ABO blood group system

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"ABO" redirects here. For other uses, see ABO (disambiguation).
"H substance" redirects here. For use in inflammation, see histamine.

ABO blood group antigens present on red blood cells and IgM antibodies present in the serum

The ABO blood group system is the most important blood type system (or blood group system)
in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually
IgM antibodies, which are usually produced in the first years of life by sensitization to
environmental substances such as food, bacteria and viruses. ABO blood types are also present in
some animals, for example apes such as chimpanzees, bonobos, and gorillas.[1]

Contents
[hide]

• 1 History of discoveries
• 2 ABO antigens
• 3 Serology
o 3.1 Origin theories
• 4 Nonantigen biology
• 5 Transfusion reactions
• 6 ABO hemolytic disease of the newborn
• 7 Inheritance
• 8 Distribution and evolutionary history
o 8.1 ABO and Rh distribution by country
• 9 Association with von Willebrand factor
 • 10 Disease association
• 11 Subgroups
o 11.1 A1 and A2
• 12 Bombay phenotype
• 13 Nomenclature in Europe and former USSR
• 14 Examples of ABO and Rhesus D slide testing method
• 15 Universal blood created from other types, and artificial blood
• 16 Conjectures
• 17 See also
• 18 References
• 19 Further reading

• 20 External links

[edit] History of discoveries

The ABO blood group system is widely credited to have been discovered by the Austrian
scientist Karl Landsteiner, who found three different blood types in 1900;[2] he was awarded the
Nobel Prize in Physiology or Medicine in 1930 for his work. Due to inadequate communication
at the time it was subsequently found that Czech serologist Jan Janský had independently
pioneered the classification of human blood into four groups,[3] but Landsteiner's independent
discovery had been accepted by the scientific world while Janský remained in relative obscurity.
Janský's classification is however still used in Russia and states of former USSR (see below). In
America, Moss published his own (very similar) work in 1910.[4]

Landsteiner described A, B, and O; Alfred von Decastello and Adriano Sturli discovered the
fourth type, AB, in 1902.[5] Ludwik Hirszfeld and E. von Dungern discovered the heritability of
ABO blood groups in 1910–11, with Felix Bernstein demonstrating the correct blood group
inheritance pattern of multiple alleles at one locus in 1924.[6] Watkins and Morgan, in England,
discovered that the ABO epitopes were conferred by sugars, specifically N-acetylgalactosamine
for the A-type and galactose for the B-type.[7][8][9] After much published literature claiming that
the ABH substances were all attached to glycosphingolipids, Laine's group (1988) found that the
band 3 protein expressed a long polylactosamine chain[10] which contained the major portion of
the ABH substances attached.[11] Later, Yamamoto's group showed the precise glycosyl
transferase set that confers the A, B and O epitopes.[12]

[edit] ABO antigens

Diagram showing the carbohydrate chains which determine the ABO blood group

The H antigen is an essential precursor to the ABO blood group antigens. The H locus is located
on chromosome 19. It contains 3 exons that span more than 5 kb of genomic DNA, and it
encodes a fucosyltransferase that produces the H antigen on RBCs. The H antigen is a
carbohydrate sequence with carbohydrates linked mainly to protein (with a minor fraction
attached to ceramide moiety). It consists of a chain of β-D-galactose, β-D-N-acetylglucosamine,
β-D-galactose, and 2-linked, α-L-fucose, the chain being attached to the protein or ceramide.

The ABO locus is located on chromosome 9. It contains 7 exons that span more than 18 kb of
genomic DNA. Exon 7 is the largest and contains most of the coding sequence. The ABO locus
has three main alleleic forms: A, B, and O. The A allele encodes a glycosyltransferase that bonds
α-N-acetylgalactosamine to D-galactose end of H antigen, producing the A antigen. The B allele
encodes a glycosyltransferase that joins α-D-galactose bonded to D-galactose end of H antigen,
creating the B antigen.

In case of O allele, the exon 6 contains a deletion that results in a loss of enzymatic activity. The
O allele differs slightly from the A allele by deletion of a single nucleotide – guanine at position
261. The deletion causes a frameshift, and results in translation of an almost entirely different
protein that lacks enzymatic activity. This results in H antigen remaining unchanged in case of O
groups.

