RhD typing (Section 5.7), but also to Rh C, c, and E, and K of the Kell system.
Molecular methods are routinely used for extended blood group typing (beyond ABO and RhD) on multiply transfused patients, where serological methods are unsatisfactory because of the presence of transfused red cells. These patients are usually transfusion dependent and knowledge of their blood groups means that matched blood can be provided in an attempt to save them from making multiple antibodies and, if the patient is already immunised, to facilitate antibody identification. Molecular methods can be used for determining blood group phenotypes on red cells that are DAT-positive (i.e. coated with immunoglobulin), which makes serological testing difficult. This is particularly useful in helping to identify underlying alloantibodies in patients with autoimmune haemolytic anaemia (AIHA).
There are numerous variants of D. Some result in loss of D epitopes and some in reduced expression of D; most probably involve both (Section 5.6). Individuals with some of these variant D antigens can make a form of alloanti-D that detects those epitopes lacking from their own red cells. In many cases D variants cannot be distinguished by serological methods, so molecular methods are often used for their identification. This assists in the selection of the most appropriate red cells for transfusion in order to avoid immunisation whilst conserving D-negative blood. There are some rare D antigens, such as DEL, that are not detected by routine serological methods. Consequently, blood donors with these phenotypes would be labelled as D-negative, although evidence exists that transfusion of DEL red cells can immunise a D-negative recipient to make anti-D. As DEL and other very weak forms of D are associated with the presence of a mutated RHD gene, they can be detected by molecular methods. In some transfusion services all D-negative donors are tested for the presence of RHD, although this is still not generally considered necessary (Section 5.6.9).
Molecular tests can be used for screening for donors when serological reagents are of poor quality or in short supply. For example, anti-Doa and -Dob have the potential to be haemolytic, yet satisfactory reagents are not available for finding donors for a patient with one of these antibodies (Chapter 14). Some Rh variants, such as hrB-negative and hrS-negative, are relatively common in people of African origin but are difficult to detect serologically (Section 5.9.5). Molecular tests are often employed to assist in finding suitable blood for patients with sickle cell disease, to reduce alloimmunisation and the risks of delayed HTRs [14,15].
Molecular methods are extremely useful in the blood group reference laboratory for helping to solve serological difficult problems.
In most countries, all blood donors are tested for ABO and D, but often a proportion of the donors are also tested for additional blood group antigens, especially C, c, E, e, and K, but sometimes also Cw, M, S, s, Fya, Fyb, Jka, and Jkb. This testing is usually performed by automated serological methods, but it is likely that in the future these serological methods will be replaced by molecular methods [16–18]. Molecular typing for this purpose has already been introduced in some services [19,20]. Molecular methods are more accurate than serological methods, they are more suited to high-throughput methods, and they are either cheaper or are likely to become so in the near future. This provides justification for a switch of technologies.
1.4.2 Current and Future Technologies
Laboratories performing blood group testing on cell-free fetal DNA in the maternal plasma generally use real-time quantitative PCR with Taqman technology, but an alternative technology that is becoming available involves the application of matrix-assisted laser desorption/ionisation time-of-flight (MALDI TOF) mass spectrometry [21].
For other applications of molecular blood grouping, many laboratories use methods traditionally applied to single nucleotide polymorphism (SNP) testing, involving PCR with the application of restriction enzymes or PCR with allele-specific primers, followed by gel electrophoresis. Other technologies that are becoming more commonly used involve the application of allele-specific extension of primers tagged with single fluorescent nucleotides, pyrosequencing, DNA microarray technology, on chips or coloured beads coated with oligonucleotides, and MALDI TOF [18,22]. The future of molecular blood grouping and of molecular diagnostics probably lies with next generation (massively parallel) sequencing, which will be truly high-throughput [23,24]. Next generation sequencing is an extremely powerful technology that provides the capacity to sequence many regions of the genome in numerous different individuals in one run, including fetal DNA from maternal plasma [25].
