Anti a and anti-b

grupos sanguineos

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Anti-A and anti-B: what are they and where do
they come from?
Article in Transfusion · July 2015
DOI: 10.1111/trf.13087 · Source: PubMed
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2. PRODUCTRISKFACTORS
Anti-A and anti-B: what are they and where do they come from?
Donald R. Branch
Intravenous immunoglobulin (IVIG) is made from
thousands of donors having a variety of blood groups. All
of the donors being used for IVIG production, with the
exception of group AB donors, have in their plasma
antibodies of variable titer commonly known as
isohemagglutinins or ABO antibodies. As blood groups O
and A are the most commonly found in the world
population, most of the plasma used in IVIG production is
from donors having these blood groups, with group B and
group AB donors being fewer in number. Consequently,
all batches of IVIG contain antibodies that are reactive
with individuals of group A, group B, and group AB.
These antibodies were originally discovered by Dr Karl
Landsteiner in the early 1900s and are now known to
consist of immunoglobulin (Ig)M, IgG, and IgA classes.
As the process for producing IVIG results in almost
exclusively IgG, isohemagglutinins contained in IVIG are
of this immunoglobulin class. ABO antibodies are highly
clinically significant and, because of this, blood bank
cross-matching is done to ensure that blood of the
correct type is transfused into recipients to avoid a so-
called major mismatch or major incompatibility that can
cause significant morbidity and often death.
Administration of IVIG, which contains ABO antibodies,
is often infused into individuals who have the
corresponding ABO antigens, commonly called a minor
mismatch, and although not as significant as a major
mismatch, the isohemagglutinins contained in the IVIG
have some risk for a significant transfusion reaction due
to the ABO incompatibility. Indeed, currently there is no
way to match IVIG to recipients according to blood type,
so when IVIG is administered to group A, B, or AB
recipients, there is potential for transfusion reactions
analogous to a blood transfusion mismatch. For this
reason, strict guidelines have been put into place to
restrict the titers of the ABO antibodies contained in IVIG.
This review will provide background information about
the discovery and biochemistry of the ABO antigens and
discuss the various isohemagglutinins that are found in
plasma of the different ABO blood types and their
potential clinical significance. In addition, a brief
discussion of the controversial topic of the origins of
these antibodies will conclude this review.
DISCOVERY OF THE ABO BLOOD GROUP
SYSTEM
T
he 1930 Nobel Prize in Physiology or Medicine
was awarded to Dr Karl Landsteiner “for his dis-
covery of human blood groups.” Dr Landsteiner
(Fig. 1) performed a simple experiment using
blood from himself and his available staff. Published in
1901,
1
Landsteiner found that when he mixed different
combinations of red blood cells (RBCs) and plasma he
obtained agglutination but with different patterns depend-
ingontheRBCsandplasmathatwerebeingmixed.One
pattern of agglutination resulted in what Landsteiner called
“A” and a different pattern he called “B.” There were two
individuals’ RBCs that did not agglutinate with any of the
plasma, which Landsteiner termed “C.” The “C” was even-
tually replaced with the letter “O” (that may, initially, have
been a numerical zero to indicate zero reaction with
plasma) and thus was born the ABO blood group system.
One year later, colleagues in Landsteiner’s lab identified the
AB blood group where the RBCs agglutinated with most
plasma tested but the plasma did not agglutinate other
RBCs.
2
Although Landsteiner was awarded the Nobel Prize
for his discovery of the ABO antigens and antibodies, he was
not pleased with this accolade as he viewed his other work
on viruses and haptens as more substantial and important.
LANDSTEINER’S LAW
Landsteiner’s findings of four different “types” of blood
based in good part on antibodies contained in plasma led
From the Centre for Innovation, Canadian Blood Services; and
the Departments of Medicine and Laboratory Medicine and
Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Address reprint requests to:Dr Donald R. Branch, Cana-
dian Blood Services, 67 College Street, Toronto, Ontario, M5G
2M1, Canada; e-mail: [email protected].
doi:10.1111/trf.13087
VC2015 AABB
TRANSFUSION2015;55;S74–S79
S74 TRANSFUSION Volume 55, July 2015

3. him to postulate what has become known as
“Landsteiner’s Law.”