The majority of the ABO antigens are expressed on the ends of long polylactosamine chains
attached mainly to band 3 protein, the anion exchange protein of the RBC membrane, and a
minority of the epitopes are expressed on neutral glycosphingolipids.

[edit] Serology
Anti-A and anti-B antibodies (called isohaemagglutinins), which are not present in the newborn,
appear in the first years of life. They are isoantibodies, that is, they are produced by an individual
against antigens produced by members of the same species (isoantigens). Anti-A and anti-B
antibodies are usually IgM type, which are not able to pass through the placenta to the fetal blood
circulation. O-type individuals can produce IgG-type ABO antibodies.
[edit] Origin theories

It is possible that food and environmental antigens (bacterial, viral, or plant antigens) have
epitopes similar enough to A and B glycoprotein antigens. The antibodies created against these
environmental antigens in the first years of life can cross react with ABO-incompatible red blood
cells which it comes in contact with during blood transfusion later in life. Anti-A antibodies are
hypothesized to originate from immune response towards influenza virus, whose epitopes are
similar enough to the α-D galactose on the B glycoprotein antigens to be able to elicit a cross-
reaction. Anti-B antibodies are hypothesized to originate from antibodies produced against
Gram-negative bacteria, such as E. coli, cross-reacting with the α-N galactosamine on the A
glycoprotein.[13]

The "Light in the Dark theory" (DelNagro, 1998) suggests that when budding viruses acquire
host cell membranes from one human patient (in particular from the lung and mucosal epithelium
where they are highly expressed) they also take along ABO blood antigens from those
membranes, and may carry them into secondary recipients where these antigens can elicit a host
immune response against these non-self foreign blood antigens. These viral-carried human blood
antigens may be responsible for priming newborns into producing neutralizing antibodies against
foreign blood antigens. Support for this theory has come to light in recent experiments with HIV.
HIV can be neutralized in "in-vitro" experiments using antibodies against blood group antigens
specifically expressed on the HIV producing cell lines.[14][15]

The "Light in the Dark theory" suggests a new novel evolutionary hypothesis: that there is true
communal immunity, which has developed to reduce the inter-transmissibility of viruses within a
population. It suggests that individuals in a population supply and make a diversity of unique
antigenic moieties so as to keep the population as a whole more resistant to infection. A system
set up ideally to work with variable recessive alleles.[citation needed]

However it is more likely that the force driving evolution of allele diversity is simply negative
frequency dependent selection; cells with rare variants of membrane antigens are more easily
distinguished by the immune system from pathogens carrying antigens from other hosts. Thus
individuals possessing rare types are better equipped to detect pathogens. The high within-
population diversity observed in human populations would then be a consequence of natural
selection on individuals [16]

[edit] Nonantigen biology

The carbohydrate molecules on the surfaces of red blood cells have roles in cell membrane
integrity, cell adhesion, membrane transportation of molecules, and acting as receptors for
extracellular ligands, and enzymes. ABO antigens are found having similar roles on epithelial
cells as well as red blood cells.[17][18]

[edit] Transfusion reactions

Due to the presence of isoantibodies against non-self blood group antigens, individuals of type A
blood group immediately raises anti-B antibodies against B-blood group RBCs if transfused with
blood from B group. The anti-B antibodies bind to B antigens on RBCs and cause complement-
mediated lysis of the RBCs. The same happens for B and O groups (which raises both anti-A
and anti-B antibodies). However, only blood group AB does not have anti-A and anti-B
isoantibodies. This is because both A and B-antigens are present on the RBCs and are both self-
antigens, hence they can receive blood from all groups and are universal recipient.

As far as transfusion compatibility is concerned, unfortunately it is not strictly as simple as

matching A, B and O groups. In other words, no individual will ever receive a blood transfusion
based on the ABO system alone. The rhesus factor must also be considered. Together, the rhesus
factor and ABO grouping are the two most important compatibility factors to consider. An
individual may be Rh+ or Rh-. More simply, if an individual is blood type A and positive for the
rhesus factor, then he or she is deemed "A+".

• Individuals with type A- blood can receive blood from donors of type A- and type O-
blood.
• Individuals with type A+ blood can receive blood from donors of type A-, type A+, type
O- and type O+ blood.