1.5 Structures and Functions of Blood Group Antigens
For the half-century following Landsteiner’s discovery, human blood groups were understood predominantly as patterns of inherited serological reactions. From the 1950s some structural information was obtained through biochemical analyses, firstly of the carbohydrate antigens and then of the proteins. In 1986, GYPA, the gene encoding the MN antigens, was cloned and this led into the molecular genetic era of blood groups. A great deal is now known about the structures of many blood group antigens, yet remarkably little is known about their functions and most of what we do know has been deduced from their structures. Functional aspects of blood group antigens are included in the appropriate chapters of this book; provided here is a synopsis of the relationship between their structures and putative functions. The subject is reviewed in [26] and computer modelling of blood group proteins, which gives detailed information about protein structure, is reviewed in [27].
1.5.1 Membrane Transporters
Membrane transporters facilitate the transfer of biologically important molecules in and out of the cell. In the red cell they are polytopic, crossing the membrane several times, with cytoplasmic N- and C-termini, and are N-glycosylated on one of the external loops. Band 3, the Diego blood group antigen (Chapter 10) is an anion exchanger, the Kidd glycoprotein (Chapter 9) is a urea transporter, the Colton glycoprotein is a water channel (Chapter 15), the Gill glycoprotein is a water and glycerol channel (Chapter 26), and the Lan and Junior glycoproteins are ATP-fuelled transporters of porphyrin and uric acid (Chapter 27). Band 3 is at the core of a membrane macrocomplex, which contains the Rh proteins and the Rh-associated glycoprotein, which probably function as a CO2 channel (Chapters 5 and 10).
1.5.2 Receptors and Adhesion Molecules
The Duffy glycoprotein is polytopic, but has an extracellular N-terminus. It is a member of the G protein-coupled superfamily of receptors and functions as a receptor for chemokines (Chapter 8).
The glycoproteins carrying the antigens of the Lutheran (Chapter 6), LW (Chapter 16), Scianna (Chapter 13), and Ok (Chapter 22) systems are members of the immunoglobulin superfamily (IgSF). The IgSF is a large family of receptors and adhesion molecules with extracellular domains containing different numbers of repeating domains with sequence homology to immunoglobulin domains. The functions of these structures on red cells are not known, but there is evidence to suggest that the primary functional activities of the Lutheran and LW glycoproteins occur during erythropoiesis, with LW probably playing a role in stabilising the erythropoietic islands.
The Indian antigen (CD44), a member of the link module superfamily, functions as an adhesion molecule in many tissues, but its erythroid function is unknown (Chapter 21). The glycoproteins of the Xg (Chapter 12) and JMH (Chapter 24) systems also have structures that suggest they could function as receptors and adhesion molecules. The Raph antigen, a tetraspanin, may associate with integrin in red cell progenitors to generate complexes that bind the extracellular matrix (Chapter 23).
1.5.3 Complement Regulatory Glycoproteins
Red cells have at least three glycoproteins that function to protect the cell from destruction by autologous complement. The Cromer glycoprotein, decay-accelerating factor (Chapter 19), and the Knops glycoprotein, complement receptor-1 (CR1) (Chapter 20), belong to the complement control protein superfamily; CD59 is not polymorphic and does not have blood group activity (Chapter 19). The major function of red cell CR1 is to bind and process C3b/C4b coated immune complexes and to transport them to the liver and spleen for removal from the circulation.
1.5.4 Enzymes
Two blood group glycoproteins have enzymatic activity. The Yt glycoprotein is acetylcholinesterase, a vital enzyme in neurotransmission (Chapter 11), and the Kell glycoprotein is an endopeptidase that can cleave a biologically inactive peptide to produce the active vasoconstrictor, endothelin (Chapter 7). The red cell function for both of these enzymes is unknown. The Dombrock glycoprotein belongs to a family of ADP-ribosyltransferases, but there is no evidence that it is an active enzyme (Chapter 14).
