Helmut Schenkel-Brunner

Human Blood Groups

Chemical and Biochemical Basis of Antigen Specificity

Second, completely revised edition

Springer-Verlag Wien GmbH

Dr. Helmut Schenkel-Brunner Institut für Medizinische Biochemie Universität Wien, Vienna, Austria

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machines or similar means, and storage in data banks. © 1995 and 2000 Springer-Verlag Wien Originally publ ished by Springer-Verlag/Wien in 2000 Softcover reprint of the hardcover 2nd edition 1995 and 2000

Editorial Consultant: Alexandra Salvini-Plawen Camera-ready copies provided by the author Printed by Druckerei Theiss GmbH, A-9400 Wolfsberg Graphic design: Ecke Bonk Printed on acid-free and chlorine-free bleached paper SPIN 10764127

Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

With 173 Figures

ISBN 978-3-7091-7244-5 ISBN 978-3-7091-6294-1 (eBook) DOI 10.1007/978-3-7091-6294-1

Foreword

As President and organiser of the 26th Congress of the International Society pf Blood Transfusion 'ISBT 2000', I am pleased to introduce this work on the biochemistry of human blood groups, which will serve as a valuable complement to blood group serology work. For this new edition the author has singlehandedly covered virtually all blood group research published before the current year. It is my firm belief that all participants in the ISBT conference will find this book a highly useful addition to their scientific libraries.

Vienna, April 2000 W.R. Mayr Congress President

Preface

This revised and updated edition of the monograph on the chemistry and biochemistry of human blood groups is being published to honour the 1 Oath anniversary of Dr. Karl Landsteiner's discovery of human blood groups here in Vienna.

Five years have passed since publication of the first edition, and in this time research on the biochemistry of human blood groups has reached staggering proportions. Thanks to extensive molecular biological applications, research groups have identified the bearer molecules of even more blood groups, and are now able to clarify the molecular basis of a vast number of blood group specificities.

Human blood group research has become one of the most fruitful of all biochemical research fields. While this development is immensely gratifying to a researcher like myself, who has worked in human blood groups for the past 34 years, coping with the close to overwhelming number of publications has proved a highly challenging task.

In order to keep the number of pages of this edition from reaching a condition close to critical mass, my criteria in selecting the literature for this edition have had to be far more stringent than those applied for the first edition. Thus it has not been possible to offer a more thorough discussion of the serology involved; for this, the interested reader is encouraged to refer to Geoff Daniels' book "Human Blood Groups" (Blackwell Science, Ltd.). I have only briefly touched on the physiological aspects of blood groups (e.g. their function in cell adhesion and regulation of tissue formation in embryonal development; their role in defending tissues from viruses, microorganisms, and parasites; as well as the thousands of investigations on blood groups in malignantly transformed tissue). I hope, nevertheless, that readers will find the references I have selected useful in establishing a good grasp of this field.

Like the first edition, the second is a single-author opus. The author is aware that mistakes cannot have been completely avoided, and will gratefully acknowledge all suggestions and constructive criticism.

My thanks go to DiaMed Diagnostica for its financial support of the publishing of, and to Sandra Salvini-Plawen for the English language editing of this second edition.

Vienna, May 2000 Helmut Schenkel-Brunner

Preface to the First Edition

Although a few books covering primarily serological aspects of human blood groups are available, it became clear to me in the course of my research that no compendium of the non-serological aspects of human blood group systems exists. This book has been written to facilitate access to the vast number of publications scattered throughout the literature in both chemical and medical journals on the chemistry, biochemistry, and molecular biology of blood groups. It is designed as a concise survey for use by blood bankers and researchers in biochemistry, blood group serology, immunohaemotology, forensic medicine, population genetics, and anthropology; the text is supplemented by numerous illustrations and tables.

This volume encompasses the entire field of blood group serology and provides a comprehensive survey of present knowledge in the field. The serological aspects have been kept to a minimum. I have emphasised the chemical, biochemical and molecular genetic basis of blood group specificity and given full consideration to molecular biology investigations, in particular to those on the structure of blood group genes and the structural basis of alleles and rare blood group variants. The book covers the latest developments in research and discusses literature up to the beginning of 1995.

The generosity of the publisher has made it possible for me to include a fairly detailed reference list, which nevertheless - in view of the vast number of publications on the various aspects of blood group science - had to be restricted to an absolute minimum. Since this book is conceived both as a textbook for newcomers in the field and as a reference book for experts, I have done my best to facilitate studies on each topic: all groups working in a given field were mentioned, and reference made in each case to at least the first relevant paper and the most recent publication.