2,3
Simply put, Landsteiner’s Law
states that whichever ABO antigens are lacking on a given
person’s RBCs, that person willalwayshave the corre-
sponding antibody or isohemagglutinin.
3
Thus, Group A
individuals, lacking B antigen, always have anti-B in their
plasma, while group B, lacking A antigen, always have
anti-A. Group O, lacking both A and B antigens, always
have both anti-A and anti-B, and group AB, having both A
and B antigens, do not have any isohemagglutinins. The
very rare Bombay phenotype has anti-A, -B, and -H, as
this rare ABO blood group lacks A and B antigens but also
lacks the H antigen (see below).
In 1952, Dodd
4
described an unexpected isohemag-
glutinin in serum that was only found in group O individ-
uals. This antibody appeared to recognize both A and B
antigens and was called a linked anti-A and anti-B.
2,4
This
antibody is now known as anti-A,B
2,5-7
and reacts with a
recognition determinant that is found on both A and B
RBCs and can be identified only by absorption-elution
studies.
2,5,6
The anti-A,B follows Landsteiner’s Law so that
it is found only in group O or Bombay individuals (Fig. 2).
ANTIGENS OF THE ABO BLOOD GROUP
SYSTEM
The antigens of the ABO system are controlled by the
action of transferases.
2,8
These transferases are enzymes
that are responsible for the addition of specific sugars to
an oligosaccharide precursor chain having a terminal gal-
actose (Fig. 3). Group O individuals have an H gene
located on chromosome 19 that encodes for a fucosyl-
transferase that adds a fucose sugar ina1,2-linkage to the
terminal galactose on the precursor oligosaccharide,
forming the so-called H antigen. H antigen forms a pre-
cursor oligosaccharide necessary to form A antigen and B
antigen. Group A is formed by a gene located on
Chromosome 9 that encodes for another transferase,a1,3-
N-acetylgalactosaminyltransferase, that addsN-acetylga-
lactosamine ina1,3 linkage to the terminal H-antigen.
Group B gene, also encoded by Chromosome 9, produces
a1,3-galactosyltransferase, which adds a galactose ina1,3
linkage to the H antigen. If both A and B genes are pres-
ent, some H antigen will be converted to A antigen and
some to B antigen creating the blood group AB. If the H
gene is absent or defective, no H antigen can be formed
and therefore no A or B antigen. These rare individuals are
called Bombay (Fig. 3).
ABO ISOHEMAGGLUTININS: RELEVANCE
TO INTRAVENOUS IMMUNOGLOBULIN
ABO isohemagglutinins are mostly immunoglobulin (Ig)M
antibodies but IgG and IgA classes also exist in plasma.
The fractionation and manufacturing process for the pro-
duction of intravenous immunoglobulin (IVIG) basically
removes the majority of the IgM and IgA antibodies, leav-
ing most of the IgG isohemagglutinins. As IVIG is fractio-
nated from plasma pools containing a high proportion of
group O donor plasma, IVIG must contain, in addition to
anti-A and anti-B, anti-A,B, as this antibody is mostly
found as IgG in group O people.
2,5
IVIG is not expected to
contain anti-H, given the rarity of the Bombay phenotype.
There may be, however, some low levels of anti-A
1,an
antibody that specifically recognizes a majority of group A
people and is made, again, according to Landsteiner’s
Law, from a subset of group A individuals who lack the A
1
phenotype
2,5
(Fig. 2).
All ABO isohemagglutinins have the potential for clin-
ical significance.
2,5
Both IgM and IgG classes can activate
complement and cause intravascular lysis.