1.5.5 Structural Components
The shape and integrity of the red cell is maintained by the cytoskeleton, a network of glycoproteins beneath the plasma membrane. At least two blood group glycoproteins anchor the membrane to its skeleton: band 3, the Diego antigen (Chapter 10), and glycophorin C and its isoform glycophorin D, the Gerbich blood group antigens (Chapter 18). Mutations in the genes encoding these proteins can result in abnormally shaped red cells. In addition, there is evidence that glycoproteins of the Lutheran (Chapter 6), Kx (Chapter 7), and RHAG (Chapter 5) systems interact with the cytoskeleton and their absence is associated with some degree of abnormal red cell morphology.
1.5.6 Components of the Glycocalyx
Glycophorin A, the MN antigen (Chapter 3), band 3 are the two most abundant glycoproteins of the red cell surface. The N-glycans of band 3, together with those of the glucose transporter, provide the majority of red cell ABH antigens, which are also expressed on other glycoproteins and on glycolipids (Chapter 2). The extracellular domains of glycophorin A and other glycophorin molecules are heavily O-glycosylated. Carbohydrate at the red cell surface constitutes the glycocalyx, or cell coat, an extracellular matrix of carbohydrate that protects the cell from mechanical damage and microbial attack.
1.5.7 What Is the Biological Significance of Blood Group Polymorphism?
Very little is known about the biological significance of the polymorphisms that make blood groups alloantigenic. In any polymorphism one of the alleles is likely to have, or at least to have had in the past, a selective advantage in order to achieve a significant frequency in a large population, though genetic drift and founder effects may also have played a part [28]. Glycoproteins and glycolipids carrying blood group activity are often exploited by pathogenic micro-organisms as receptors for attachment to the cells and subsequent invasion; surviving malaria possibly being the most significant force affecting blood group expression. In some cases, however, selection may have nothing to do with red cells; the target for the parasite could be other cells that carry the protein. It is likely that most blood group polymorphism is a relic of the selective balances that can result from mutations making cell surface structures less suitable as pathogen receptors and resultant adaptation of the parasite in response to these selective pressures. It is important to remember that whilst blood group polymorphism undoubtedly arose from the effects of selective pressures, these factors may have disappeared long ago, so that little hope remains of ever identifying them. To quote Darwin (The Origin of Species, 1859), ‘The chief part of the organisation of any living creature is due to inheritance; and consequently, though each being assuredly is well fitted for its place in nature, many structures have now no very close and direct relations to present habits of life’.
References
1 Landsteiner K. Zur Kenntnis der antifermentativen, lytischen und agglutinietenden Wirkungen des Blutserums und der Lymphe. Zbl Bakt 1900;27:357–366.
2 Landsteiner K. Über Agglutinationserscheinungen normalen menschlichen Blutes. Wien Klein Wochenschr 1901;14:1132–1134.
3 Coombs RRA, Mourant AE, Race RR. Detection of weak and ‘incomplete’ Rh agglutinins: a new test. Lancet 1945;ii:15.
4 Coombs RRA, Mourant AE, Race RR. A new test for detection of weak and ‘incomplete’ Rh agglutinins. Br J Exp Path 1945;26:255–266.
5 Daniels GL and members of the Committee on Terminology for Red Cell Surface Antigens. Blood group terminology 2004. Vox Sang 2004;87:304–316.
6 Storry JR and members of the ISBT Working Party on red cell immunogenetics and blood group terminology: Berlin report. Vox Sang 2011;101:77–82.
7 The International Society of Blood Transfusion Red Cell Immunogenetics and Blood Group Terminology Working Party. http://www.isbtweb.org/working-parties/red-cell-immunogenetics-and-terminology (last accessed 5 October 2012).
8 Blood Group Antigen Gene Mutation Database (dbRBC). http://www.ncbi.nlm.nih.gov/projects/gv/mhc/xslcgi.cgi?cmd=bgmut/home (last accessed 5 October 2012).