• Individuals with type B- blood can receive blood from donors of type B- and type O-
blood.
• Individuals with type B+ blood can receive blood from donors of type B-, type B+, type
O- and type O+ blood.

• Individuals with type AB- blood can receive blood from donors of type A-, type B-, type
AB-, or type O- blood.
• Individuals with type AB+ blood can receive blood from donors of type A-, type A+,
type B-, type B+, type AB-, type AB+, type O- and type O+ blood.

Although those with AB blood type may be referred to as universal recipients, in actuality, type
AB+ blood is that of the universal recipient whereas type AB- is not. This is an important
distinction to make.

• Individuals with type O+ blood can receive blood from donors of type O- and type O+.
• Individuals with type O- blood can receive blood from donors of only type O-.
• Because A-, A+, B-, B+, AB-, AB+, O- and O+ individuals can all receive blood from
donors of type O- blood, an individual with type O- blood is deemed universal donor.
Similarly, O+ is not the universal donor blood type.

One caveat to this axiom of 'universal donor' is that this applies to packed RBCs, and not to
whole blood products. Using the first table, type O carries anti-A and anti-B antibodies in the
serum. To transfuse a type A, B, or AB recipient with type O whole blood would produce a
hemolytic transfusion reaction due to the antibodies found in the serum of whole blood.
No antibodies are formed against the H antigen, except in those individuals with the Bombay
phenotype.

In ABH secretors, ABH antigens are secreted by most mucus-producing cells of the body
interfacing with the environment, including lung, skin, liver, pancreas, stomach, intestines,
ovaries and prostate.[19]

[edit] ABO hemolytic disease of the newborn

Main article: Hemolytic disease of the newborn (ABO)

ABO blood group incompatibilities between the mother and child does not usually cause
hemolytic disease of the newborn (HDN) because antibodies to the ABO blood groups are
usually of the IgM type, which do not cross the placenta; however, in an O-type mother, IgG
ABO antibodies are produced and the baby can develop ABO hemolytic disease of the newborn.

[edit] Inheritance

A and B are codominant, giving the AB phenotype.

Blood groups are inherited from both parents. The ABO blood type is controlled by a single gene
(the ABO gene) with three alleles: i, IA, and IB. The gene encodes a glycosyltransferase—that is,
an enzyme that modifies the carbohydrate content of the red blood cell antigens. The gene is
located on the long arm of the ninth chromosome (9q34).

The IA allele gives type A, IB gives type B, and i gives type O. As both IA and IB are dominant
over i, only ii people have type O blood. Individuals with IAIA or IAi have type A blood, and
individuals with IBIB or IBi have type B. IAIB people have both phenotypes, because A and B
express a special dominance relationship: codominance, which means that type A and B parents
can have an AB child. A type A and a type B couple can also have a type O child if they are both
heterozygous (IBi,IAi) The cis-AB phenotype has a single enzyme that creates both A and B
antigens. The resulting red blood cells do not usually express A or B antigen at the same level
that would be expected on common group A1 or B red blood cells, which can help solve the
problem of an apparently genetically impossible blood group.[20]

[edit] Distribution and evolutionary history

The distribution of the blood groups A, B, O and AB varies across the world according to the
population. There are also variations in blood type distribution within human subpopulations.

In the UK, the distribution of blood type frequencies through the population still shows some
correlation to the distribution of placenames and to the successive invasions and migrations
including Vikings, Danes, Saxons, Celts, and Normans who contributed the morphemes to the
placenames and the genes to the population.[21]

There are six common alleles in white individuals of the ABO gene that produce one's blood
type:[22][23]

A B O

• A101 (A1) • B101 (B1) • O01 (O1)

• O02 (O1v)
• A201 (A2)
• O03 (O2)

Many rare variants of these alleles have been found in human populations around the world.

