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The ABO blood group system The ABO blood group system

Objectives Lecture Contents

1. Understand the glyco-biology of the ABO, Hh and Lewis blood 1. Biochemistry of ABO blood group system
group systems 2. Molecular genetics of the ABO blood group system
2. Understand the molecular basis of the ABO system as an 3. Unusual variants of ABO blood groups
example of the role of SNPs in determining phenotypic 4. Immunology of the ABO blood group system
expression of an oligosaccharide blood group system
5. Biochemistry of the Hh and Lewis blood group system

Oligosaccharide Blood Groups In the beginning


System Locus Chr. Nr. of Nr. of alleles • Karl Landsteiner describes the ABO blood group in 1900
Location genes • Deductions based entirely on pattern of reaction between sera and red
ABO ABO 9q34 1 184 cells i.e. phenotypic prediction based on immunological reactions

H/h FUT1 19q13.3 2 40(FUT1) • Phenotypic expression is genetically determined - classical Mendelian
laws
FUT2 38(FUT2)
Lewis FUT3 19p13 1 17

Ii GCNT2 6p24 1 13

P-related A4GALT 22q11.2 2 33(A4GALT)


B3GALT 3q25 9(B3GALT)

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ABO System
ABO antigens
Antigens Phenotypes Genotypes Antibodies
• Carbohydrate structures present on glycoprotein structures
– band 3(AE1)
– glucose transporter
A A A/A or A/O Anti-B
– RhAg
– aquaphorin
B B B/B or B/O Anti-A
– glycosphingolipid

A&B AB A/B none • Expressed on many tissues - RBC, renal


• Also present in secretions - saliva, seminal fluid
None O O/O Anti – A,B • Not restricted to humans
• Antigen expression changes during development or in certain
disease states e.g. prostate ca

ABO antigens ABO antigens

• Synthesised by a series of enzymatic reactions catalysed by


enzymes called glycosyltransferase
• Final step involves specific A and B glycosyltransferase encoded
by the ABO gene

• A: N-acetyl-D-galactosamine transferase
• B: D-galactose transferase

• H: Fucose transferase (encoded by independent


H/h gene on chr19)

Yazer M, Transfusion Medicine Reviews, 19(3), 2005

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ABO blood group system ABO Gene
• A single gene gives rise to all 3 common phenotypes
• Occurs in several allelic forms – all with 7 exons encoding
Minimal determinant
Antigen Structure
structure glycosyltransferases of 354 aa
• 90% of total coding region in ex6 and 7 and encodes entire catalytic
domain
H
• A and B transferase results from different amino acid sequences
conferring different sugar specificities
B

*: residue could be glucose in case of glycolipids; yellow shade: minimal determinant or core structure; blue arrow: residue added by blood group gene product;
examples of type 1 and 2 core structures are illustrated above but they can vary widely, as they can be assembled on at least six possible types of carbohydrate
chains; they can reside on a variety of protein or lipid glycan structures containing branches, repeats, etc.

ABO Gene ABO Gene

• A and B difference due


to 7nt substitutions
leading to 4 aa changes
– Arg176Gly
– Gly235Ser
– Leu266Met
– Gly268Ala

3
ABO Gene ABO Gene

• A2 – single base change


• O phenotype results from
(P156L), frame shift, loss of
single nt deletion (261 delG)
translation stop codon, extra
causing frame shift
21 aa
• Leads to rapid degradation of
• Many ABO subgroups
mRNA and production of
associated with point
inactive transferase
mutations and deletions in
trasferase gene (exon 6 and
7)
• Reduced enzyme activity –
weak A/B

Yamamoto F, Immunohaematology 20(1), 2004 Yamamoto F, Immunohaematology 20(1), 2004

ABO Gene Product ABO antibodies


• Naturally occurring antibody
• IgM and IgG capable of activating C’
• Intravascular transfusion reactions
– Very mild to severe - ~1 in 10 fatal, due to DIC or
renal failure

• ABO HDN
– IgG anti A,B in group O mothers
– Not common
• A/B not fully expressed on foetal cells
• A/B present on many tissues

4
ABO subgroups ABO subgroups
Phenotype Anti-A Anti-A1 Dolichos
biflorus • A1
A1 +++ ++ +++ • A2
• A3, Aend, Ax, Am, Ay, Ael
A2 ++ - -
• B
• B3, Bx, Bm, Bel
A1B +++ ++ ++
• Show weakened expression of A/B antigen with increased H
antigen due to reduced transferase activity
A2B + - -

ABO subgroups
anti-A Anti-A,B Ab in serum

A3 mf mf Sometimes anti-A1

Ax Weak + Usually anti-A1 AB O


Ael _ _ anti-A1, Sometimes anti-A

O AB
anti-B Anti-A,B

B3 mf mf none

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Cis AB / B(A) phenotypes

AB O
B O

O AB
SNPs leads translation of A
enzymes with both A and B
transferase activity

Cis-AB usually presents as A2B3


phenotype

Relatively more common in Asia Yamamoto F, Immunohaematology 20(1), 2004

Allelic hybridisation Acquired B

B • Acquisition of weak B antigen in a A individual


B O O • Bacterial enzymes deacetylate NAc-galactosamine to
galactosamine
• Cross reacts with some anti-B (ES-4 clones)
– Does not react at pH 6.0
A B-O A • Reacetylation with acetic anhydride may abolish
reactivity
Occurs from the recombination of the proximal end of the B gene with the
distal end of the O gene, thus generating a A gene

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Hh blood group system (FUT1 and FUT2) ABH secretion
Minimal • ABH on red cells – glycoprotein and glycolipid
Phenoty
Structure determinant
pe
structure • ABH in secretions – soluble glycoprotein
– 80% secretors of H (A and/ or B)
– 20% non secretors
H

• FUT2 (Se) gene is expressed predominantly in secretory tissues


h giving rise to FUT2 (Se enzyme) and to products that reside on
mucins in secretions.
• When alleles of both genes (se/se) fail to express active
*: residue could be glucose in case of glycolipids; yellow shade:
minimal determinant or core structure; blue arrow: residue enzymes, individuals bearing them, in homozygous state, lack
added by blood group gene product;examples of type 1 and 2
core structures are illustrated above but they can vary widely, as
the substrates for the A or B glycosyltransferases and do not
they can be assembled on at least six possible types of express the A and B epitopes – non secretors
carbohydrate chains; also they can reside on a variety of protein
or lipid glycan structures containing branches, repeats, etc.

H-deficient red cell phenotypes Lewis phenotypes


• No H, A or B on red cells
• Non- secretors
– Bombay phenotype
• Le(a-b+) H secretors
– Anti-H (+ anti-A,B)
• Le(a+b-) H non-secretors
– Clinically significant
• Le(a+b+) H partial secretors
• Le(a-b-) H secretors, non secretors or partial secretors
• Secretors
– Para-Bombay phenotype
– Anti-HI
– Less clinically significant

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Phenotype Structure Minimal determinant structure

Lea

Leb

Lex

Ley

*: residue could be glucose in case of glycolipids; yellow shade: minimal determinant or core
structure; blue arrow: residue added by blood group gene product;examples of type 1 and 2 core
structures are illustrated above but they can vary widely, as they can be assembled on at least six
possible types of carbohydrate chains; also they can reside on a variety of protein or lipid glycan
structures containing branches, repeats, etc.