2,5
IVIG con-
tains almost exclusively IgG without IgM or IgA; thus,
there is potential for clinical sequelae when IVIG is
administered if the recipient is group A, B, or AB. Indeed,
extravascular hemolysis has been shown to occur in ABO
hemolytic disease of the fetus and newborn (HDFN) when
anti-A, -B, or -A,B cross the placenta.
5
Of note, anti-A,B
can often be eluted from infants’ RBCs born to group O
mothers and has been shown to be a highly clinically sig-
nificant antibody.
5
In one study, six of nine babies
required treatment due to anti-A,B hemolytic disease of
the fetus and newborn, whereas in babies having only
Fig. 1. Dr. Karl Landsteiner (circa 1920): Father of the ABO
blood group system and 1930 Nobel Prize winner for this
pioneering discovery.
ABO ISOHEMAGGLUTININS
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4. anti-A or anti-B on their RBCs, only five of 14 required
treatment.
5
Although the contribution of anti-A,B to
hemolysis after administration of IVIG to either group A
or group B individuals has not been addressed, a signifi-
cant number of ABO-associated hemolysis cases have
been reported after IVIG administration and can be
severe.
9-12
One way manufacturers and regulatory agencies
attempt to avoid the potential for hemolysis after IVIG
therapy is to control the levels of anti-A and anti-B in the
product.
13
This can be achieved by limiting the potency of
these antibodies by avoiding high titers. Thus, the Food
and Drug Administration (FDA) has required IVIG not to
have titers of anti-A and/or anti-B in IVIG higher than
64.
13,14
In practice most manufacturers’ isohemagglutinin
titers are lower than the FDA requirements. One potential
problem with this approach is that all manufacturers and
the FDA have ignored the anti-A,B isohemagglutinin con-
tained in IVIG. Indeed, when performing titration studies
of IVIG against either A or B RBCs, there is no certainty
that the resulting endpoint is due to anti-A or anti-B as at
least the possibility exists of anti-A,B reactivity. This is
because anti-A,B reacts with an as-yet-undefined, shared
epitope on either A or B cells. This is an important con-
cept as new-generation IVIG products have slightly higher
titers, but within FDA guidelines, of anti-A and anti-B
13
but the titers of anti-A,B are unknown. To obtain the spe-
cific titer of anti-A or anti-B in IVIG one would have to
first adsorb the IVIG using group B cells to obtain an accu-
rate titration of anti-A and, likewise, adsorb the IVIG with
group A
1cells to obtain and accurate titration of the anti-
B contained in the IVIG. If one compares the titer results
of the adsorbed against unadsorbed IVIG, one could get
an idea of the titer of the anti-A,B in the IVIG preparation.
More recently, manufacturers are turning to affinity
chromatography to remove anti-A and anti-B from
Fig. 2. The five major ABO blood groups. Type A is found in approximately 35% to 36% of Caucasians. It follows Landsteiner’s
Law by always having anti-B in the serum or plasma. Certain subtypes of A, that lack A
1, can also have anti-A
1. Type B is found
in approximately 7% to 9% of Caucasians and follows Landsteiner’s Law by always having anti-A in the serum or plasma. Type
AB is found in approximately 2% to 4% of Caucasians and has no isohemagglutinins in the serum or plasma. Type O is the most
common ABO blood group comprising approximately 37% to 40% of Caucasians and follows Landsteiner’s Law by always having
anti-A, anti-B, and anti-A,B in the serum or plasma. Finally, Type Bombay lacks the ability to add fucose to the oligosaccharide
backbone and, thus, lacks H antigen, making it impossible to generate A or B antigens. Bombay is very rare, comprising less
than one in 250,000 of the Caucasian population but can be found in one in 10,000 people in India. It follows Landsteiner’s Law
by having not only anti-A, anti-B, and anti-A,B in the serum or plasma but also anti-H, as it lacks this ABO antigen.