Some evolutionary biologists theorize that the IA allele evolved earliest, followed by O (by the
deletion of a single nucleotide, shifting the reading frame) and then IB.[citation needed] This chronology
accounts for the percentage of people worldwide with each blood type. It is consistent with the
accepted patterns of early population movements and varying prevalent blood types in different
parts of the world: for instance, B is very common in populations of Asian descent, but rare in
ones of Western European descent.) Another theory states that there are four main lineages of the
ABO gene and that mutations creating type O have occurred at least three times in humans.[24]
From oldest to youngest, these lineages comprise the following alleles: A101/A201/O09, B101,
O02 and O01. The continued presence of the O alleles is hypothesized to be the result of
balancing selection.[24] Both theories contradict the previously-held theory that type O blood
evolved earliest, supported by the fact that all human beings (except Type hh) can receive it.
[citation needed]
The British National Blood Transfusion Service states this to be the case (see the web-
link under External Links below) and says that originally all human beings were type O.

[edit] ABO and Rh distribution by country

ABO and Rh blood type distribution by nation (population averages)

Country Population[25] O+ A+ B+ AB+ O- A- B- AB-
Australia[26] 21,262,641 40% 31% 8% 2% 9% 7% 2% 1%
Austria[27] 8,210,281 30% 33% 12% 6% 7% 8% 3% 1%
Belgium[28] 10,414,336 38% 34% 8.5% 4.1% 7% 6% 1.5% 0.8%
Brazil[29] 198,739,269 36% 34% 8% 2.5% 9% 8% 2% 0.5%
Canada[30] 33,487,208 39% 36% 7.6% 2.5% 7% 6% 1.4% 0.5%
Denmark[31] 5,500,510 35% 37% 8% 4% 6% 7% 2% 1%
Estonia[32] 1,299,371 30% 31% 20% 6% 4.5% 4.5% 3% 1%
Finland[33] 5,250,275 27% 38% 15% 7% 4% 6% 2% 1%
France[34] 62,150,775 36% 37% 9% 3% 6% 7% 1% 1%
Germany[35] 82,329,758 35% 37% 9% 4% 6% 6% 2% 1%
Hong Kong SAR[36] 7,055,071 40% 26% 27% 7% 0.31% 0.19% 0.14% 0.05%
Iceland[37] 306,694 47.6% 26.4% 9.3% 1.6% 8.4% 4.6% 1.7% 0.4%
India[38] 1,166,079,217 36.5% 22.1% 30.9% 6.4% 2.0% 0.8% 1.1% 0.2%
Ireland[39] 4,203,200 47% 26% 9% 2% 8% 5% 2% 1%
Israel[40] 7,233,701 32% 34% 17% 7% 3% 4% 2% 1%
Netherlands[41] 16,715,999 39.5% 35% 6.7% 2.5% 7.5% 7% 1.3% 0.5%
New Zealand[42] 4,213,418 38% 32% 9% 3% 9% 6% 2% 1%
Norway[43] 4,660,539 34% 42.5% 6.8% 3.4% 6% 7.5% 1.2% 0.6%
Poland[44] 38,482,919 31% 32% 15% 7% 6% 6% 2% 1%
Portugal[45] 10,707,924 36.2% 39.8% 6.6% 2.9% 6.0% 6.6% 1.1% 0.5%
Saudi Arabia[46] 28,686,633 48% 24% 17% 4% 4% 2% 1% 0.23%
South Africa[47] 49,320,000 39% 32% 12% 3% 7% 5% 2% 1%
Spain[48] 40,525,002 36% 34% 8% 2.5% 9% 8% 2% 0.5%
Sweden[49] 9,059,651 32% 37% 10% 5% 6% 7% 2% 1%
Turkey[50] 76,805,524 29.8% 37.8% 14.2% 7.2% 3.9% 4.7% 1.6% 0.8%
United Kingdom[51] 61,113,205 37% 35% 8% 3% 7% 7% 2% 1%
United States[52] 307,212,123 37.4% 35.7% 8.5% 3.4% 6.6% 6.3% 1.5% 0.6%