This work is the culmination of years of study: I wrote my doctoral thesis on the biosynthesis of blood group A determinant after completing my stUdies in chemistry, physics, and zoology at the University of Vienna. During my further investigations into the biosynthesis of blood group ASH and Lewis substances, the structure of glycoconjugates, and the distribution and function of animal lectins, I have been able to follow developments from the very first models of the ASH determinants advanced by Watkins and Kabat in 1966 to the most recent investigations on the molecular basis of blood group allelism and the elucidation of the structure of blood group genes. These investigations offered insight into genetic mechanisms and cast light on

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Preface

interrelations which classical serological methods could not explain. New methods made it possible to locate rare blood groups on previously unknown membrane constituents, thus providing a means of investigating their function and in some cases finding the cause of diseases. No wonder this field has fascinated me ever since my student days!

Let me stress here that this entire monograph is a single-author synthesis of the current state of blood group chemistry and biochemistry. The task was not confined to evaluating the extensive literature and compiling the results in a comprehensible and logical form: it also comprised typing, proof-reading, desktop publishing, and preparing the camera-ready manuscript to keep printing costs down. I am aware that misinterpretations and mistakes may have crept into the manuscript, although every effort has been made to avoid them. All relevant criticism, suggestions and corrections will be gratefully acknowledged and taken into consideration in a second edition.

My special thanks go to Sandra Salvini-Plawen, who is by training a translator specialising in scientific texts. She not only transformed my English original into correct English but also in the course of our many fruitful discussions helped to make the text more accessible to non-specialists.

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Contents

1. Introduction ......................................................................................................................... 1

2. Glycoconjugates .................................................................................................................... 8

2.1 Glycolipids ....................................................................................................................... 9

2.2 Glycoproteins ................................................................................................................. 13

3. Biosynthesis of Glycoconjugates .......... ........................................................................... 18

3.1 Biosynthesis of Glycoproteins ....................................................................................... 20

3.1.1 Biosynthesis of N-linked Carbohydrate Chains .................................................. 20

3.1.2 Biosynthesis of O-linked Carbohydrate Chains .................................................. 23

3.2 Biosynthesis of Glycosphingoliopids ............................................................................. 24

3.3 Regulation of Chain Structure ....................................................................................... 24

4. Erythrocyte Membrane ....................................................................................................... 30

4.1 Constituents of the Erythrocyte Membrane ................................................................... 30

4.1.1 Membrane Lipids ................................................................................................. 31

4.1.2 Membrane Proteins ............................................................................................. 34

4.1.3 Carbohydrate Moiety of Glycoconjugates .......................................................... .43

4.2 Molecular Architecture of the Erythrocyte Membrane .................................................. .45

4.3 Architecture of the Membranes of Nucleated Cells ..................................................... .48

5. ABO(H) System .................................................................................................................... 54

5.1 Genetics ......................................................................................................................... 55

5.2 Antisera and Lectins ...................................................................................................... 57

5.2.1 Anti-A and Anti-B Reagents ................................................................................ 57

5.2.2 Anti-AI Reagents ................................................................................................. 60

5.2.3 Anti-H Reagents .................................................................................................. 60

5.3 Blood Group ABH Substances ...................................................................................... 61

5.3.1 Structures of the ABH Determinants .................................................................. 62

5.3.2 Blood Group ABH Substances of Erythrocytes .................................................. 67

5.3.3 Blood Group ABH Substances of Human Plasma ............................................. 78

5.3.4 Secreted Blood Group Substances (Mucins) ..................................................... 80

5.3.5 Blood Group ABH Active Oligosaccharides from Milk and Urine ....................... 86

5.3.6 Other Sources of Blood Group ABH Active Material ........................................ 86

5.3.7 Distribution of Blood Group ABH Active Material in Human Tissues ................. 88

5.3.8 Occurrence of ABH Antigens in the Course of Embryonic Development... ....... 89

5.3.9 ABH Antigens in Malignantly Transformed Human Tissues .............................. 90

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Contents

5.4 Biosynthesis of ABH Antigens and Its Genetic Regulation .......................................... 91

5.4.1 Products of the ABO Gene System .................................................................... 93

5.4.2 Products of the Gene Systems Hh and Sese .................................................... 96

5.4.3 Cellular Origin of the Plasma Glycosyltransferases ......................................... 100

5.4.4 Expression of Glycosyltransferases in Malignantly Transformed Tissues ....... 1 00

5.4.5 Molecular Biological Investigations on the Glycosyltransferases

Encoded by A, B, and 0 Genes ....................................................................... 101

