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ABO Blood Group System. October 19, 2004. Steven L. Spitalnik, M. ... Every donor and donor unit it ABO typed every time. Every recipient is ABO typed every time ... – PowerPoint PPT presentation

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Title: ABO%20Blood%20Group%20System


1
ABO Blood Group System October 19, 2004 Steven
L. Spitalnik, M.D. Phone 212-305-2204 email
ss2479_at_columbia.edu Lab PS 15-408
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Hemolytic Transfusion Reactions
6
Landsteiner Experiment 1900
Mix serum and RBC from random individuals Incubate
at RT Observe for RBC agglutination
Modern interpretation All humans have
naturally-occurring IgM antibodies to the
carbohydrate ABO antigens they lack
7
Landsteiner Experiment 1900
Why do we care? ABO incompatible RBC ?
death ABO incompatible xplant ? hyperacute
rejection We go to extraordinary lengths to
prevent this Every donor and donor unit it ABO
typed every time Every recipient is ABO typed
every time The front and back type must
agree Lots of barriers and requirements from
phlebotomy to transfusion Still we have problems
8
Hemolytic Transfusion Reactions
Elliott et al. Visualizing the hemolytic
transfusion reaction. Transfusion 43 297, 2003.
9
Hemolytic Transfusion Reactions
Acute HTRs IgM-mediated ABO Clinical course
severe significant mortality Malpractice
10
Hemolytic Transfusion Reactions
Acute HTRs 14 x 106 RBC transfused/year in
USA 1000 clinically significant ABO
incompatible transfusions 10 deaths in US from
ABO HTRs Risk of death 1/106 per transfusion
11
Hemolytic Transfusion Reactions
Linden et al. Transfusion errors in New York
State an analysis of 10 years experience.
Transfusion 401207-1213, 2000.
12
Hemolytic Transfusion Reactions
Linden et al. Transfusion errors in New York
State an analysis of 10 years experience.
Transfusion 401207-1213, 2000.
13
Hemolytic Transfusion Reactions
14
Hemolytic Transfusion Reactions
RBC IgM
Complement activation
Intravascular hemolysis
Magic happens
Shock, renal failure, death
15
Red Blood Cells (RBC) Basic stuff
Biconcave disk Membrane structure Cytoplasm Hgb,
LDH, K No internal membranes No nucleus No RNA No
synthetic capacity Terminally differentiated
16
RBC MEMBRANE
17
CONSTITUENTS OF THE RBC MEMBRANE
Lipid bilayer phospholipids,
cholesterol Glycosphingolipids Proteins Transm
embrane proteins (RhD) Transmembrane
glycoproteins Single span (Glycophorin
A) Multispan (Band 3) GPI-anchored (DAF)
18
LIPID BILAYER (PHOSPHOLIPIDS)
19
STRUCTURE OF THE LIPID BILAYER
20
STRUCTURES OF PHOSPHOLIPIDS
(CH3)3NCH3CH2O-HPO2-OCH2
\
H2CO-COCH2CH2CH2CH2CH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2CH3
/
H2CO-COCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2C
H2CH2CH2CH3
(CH3)3NCH3CH2O-HPO2
\
OCH2CHCHCHCHCH2CH2CH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2CH3
/ /
NH OH
/
COCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2
CH3
21
STRUCTURES OF PHOSPHOLIPIDS Lipid tails
HOCH3
\

H2CO-COCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2C
H3
/
H2CO-COCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2C
H3