2,261,025,244
Population-weighted mean 36.44% 28.27% 20.59% 5.06% 4.33% 3.52% 1.39% 0.45%
(total)
[show]Racial & Ethnic Distribution of ABO (without Rh) Blood Types[53]
(This table has more entries than the table above but does not distinguish between Rh types.)
 PEOPLE GROUP O (%) A (%) B (%) AB (%)
Aborigines 61 39 0 0
Abyssinians 43 27 25 5
Ainu (Japan) 17 32 32 18
Albanians 38 43 13 6
Grand Andamanese 9 60 23 9
Arabs 34 31 29 6
Armenians 31 50 13 6
Asian (in USA - General) 40 28 27 5
Austrians 36 44 13 6
Bantus 46 30 19 5
Basques 51 44 4 1
Belgians 47 42 8 3
Blackfoot (N. Am. Indian) 17 82 0 1
Bororo (Brazil) 100 0 0 0
Brazilians 47 41 9 3
Bulgarians 32 44 15 8
Burmese 36 24 33 7
Buryats (Siberia) 33 21 38 8
Bushmen 56 34 9 2
Chinese-Canton 46 23 25 6
Chinese-Peking 29 27 32 13
Chuvash 30 29 33 7
Czechs 30 44 18 9
Danes 41 44 11 4
Dutch 45 43 9 3
Egyptians 33 36 24 8
English 47 42 9 3
Eskimos (Alaska) 38 44 13 5
Eskimos (Greenland) 54 36 23 8
Estonians 34 36 23 8
Fijians 44 34 17 6
Finns 34 41 18 7
French 43 47 7 3
Georgians 46 37 12 4
Germans 41 43 11 5
Greeks 40 42 14 5
Gypsies (Hungary) 29 27 35 10
Hawaiians 37 61 2 1
Hindus (Bombay) 32 29 28 11
Hungarians 36 43 16 5
Icelanders 56 32 10 3
Indians (India - General) 37 22 33 7
Indians (USA - General) 79 16 4 1
Irish 52 35 10 3
Italians (Milan) 46 41 11 3
Japanese 30 38 22 10
Jews (Germany) 42 41 12 5
Jews (Poland) 33 41 18 8
Kalmuks 26 23 41 11
Kikuyu (Kenya) 60 19 20 1
Koreans 28 32 31 10
Lapps 29 63 4 4
Latvians 32 37 24 7
Lithuanians 40 34 20 6
Malaysians 62 18 20 0
Maoris 46 54 1 0
Mayas 98 1 1 1
Moros 64 16 20 0
Navajo (N. Am. Indian) 73 27 0 0
Nicobarese (Nicobars) 74 9 15 1
Norwegians 39 50 8 4
Papuas (New Guinea) 41 27 23 9
Persians 38 33 22 7
Peru (Indians) 100 0 0 0
Filipinos 45 22 27 6
Poles 33 39 20 9
Portuguese 35 53 8 4
Romanians 34 41 19 6
Russians 33 36 23 8
Sardinians 50 26 19 5
Scots 51 34 12 3
Serbians 38 42 16 5
Shompen (Nicobars) 100 0 0 0
Slovaks 42 37 16 5
South Africans 45 40 11 4
Spanish 38 47 10 5
Sudanese 62 16 21 0
Swedes 38 47 10 5
Swiss 40 50 7 3
Tartars 28 30 29 13
Thais 37 22 33 8
Turks 43 34 18 6
Ukrainians 37 40 18 6
USA (US blacks) 49 27 20 4
USA (US whites) 45 40 11 4
Vietnamese 42 22 30 5

Mean 43.91 34.80 16.55 5.14

Standard deviation 16.87 13.80 9.97 3.41

Blood group B has its highest frequency in Northern India and neighboring Central Asia, and its
incidence diminishes both towards the west and the east, falling to single digit percentages in
Spain.[54][55] It is believed to have been entirely absent from Native American and Australian
Aboriginal populations prior to the arrival of Europeans in those areas.[55][56]

Blood group A is associated with high frequencies in Europe, especially in Scandinavia and
Central Europe, although its highest frequencies occur in some Australian Aborigine populations
and the Blackfoot Indians of Montana.[57][58]

[edit] Association with von Willebrand factor

The ABO antigen is also expressed on the von Willebrand factor (vWF) glycoprotein,[59] which
participates in hemostasis (control of bleeding). In fact, having type O blood predisposes to
bleeding,[60] as 30% of the total genetic variation observed in plasma vWF is explained by the
effect of the ABO blood group,[61] and individuals with group O blood normally have
significantly lower plasma levels of vWF (and Factor VIII) than do non-O individuals.[62][63] In
addition, vWF is degraded more rapidly due to the higher prevalence of blood group O with the
Cys1584 variant of vWF (an amino acid polymorphism in VWF):[64] the gene for ADAMTS13
(vWF-cleaving protease) maps to the ninth chromosome (9q34), the same locus as ABO blood
type. Higher levels of vWF are more common amongst people who have had ischaemic stroke
(from blood clotting) for the first time.[65] The results of this study found that the occurrence was
not affected by ADAMTS13 polymorphism, and the only significant genetic factor was the
person's blood group.