5.4.6 Molecular Biological Investigations on the Glycosyltransferases

Encoded by the Hh and Secretor Genes .......................................................... 110

5.4.7 Biosynthesis of Type-14 Substance ................................................................. 117

5.5 ABH Subgroups and Variants ..................................................................................... 118

5.5.1 A Subgroups ..................................................................................................... 120

5.5.2 Variations in Blood Group B ............................................................................. 136

5.5.3 Expression of A and B Antigens in AB Heterozygotes .................................... 141

5.5.4 Cis AB ............................................................................................................... 145

5.5.5 Acquired B ......................................................................................................... 148

5.5.6 H Deficient Variants .......................................................................................... 150

6. Lewis System and the Antigens Lex and Ley .................................................................. 184

6.1 Genetics ....................................................................................................................... 185

6.2 Antisera and Lectins .................................................................................................... 186

6.2.1 Descriptive Listing of Antisera with Their Specificities ..................................... 187

6.3 Blood Group Lewis Substances .................................................................................. 190

6.3.1 Occurrence of Blood Group Lewis Substances ................................................ 190

6.3.2 Chemical Structures of the Blood Group Lewis Determinants ......................... 193

6.3.2 Sterical Configuration of the Blood Group Lewis Determinants ....................... 198

6.3.4 Structures of the Blood Group Lewis Substances ............................................ 198

6.3.5 Chemical Synthesis of Blood Group Lewis Determinants ................................ 205

6.4 Biosynthesis of Blood Group Lewis Determinants ...................................................... 205

6.4.1 Enzymes ............................................................................................................ 205

6.4.2 Biosynthetic Pathways ...................................................................................... 211

6.5 Antigens Lex and Ley ................................................................................................... 213

6.5.1 Chemical Structures of the LeX and LeY Antigens ............................................ 213

6.5.2 Lex and LeY Substances .................................................................................... 213

6.5.3 Chemical Synthesis of LeX and LeY Determinants ............................................ 218

6.5.4 Biosynthesis of Lex and LeY Determinants ........................................................ 218

6.5.5 Physiological Role of Lex and LeY and their Derivatives .................................. 224

7. Antigens I and I ........................................................................................................... 249

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Contents

7.1 Antisera ........................................................................................................................ 249

7.2 Blood Group I and i Determinants .............................................................................. 250

7.3 Blood Group I and i Substances ................................................................................. 253

7.3.1 Blood Group I and i Substances of Erythrocytes ............................................. 253

7.3.2 Blood Group I and i Determinants on Other Cell Types .................................. 254

7.3.3 Water-Soluble Blood Group I and i Substances ............................................... 254

7.3.4 Chemical Synthesis of I and i Determinant Structures ..................................... 255

7.3.5 Conformation of i Determinant Structures ........................................................ 255

7.4 Expression of I and i Activity during Embryonic Development and under

Various Pathological Conditions .............................................................................. .255

7.5 Biosynthesis of I and i Determinant Structures ........................................................... 259

8. P System ............................................................................................................................ 273

8.1 Antisera and Lectins .................................................................................................... 274

8.2 Blood Group P Substances ......................................................................................... 277

8.2.1 Occurrence of Blood Group P Active Substances ........................................... 277

8.2.2 Chemical Structures of the Blood Group P Substances .................................. 278

8.2.3 Occurrence of Blood Group P Active Glycosphingolipids in

Erythrocytes and Fibroblasts of Different P Phenotypes .................................. 284

8.2.4 Blood Group P Antigens as Receptors for Bacteria and Viruses .................... 286

8.2.5 Chemical Synthesis of the P Determinants ...................................................... 286

8.3 Biosynthesis of the Blood Group P Antigens .............................................................. 288

8.3.1 Biosynthetic Pathway ........................................................................................ 288

8.3.2 Investigations on Enzymes ............................................................................... 290

8.3.3 Genetic Regulation of the Biosynthesis of Blood Group P Substances .......... 293

9. MNS System ....................................................................................................................... 304

9.1 Genetics ....................................................................................................................... 306

9.2 Antisera and Lectins .................................................................................................... 306