9 HUGO Gene Nomenclature Committee. http://www.genenames.org (last accessed 5 October 2012).
10 Mohr J. A search for linkage between the Lutheran blood group and other hereditary characters. Acta Path Microbiol Scand 1951;28:207–210.
11 Mohr J. Estimation of linkage between the Lutheran and the Lewis blood groups. Acta Path Microbiol Scand 1951;29:339–344.
12 Donahue RP, Bias WB, Renwick JH, McKusick VA. Probable assignment of the Duffy blood group locus to chromosome 1 in man. Proc Natl Acad Sci USA 1968;61:949–955.
13 Daniels G, Finning K, Martin P, Massey E. Non-invasive prenatal diagnosis of fetal blood group phenotypes: current practice and future prospects. Prenat Diagn 2009;29:101–107.
14 Pham B-N, Peyrard T, Juszczak G, et al. Analysis of RhCE variants among 806 individuals in France: consideration for transfusion safety, with emphasis on patients with sickle cell disease. Transfusion 2011;51:1249–1260.
15 Wilkinson K, Harris S, Gaur P, et al. Molecular typing augments serologic testing and allows for enhanced matching of red blood cell for transfusion in patients with sickle cell disease. Transfusion 2012;52:381–388.
16 Avent ND. Large-scale blood group genotyping: clinical implications. Br J Haematol 2008;144:3–13.
17 Anstee DJ. Red cell genotyping and the future of pretransfusion testing. Blood 2009;114:248–256.
18 Veldhuisen B, van der Schoot CE, de Haas M. Blood group genotyping: from patient to high-throughput donor screening. Vox Sang 2009;97:198–206.
19 Perreault J, Lavoie J, Painchaud P, et al. Set-up and routine use of a database of 10 555 genotyped blood donors to facilitate the screening of compatible blood components for alloimmunized patients. Vox Sang 2009;87:61–68.
20 Jungbauer C, Hobel CM, Schwartz DWM, Mayr WR. High-throughput multiplex PCR genotyping for 35 red blood cell antigens in blood donors. Vox Sang 2011;102:234–242.
21 Bombard AT, Akolekar R, Farkas DH, et al. Fetal RHD genotype detection from circulating cell-free fetal DNA in maternal plasma in non-sensitised RhD negative women. Prenat Diagn 2011;31:802–808.
22 Monteiro F, Tavares G, Ferreira M, et al. Technologies involved in molecular blood group genotyping. ISBT Sci Ser 2011;6:1–6.
23 ten Bosch JR, Grody WW. Keeping up with the next generation. Massively parallel sequencing in clinical diagnosis. J Molec Diagn 2008;10:484–492.
24 Su Z, Ning B, Fang H, et al. Next-generation sequencing and its applications in molecular diagnosis. Expert Rev Mol Diagn 2011;11:333–343.
25 Liao GJW, Lun FMF, Zheng YWL, et al. Targeted massively parallel sequencing of maternal plasma DNA permits efficient and unbiased detection of fetal alleles. Clin Chem 2011;57:92–101.
26 Daniels G. Functions of red cell surface proteins. Vox Sang 2007;93:331–340.
27 Burton NM, Daniels G. Structural modelling of red cell surface proteins. Vox Sang 2011;100:129–139.
28 Anstee DJ. The relationship between blood groups and disease. Blood 2010;115:4635–464
2
ABO, H, and Lewis Systems
Part 1: History and Introduction
Described in this chapter are three blood group systems, ABO, H, and Lewis (Table 2.1), although Lewis is really an ‘adopted’ blood group system because the antigens are not intrinsic to the red cells, but introduced into the membrane from the plasma. These three systems are genetically discrete, but are discussed in the same chapter because they are phenotypically and biochemically closely related. A complex interaction of genes at several loci controls the expression of ABO, H, Lewis, and other related antigens on red cells and in secretions.
Table 2.1 Numerical notation for the ABO, Lewis, and H systems, and for Lec and Led.