[edit] Disease association

O group compared to non-O group (A, AB, and B) individuals have a 14% reduced risk of
squamous cell carcinoma and 4% reduced risk of basal cell carcinoma.[66] It is also associated
with a reduced risk of pancreatic cancer.[67][68] The B antigen links with increased risk of ovarian
cancer,[69] Gastric cancer has reported to be more common in blood group A and least in group O.
[70]

[edit] Subgroups
This section requires expansion.

[edit] A1 and A2

The A blood type contains about twenty subgroups, of which A1 and A2 are the most common
(over 99%). A1 makes up about 80% of all A-type blood, with A2 making up the rest.[71] These
two subgroups are interchangeable as far as transfusion is concerned, however complications can
sometimes arise in rare cases when typing the blood.[71]

[edit] Bombay phenotype

Main article: Hh antigen system

Individuals with the rare Bombay phenotype (hh) do not express antigen H on their red blood
cells. As H antigen serves as precursor for producing A and B antigens, the absence of H antigen
means the individuals do not have A or B antigens as well (similar to O blood group). However,
unlike O group, the H antigen is absent, hence the individuals produce isoantibodies to antigen H
as well as to both A and B antigens. In case they receive blood from O blood group, the anti-H
antibodies will bind to H antigen on RBC of donor blood and destroy the RBCs by complement-
mediated lysis. Therefore Bombay phenotype can receive blood only from other hh donors
(although they can donate as though they were type O).

[edit] Nomenclature in Europe and former USSR

In parts of Europe the "O" in ABO blood type is substituted with "0" (zero), signifying the lack
of A or B antigen. In the former USSR blood types are referenced using numbers and Roman
numerals instead of letters. This is Janský's original classification of blood types. It designates
the blood types of humans as I, II, III, and IV, which are elsewhere designated, respectively, as
O, A, B, and AB.[72] The designation A and B with reference to blood groups was proposed by
Ludwik Hirszfeld.

[edit] Examples of ABO and Rhesus D slide testing method

Blood group O positive: neither anti-A nor Result: Blood group B negative: anti-A and anti-
anti-B have agglutinated, but anti-Rh has Rh have not agglutinated but anti-B has

In the slide testing method shown above, three drops of blood are placed on a glass slide with
liquid reagents. Agglutination indicates the presence of blood group antigens in the blood.

[edit] Universal blood created from other types, and

artificial blood
In April 2007 an international team of researchers announced in the journal Nature
Biotechnology an inexpensive and efficient way to convert types A, B and AB blood into type O.
[73]
This is done by using glycosidase enzymes from specific bacteria to strip the blood group
antigens from red blood cells. The removal of A and B antigens still does not address the
problem of the Rhesus blood group antigen on the blood cells of Rhesus positive individuals, and
so blood from Rhesus negative donors must be used. Patient trials will be conducted before the
method can be relied on in live situations.

Another approach to the blood antigen problem is the creation of artificial blood which could act
as a substitute in emergencies. BBC.

[edit] Conjectures
There are numerous popular conjectures surrounding ABO blood groups. These beliefs have
existed since the ABO blood groups were identified and can be found in different cultures
throughout the world. For example, during the 1930s, connecting blood groups to personality
types became popular in Japan and other areas of the world.[74]

The popularity of Peter J. D'Adamo's book, Eat Right For Your Blood Type suggests that these
conjectures persist. This book claims that ABO blood type determines one's optimal diet.[75]

Additional myths include the idea that group A causes severe hangovers, group O is associated
with perfect teeth, and those with blood group A2 have the highest IQs. Scientific evidence in
support of these concepts is nonexistent.[76]