9.3 Blood Group MNS Substances ................................................................................... 308

9.4 Structure and Organisation of the MNS Gene Complex ............................................ 314

9.5 Chemical Structures of the Main Determinants of the MNS System ......................... 319

9.6 Rare Variants of the MNS Antigens, MNS-Deficient Phenotypes, and Antigens

Associated with the MNS System .............................................................................. 324

I O. Polyagglutination ............................................................................................................. 364

10.1 Antisera and Lectins .................................................................................................. 365

10.2 T Antigen ................................................................................................................... 366

10.3 Tk Antigen ................................................................................................................. 368

10.4 Th Antigen ................................................................................................................. 370

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Contents

10.5 Tx Antigen ................................................................................................................. 371

10.6 Tn Antigen ................................................................................................................. 371

10.7 VA and NOR .............................................................................................................. 375

11. Sid and Cad ....................................................................................................................... 382

11.1 Antisera and Lectins .................................................................................................. 383

11.2 Sda Active Substances .............................................................................................. 384

11.3 Cad Active Substances ............................................................................................. 388

11.4 Investigations on the Biosynthesis of Sda and Cad Determinants ........................... 390

12. Sialic ACid-Containing Receptors for Cold Agglutinins .............................................. 398

12.1 Antisera ...................................................................................................................... 398

12.2 Structures of Antigenic Determinants ........................................................................ 399

12.3 Occurrence of Pr, Gd, and Sa Antigens on Other Cell Types ................................ .404

12.4 Other Receptors for Cold Agglutinins ...................................................................... .405

13. Rh System ........................................................................................................................ .409

13.1 Genetics .................................................................................................................... .411

13.2 Rh Antisera ............................................................................................................... .412

13.3 Chemical Properties of Rh Antigens ........................................................................ .412

13.4 Number of Rh Sites .................................................................................................. .413

13.5 Molecular Biological Investigations .......................................................................... .414

13.5.1 Rh Proteins .................................................................................................... .414

13.5.2 Rh-Associated Proteins .................................................................................. .417

13.5.3 Diagnostic Application of Molecular Biological Investigations ....................... .421

13.6 Rh Antigens and Phenotypes ................................................................................... .421

14. Landsteiner-Wiener System ............................................................................................ 458

15. Chido I Rodgers System ................................................................................................. .464

16. Duffy System .................................................................................................................... .474

17. Kell System ...................................................................................................................... .485

17.1 Antibodies ................................................................................................................. .487

17.2 Kell-Deficient Phenotypes ........................................................................................ .488

17.3 Kell Glycoprotein ...................................................................................................... .489

17.4 Kell Alleles ................................................................................................................ .493

17.5 Kx Antigen ................................................................................................................ .495

18. Gerbich System ................................................................................................................ 504

18.1 Glycophorin C and Glycophorin 0 ............................................................................ 504

18.2 Antigen Characters Ge1, Ge2, Ge3, and Ge4, and the Lsa Determinant. ............... 507

18.3 Wb (Webb) ................................................................................................................ 512

18.4 Dha (Ouch) ................................................................................................................. 512

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Contents

18.5 Ana (Ahonen) ............................................................................................................. 512

19. Lutheran System .............................................................................................................. 518

20. Diego System .................................................................................................................... 527

20.1 Antibodies .................................................................................................................. 527

20.2 Antigens of the Diego System ................................................................................... 528

20.2.1 Diego Antigens ................................................................................................ 530

20.2.2 Wright Antigens ............................................................................................... 531

20.2.3 Low-Incidence Blood Group Antigens Carried by the Band 3 Protein

of the Erythrocyte Membrane ............................................................................ 533

21. Cromer System ................................................................................................................. 539

22. Dombrock System ............................................................................................................ 551

23. Vt System .......................................................................................................................... 553

24. Indian System ..................... , ............................................................................................. 556

25. Knops System ................................................................................................................... 565

26. Kidd System ...................................................................................................................... 571

27. Xg System ......................................................................................................................... 576

28. Colton System .................................................................................................................. 582

29. OK System ........................................................................................................................ 589

30. JMH Antigen ...................................................................................................................... 592

31. Antigens of the Major Histocompatibility Complex (HLA Antigens) .......................... 595

30.1 Genetics ..................................................................................................................... 595

30.2 HLA Antisera ............................................................................................................. 596

30.3 HLA Gene Products .................................................................................................. 599

32. HEMP AS ............................................................................................................................ 606

33. Carcinoembryonic Antigen (CEA) Family ...................................................................... 615

Subject Index .......................................................................................................................... 622

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