BRANCH
S76 TRANSFUSION Volume 55, July 2015

5. IVIG.
13,15
Interestingly, complete exhaustion of these iso-
hemagglutinins contained in IVIG preparations appears to
be difficult if not impossible, despite multiple passages
through the affinity columns.
15
One can speculate that
this is due to residual anti-A,B, which recognizes a chi-
meric antigen of both A and B components. The recogni-
tion determinate for anti-A,B has yet to be adequately
elucidated so that currently available synthetic blood
group antigens used in affinity chromatography do not
contain the anti-A,B recognition carbohydrate sugars. The
importance of anti-A,B cannot be overstated as many
investigators have reported that this is a highly clinically
significant isohemagglutinin that is almost exclusively of
the IgG subclass.
2,5
Ongoing clinical studies of IVIGs hav-
ing ABO isohemagglutinins reduced by donor selection
and/or affinity chromatography will be helpful in deciding
on the significance of anti-A,B contained in IVIG
products.
Most ABO isohemagglutinins, even if IgG, have the
potential of causing complement-mediated, severe intra-
vascular hemolysis. These ABO isohemagglutinins are
known asABO hemolysins.
2,5
The fact that the antigen site
density is very high for ABO antigens (Fig. 2) and that IgG
antibodies can arrange themselves in close enough prox-
imity for complement activation means that intravascular
hemolysis is possible after administration of IVIG.
9
It is
possible that rare IVIG-associated hemolysis is not a result
of low-titer anti-A, anti-B, or anti-A,B but high-titer
hemolysin activity. Hemolysin activity is easy to test
2
but
is not routinely done for IVIG. However, hemolysin testing
could be performed on individual lots of IVIG before
release and may provide for an extra measure of safety.
Briefly, using a two-stage method, one would add group
A
1, B, and O RBCs into separate tubes; add IVIG to each
tube; and incubate at 37

C for 30 minutes. The tubes are
removed and centrifuged, the supernatant is removed, an
equal volume of freshly drawn normal group AB serum
(can be previously fresh-frozen) is added to each tube as a
source of complement, and the tubes are incubated again
at 37

C for 30 minutes. The tubes are centrifuged and
observed for reduction in size of the cell pellet and for free
hemoglobin (Hb; pink to red supernatant), which can be
quantified if desired. The group O tube is the negative
control and should not show any evidence of RBC pellet
reduction or free Hb. Any level of cell pellet reduction or
pink color in either the A
1or the B tube and a negative
finding in the O tube is considered a positive result, with
the strength of the hemolysin activity dependent on the
remaining cell pellet and intensity of the red color of the
supernatant.
2
ORIGINS OF ABO ISOAGGLUTININS
The origin of the ABO isohemagglutinins is not really
resolved. The question is whether these antibodies are pro-
duced through some inherited, “natural” innate mecha-
nism, not requiring antigenic stimulation or, instead,
follow classical adaptiveimmune-mediated mecha-
nisms.
2,16,17
An answer to this was attempted in the
late 1950s and early 1960s when Springer and his associ-
ates
17-19
published a series of landmark papers that sug-
gested the ABO isohemagglutinins were produced by
classical adaptive immunity in response to bacterial anti-
gens. They showed that chickens kept in a germ-free envi-
ronment would produce anti-B but not anti-A when fed
bacteria expressing high levels of a B-like antigen and
lower levels of an A-like antigen.
17
Later Springer and
colleagues
18
showed that bacteria reacted with anti-A and
Fig. 3. Schematic representation of the biochemical determi-
nants of the ABO blood group system. The four blood groups
are represented based on the addition of specific sugars by
enzyme transferases to the backbone precursor oligosaccha-
ride: Bombay lacking transferase activity for addition of
fucose to the backbone oligosaccharide; group O, which
requires a fucosyltransferase to add fucose to the oligosac-
charide backbone to create the H antigen; Group A, requiring
N-acetylgalactosaminyltransferase to add anN-acetylgalac-
tosamine to the H antigen; and group B, which requires a
galactosyltransferase to add a galactose to the H antigen.