The science of immunohaematology came into existence in 1900 when Landsteiner [1] reported that, ‘The serum of healthy humans not only has an agglutinating effect on animal blood corpuscles, but also on human blood corpuscles from different individuals’. The following year Landsteiner [2] showed that by mixing together sera and red cells from different people three groups, A, B, and C (later called O), could be recognised. In group A, the serum agglutinated group B, but not A or C cells; in group B, the serum agglutinated A, but not B or C cells; and in group C (O), the cells were not agglutinated by any serum, and the serum appeared to contain a mixture of two agglutinins capable of agglutinating A and B cells. Decastello and Stürli [3] added a fourth group (AB), in which the cells are agglutinated by sera of all other groups and the serum contains neither agglutinin. Healthy adults always have A or B agglutinins in their serum if they lack the corresponding agglutinogen from their red cells (Table 2.2).
Table 2.2 The ABO system at its simplest level.
Epstein and Ottenberg [4] suggested that blood groups may be inherited and in 1910 von Dungern and Hirschfeld [5] confirmed that the inheritance of the A and B antigens obeyed Mendel’s laws, with the presence of A or B being dominant over their absence. Bernstein [6,7] showed that only three alleles at one locus were necessary to explain ABO inheritance (Table 2.2).
Some group A people produce an antibody that agglutinates the red cells of most other A individuals. Thus A was subdivided into A1 and A2, and the three allele theory of Bernstein was extended to four alleles: A1, A2, B and O [8] (Section 2.4). Many rare subgroups of A and B have now been identified (Sections 2.7 and 2.8).
The structure and biosynthesis of the ABO, H, and Lewis antigens is well understood, thanks mainly to the pioneering work in the 1950s of Morgan and Watkins [9,10] and of Kabat [11]. A and B red cell antigens are carbohydrate determinants of glycoproteins and glycolipids and are distinguished by the nature of an immunodominant terminal monosaccharide: N-acetylgalactosamine (GalNAc) in group A and galactose (Gal) in group B. The A and B genes encode glycosyltransferases that catalyse the transfer of the appropriate immunodominant sugar from a nucleotide donor to an acceptor substrate, the H antigen. The O allele produces no active transferase (Sections 2.2 and 2.3). The sequences of the A and B alleles demonstrate that A- and B-glycosyltransferases (GTA and GTB) differ by four amino acid residues; the most common O allele contains a nucleotide deletion and encodes a truncated protein.
There are a multitude of ABO alleles, many of which affect phenotype, and at least two different terminologies. In this chapter the original terminology (e.g. A1, A2, O1) will be used, with the dbRBC terminology often provided in parentheses.
H antigen is synthesised by a fucosyltransferase produced by FUT1, a gene independent of ABO. Very rare individuals lacking FUT1 have no H antigen on their red cells and, consequently, are unable to produce A or B antigens, even when the enzyme products of the A or B genes are present (Section 2.12).
H antigen is present in body secretions of about 80% of Caucasians. The presence of H in secretions is governed by FUT2, another fucosyltransferase that is closely linked to FUT1. Individuals who secrete H also secrete A or B antigens if they have the appropriate ABO alleles. Non-secretors of H secrete neither A nor B, even when those antigens are expressed on their red cells (Section 2.6).
The first two examples of anti-Lewis, later to be called anti-Lea, were described by Mourant [12] in 1946. These antibodies agglutinated the red cells of about 25% of English people. Andresen [13] found an antibody, later to become anti-Leb, that defined a determinant only present on Le(a–) cells of adults. Six percent of group O adults lacked both antigens. Although Lea and Leb are not synthesised by red cells, but are acquired from the plasma, they are considered blood group antigens because they were first recognised on red cells. The terminology Lea and Leb is misleading as these antigens are not the products of alleles.