HOCH2CHCHCHCHCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2
CH3 /
/ NH OH
/
COCH2CH2CH2CH2CH2CH2CH2CH2C
H2CH2CH2CH2CH2CH2CH2CH2CH3
22
STRUCTURES OF PHOSPHOLIPIDS Head groups
23
STRUCTURES OF PHOSPHOLIPIDS
24
GLYCOSPHINGOLIPIDS (GLYCOLIPIDS)
25
MONOSACCHARIDE STRUCTURE
Glucose Glc
Numbering Axial vs. equatorial Anomerity a vs. ß
26
MONOSACCHARIDE STRUCTURE
ß-Glc
Anomerity a vs. ß
27
MONOSACCHARIDE STRUCTURE
a-Glc
Anomerity a vs. ß
28
MONOSACCHARIDE STRUCTURE
ß-Glc
Epimers Gal vs. Glc
29
MONOSACCHARIDE STRUCTURE
ß-Gal
Epimers Gal vs. Glc
30
MONOSACCHARIDE STRUCTURE
L-a-Fuc
Fucose 6-deoxy-L-Gal
31
MONOSACCHARIDE STRUCTURE
ß-Glc
Amino sugars N-acetyl-glucosamine
GlcNAc N-acetyl CH3CONH-
32
MONOSACCHARIDE STRUCTURE
ß-GlcNAc
33
CARBOHYDRATE STRUCTURES
Disaccharides
Glc(ß1-4)GlcNAc
34
CARBOHYDRATE STRUCTURES
Type 2 Chain
Gal(ß1-4)GlcNAc
35
CARBOHYDRATE STRUCTURES
Type 1 Chain
Gal(ß1-3)GlcNAc
36
CARBOHYDRATE STRUCTURES
Type 2 Chain
Gal(ß1-4)GlcNAc
37
CARBOHYDRATE STRUCTURES
Gal(a1-4)GlcNAc
38
CARBOHYDRATE STRUCTURES
Type 2 Chain
Gal(ß1-4)GlcNAc
39
CARBOHYDRATE STRUCTURES
Type 2 H
Fuc(a1-2)Gal(ß1-4)GlcNAc
40
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GLYCOCONJUGATE BIOSYNTHESIS Glycosidic
bonds Glycosyltransferase
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BIOSYNTHESIS OF BLOOD GROUP A GLYCOLIPID
A TYPE 2
44
Glycolipids
45
CHARACTERISTICS OF THE A AND B TRANSFERASES
46
CHARACTERISTICS OF THE A AND B TRANSFERASES
A (a1-3) GalNAc-transferase (EC 2.4.1.40)

GalNAc(a1-3)
\ UDP-GalNAc
Gal(ß1)-R --gt Gal(ß1)-R
UDP /
/ Fuc(a1-2)
Fuc(a1-2)
B (a1-3) Gal-transferase (EC 2.4.1.37)

Gal(a1-3)
\ UDP-Gal Gal(ß1)-R
--gt Gal(ß1)-R UDP
/
/ Fuc(a1-2)
Fuca(1-2)
47
STRUCTURE OF THE A AND B TRANSFERASES
Yamamoto et al. Nature 345229, 1990
48
STRUCTURE OF THE A AND B TRANSFERASES
Four Critical Residues
49
STRUCTURE OF THE A AND B TRANSFERASES
Four Critical Residues
Yamamoto et al. J Biol Chem 26519257, 1990
50
STRUCTURE OF THE A AND B TRANSFERASES
Four Critical Residues
Conclusion The last two critical residues (aa
266 and 268) are very important in determining
specificity
Yamamoto et al. J Biol Chem 26519257, 1990
51
CRYSTAL STRUCTURE OF THE B TRANSFERASE
Patenaude et al. Nature Struct Biol 9685, 2002
52
ACTIVE SITE OF THE B TRANSFERASE
Patenaude et al. Nature Struct Biol 9685, 2002
53
ACTIVE SITES OF THE A AND B TRANSFERASES
GROUP A
GROUP B
Patenaude et al. Nature Struct Biol 9685, 2002
54
ABO Histo-blood group system Summary
Carbohydrate antigens
Glycolipids glycoproteins
Indirect gene product
500,000 copies/RBC
On many tissues (histoblood group Ag)
No known function
Naturally occurring IgM
T-independent
Direct agglutinin
C5b-9 membrane attack complex
Intravascular hemolysis
Acute hemolytic transfusion reaction
Hyperacute rejection of solid-organ tranplants
Mild HDN, if any
55
ACKNOWLEDGEMENTS
ABO Glycolipids K. Landsteiner Vienna and
Rockefeller E. Kabat Columbia University W.
Watkins Great Britain W. Morgan Great
Britain V. Ginsburg NIH R. Oriol France S.
Hakomori Seattle H. Clausen Seattle F.
Yamamoto Seattle
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