Red diamond5galactose; blue square5N-acetylglucosamine;
black square5fucose; green diamond5N-
acetylgalactosamine.
ABO ISOHEMAGGLUTININS
Volume 55, July 2015TRANSFUSION S77

6. anti-B suggesting a cross-reactive antigen on bacteria
responsible for induction of anti-A and anti-B via bacterial
exposure. However, Springer and colleagues
17,19
were only
ever able to show weak anti-A production despite their
many studies. Thus, the origin of these isohemagglutinins
continued to perplex. Indeed, many studies before and
after the work of Springer and colleagues have found anti-
bodies, including ABO isohemagglutinins, detectable in
neonates and newborns very close to birth that are not of
maternal origin due to crossing the placenta and that can-
not be adequately explained by an adaptive immune
response to environmental stimuli.
16,20-25
Even Landsteiner
believed that ABO isohemagglutinins were spontaneously
produced.
2
With the discovery of two distinct subsets of B lympho-
cytes,
16,26,27
one termed B1 (CD51), T-cell independent that
does not require prior stimulation, responsible for “natural”
antibody production, and the B2 subset (CD52), T-cell
dependent and responsible for humoral responses via the
adaptive immune system, the question of the origins of
ABO isohemagglutinins has become more complex. Table 1
shows a comparison of “natural” versus immune-mediated
antibody properties. Natural antibodies produced by B1 B
lymphocytes have been proposed to include the ABO isohe-
magglutinins in addition to other antibodies produced to
carbohydrate antigens as part of the innate immune sys-
tem.
16,28-31
Some investigators believe that ABO isohemag-
glutinins are initially produced “spontaneously” from a
fixed set of ancestral germline genes found in B1 B lympho-
cytes.
32
Indeed, newborns have mostly B1 B lymphocytes
and produce only IgM antibodies, including ABO isohemag-
glutinins, early in life.
16,20-25
Involvement of B2 B lympho-
cytes requires adaptive immunity, and it is known that IgG
isohemagglutinins can be simulated, perhaps in response to
bacterial and/or food antigens.
16,18,33
Wuttke and
coworkers
16
found that IgM ABO isohemagglutinins of
endogenous origin were always found in newborns by 8
months and usually much earlier, but by 8 months both B1
and B2 B lymphocytes were producing antibodies. The ABO
antibodies found in IVIG are due to B2 B lymphocytes and
an adaptive immune response.
SUMMARY
The ABO blood group system has been studied for more
than 110 years. The nomenclature has not changed since
the early 1900s with four major blood group antigens, A,
B, AB, and O. The ABO isohemagglutinins, also discovered
in the early 1900s, continue to follow Landsteiner’s Law
without exception so that in individuals lacking an ABO
antigen the isohemagglutinins corresponding to that anti-
gen are always found in the plasma. It is plasma contain-
ing these isohemagglutinins that is used in the
manufacture of IVIG and that can be potentially clinically
relevant when IVIG is infused into non–group O individu-
als. Although the biochemistry of the ABO blood group
system has been mostly worked out, elements still exist
such as the epitope recognized by anti-A,B that still eludes
investigators. Also what test may be the best predictor of
potential clinical significance of ABO antibodies contained
in IVIG or other plasma-based blood products remains a
question: titration cutoff, hemolysin activity, anti-A,B lev-
els. Although ABO antibodies can be IgM and IgG, eluci-
dation of the origin of natural, IgM ABO antibodies
compared to immune-mediated, IgG antibodies remains
controversial.
CONFLICT OF INTEREST
The author has disclosed no conflicts of interest.
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B-cell
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Immunoglobulin
class
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No Not required No Restricted germline
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IgD, IgE
Yes Requires antigen
presentation and
T-cell help
Yes Rearrangement;
hypermutation
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ABO ISOHEMAGGLUTININS
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