The Lewis gene (FUT3) encodes a fucosyltransferase that catalyses the addition of a fucose residue to H antigen in secretions to produce Leb antigen or, if no H is present (non-secretors), to the precursor of H to produce Lea. Consequently, as these structures are acquired from the plasma by the red cell membrane, red cells of most H secretors are Le(a–b+) and those of most H non-secretors are Le(a+b–). The Lewis-transferase can also convert A to ALeb and B to BLeb. About 6% of white people and 25% of black people are homozygous for a silent gene at the FUT3 locus and, as they do not produce the Lewis enzyme, have Le(a–b–) red cells and lack Lewis substances in their secretions (Sections 2.3 and 2.15). In East Asia the red cell phenotype Le(a+b+) is common, caused by a weak secretor allele (Section 2.6.3).
The antigens Lec and Led represent precursors of the Lewis antigens and are present in increased quantity in the plasma of Le(a–b–) individuals. Lec is detected on the red cells of Le(a–b–) non-secretors of H and Led is detected on the red cells of Le(a–b–) secretors of H. Lex and Ley antigens, isomers of Lea and Leb, are not present in substantial quantities on red cells (Section 2.18.2).
ABH and Lewis antigens are often referred to as histo-blood group antigens [14] because they are ubiquitous structures occurring on the surface of endothelial cells and most epithelial cells. The precise nature of the histo-blood group antigens expressed varies between tissues within the same individual because of the intricacy of the gene interactions involved (Section 2.19).
ABO is on chromosome 9; FUT1, FUT2, and FUT3 are on chromosome 19 (Sections 2.3.1, 2.3.2.4, and 2.3.5).
Part 2: Biochemistry, Inheritance, and Biosynthesis of the ABH and Lewis Antigens
2.2 Structure of ABH, Lewis, and Related Antigens
ABH and Lewis antigens are carbohydrate structures. These oligosaccharide chains are generally conjugated with polypeptides to form glycoproteins or with ceramide to form glycosphingolipids. Oligosaccharides are synthesised in a stepwise fashion, the addition of each monosaccharide being catalysed by a specific glycosyltransferase. The oligosaccharide moieties responsible for expression of ABH, Lewis, and related antigens are shown in Table 2.3 and abbreviations for monosaccharides are given in Table 2.4. The biosynthesis of these structures is described in Section 2.3 and represented diagrammatically in Figure 2.1. There is a vast literature on the biochemistry of these blood group antigens and only some of the relevant references can be given in this chapter. The following reviews are recommended: [10,14–27].
Table 2.3 Structures of A, B, H, Lewis, and related antigens (for abbreviations see Table 2.4).
Table 2.4 Some abbreviations for monosaccharides and the structures they are linked to.
Figure 2.1 Diagram representing the biosynthetic pathways of ABH, Lewis, Lex, and Ley antigens derived from Type 1 and Type 2 core chains. Genes controlling steps in the pathway are shown in italics and the gene products are listed in Table 2.6. Type 1 and Type 2 precursors differ in the nature of the linkage between the non-reducing terminal Gal and GlcNAc: β1→3 in Type 1 and β1→4 in Type 2. Type 1 and Type 2 structures and the genes acting on them are shown in black and red, respectively.
Dashed lines show how Lea (Lex) and Leb (Ley), produced from the precursor and H structures respectively, are not substrates for the H, Se, or ABO transferases and remain unconverted.
2.2.1 Glycoconjugates Expressing ABH and Lewis Antigens
Two major classes of carbohydrate chains on glycoproteins express ABH antigens:
Glycosphingolipids consist of carbohydrate chains attached to ceramide. They are classified as lacto-series, globo-series, or ganglio-series according to the nature of the carbohydrate chain. Glycosphingolipid-borne ABH and Lewis antigens are present predominantly on glycolipids of the lacto-series, although ABH antigens have also been detected on globo-series and ganglio-series glycolipids. The carbohydrate chains of most ABH-bearing glycoproteins and of lacto-series glycolipids are based on a poly-N-acetyllactosamine structure; that is, they are extended by repeating Galβ1→4GlcNAcβ1→3 disaccharides (see Table 2.5 for examples).
Table 2.5 Examples of H-active glycoconjugates with Type 2 precursor chains (for abbreviations see
