What is a system , collection & series ?

Blood group System:

Criteria:
- Alleles at a single gene locus or
- Closely linked loci so that crossing over does not occur
- Follow Medenlian inheritance(independent inheritance
- Most blood group genes are co dominant .
Hardy-weinberg principle: G.H. Hardy and W.Weinberg developed a forrmula (p2+q2+2pq-1)
where p gene frquency of D
q gene frequency of d
D and d are allelic form of a gene.
However to use this equation certain criteria must be met
1.population should be large.
2.mating should not be there in parent or offspring.
3.there should be no migration ,no mortality in genotype to be studied.

Terminology:
ISBT assigns a six digit identification number to each authenticated antigen .
First three digits represent the Blood group system
eg:(004 for RH system)
Last three digits represent Antigen specificity
eg:(001 for D antigen).
Thus For D antigen ISBT number is 004001
Alternatively, the system symbol followed by the antigen number
may be used (e.g. KEL003 or, more usually, KEL3 as sinistral zeros
may be removed).

Phenotypes are represented by the system symbol, followed by a colon, followed by a list of
antigens separated by commas. Those antigens shown to be absent are preceded by a minus
sign (e.g. KEL:1,2,3,4).
Genes are designated by the system symbol, followed by an asterisk, followed by the antigen
number, all italicised (e.g. KEL*3).
Genotypes have the system symbol, followed by an asterisk, followed by alleles or haplotypes
separated by a slash, all italicised (e.g. KEL*2,3/2,4).
Antigen, phenotype, gene, and genotype designations for collections are constructed in the
same way.
For the 700 and 901 series, 700 or 901 replaces the system symbol.





Criteria of ISBT :
For the establishment of new blood group systems :
For an antigen to form a new blood group system it must be defined by a human alloantibody,
Be an inherited character,
The gene encoding it must have been identified and sequenced, and its chromosomal location
known.
In addition the gene must be different from, and not a
closely-linked homologue of, all other genes encoding antigens of
existing blood group systems

For the inclusion of a new specificity in an established system :
All antigens awarded an ISBT number must have been shown to be inherited and at least one of
the following four criteria must be met.
(1) An antithetical relationship between a new antigen and one already assigned to the system.
(2) Demonstration that expression of the antigen is associated with a
variation in the nucleotide sequence of the gene controlling the system.
(3) Evidence, from a linkage analysis of family data, that the controlling allele is probably a
newly recognized form of the pertinent gene, and supporting serological or
biochemical information.
(4) Demonstration that an antigen is located on a protein or glycoprotein that carries other
antigens belonging to the system. It must be remembered, however, that this could result from
post-translational modification of a gene product, such as glycosylation, which would
not support inclusion within the system.

For establishment of a blood group collection
A collection must contain two or more antigens that are related serologically,
biochemically, or genetically, but which do not fit the criteria required for system status.
For inclusion in the 700 series
(1) Incidence of <1%
(2) Distinction from all other numbered low incidence antigens of the 700 series as well as those
of the
blood group systems and collections.
(3) Demonstration of inheritance through at least 2 generations.
For inclusion in the 901 series
(1) Incidence of >90%
(2) Distinction from all other numbered high incidence specificities.
(3) Demonstration that the antigen is lacking from the red cells of at least 2 sibs,
i.e. that the negative phenotype is genetically determined.
Obsolete Numbers :
Once a number has been allocated to a specificity, that number cannot be subsequently used for
any other specificity. Consequently, if the number of a specificity becomes inappropriate, then
that number becomes obsolete.
Various other blood group system






















Diego Blood group system (ISBT 010)
The Diego system consists of 21 antigens:
Two pairs of antithetical antigens, Dia and Dib, Wra and Wrb, plus 17 antigens of very low frequency
Since Wr antigens are linked with anion exchange like Deigo, the Wr antigens are reclassified
wih Deigo system.
Dia is a useful anthropological marker for Mongoloid populations.
Dia represents Leu854 and Dib Pro854 in the red cell anion exchanger, band 3 or AE1 (CD233).
Mutation in AE-1 results in hereditary spherocytosis, congenital acathocytosis.
Most examples of anti-Dia and anti-Dib are found in association with pregnancy; both antibodies
are often IgG1 + IgG3.
A naturally occurring example of anti-Dia has been described but anti-Dib seems always to be
immune.
Anti-Dia is known to have been responsible for many cases of HDN.

Wright Antigens
Wra, rst described by Holman in 1953
Wra and Wrb are antithetical antigens .
Wra, a low incidence antigen occuring in less than 0.01 % & Wrb a high indence antigen present
in more than 99.9 % of random population.
BLOOD GROUP SYSTEM ISBT
NUMBER
Diego blood group system ISBT 010
Cartwright blood group system ISBT 011
XG blood group system ISBT 012
Scianna blood group system ISBT 013
Dombrock blood group system ISBT 014
Colton blood group system ISBT 015
Chido/Rodgers Blood group system ISBT 017
Gerbich Blood group system ISBT 020
Cromer Blood group system ISBT 021
Knop Blood group system ISBT 022
Indian Blood group system ISBT 023
John Milton Hagen Blood group system ISBT 026
All Wr(a) subjects are Wr(b+),with the exception of those subjects who are GPA decient.
Wrb is a site of interaction between band 3 and GPA.
Wra represents amino acid lys-658 and Wrb represents Glu-658 housed on the anion
transporter AE-1.
Antigen Wra is extremely rare,Anti-Wra reported frequently.
Two types one is non RBC stimulated IgM and immune stimulated IgG.
Non RBC stimulated anti-wra is found in serum of individual who never have been pregnant or
receive transfusion.
RBC stimulated anti-Wra is an IgG antibody which is reported to cause mild to severe HDN and
transfusion reaction.
Anti Wrb may be commonly found as a warm autoantibody in pt with auto immune hemolytic
anaemia.

Cartwright Blood group System
Discovered in 1956 with observation of Yta.
Two antigens: Yta with high incidence present in 99.8 % of population and Ytb a low incidence
antigen present in 8% of random population.
Three phenotypes :
Yt(a+b-)
Yt(a+b+)
Yt(a-b+)
The Yt antigens are located on anticholinesterase, an enzyme involved in neurotranmission.
Yta and Ytb Antigens are inherited as co-dominant alleles on chr-7.
Yta antigen is not develoed at birth, cord blood is usually negative but it is strongly immunogenic
however Ytb antigen is well developed at birth but poorly immunogenic.
Both Yta and Ytb are IgG antibodies mostly of IgG1 and IgG4 subclass.
Yt antibodies are reactive in IAT and associated with transfusion reaction.

The XG Blood group system (ISBT 012)
Discovered in 1962.
Only Xga antigen identified with no known antithetical partner.
XG phenotype: Either Xg(a+) or Xg(a-)
Xga is represented as XG1 in ISBT.
Gene that encode Xg allele is located on short arm of X-chromosome, so gender difference in
frequency of Xg antigen expression found.
Approximately 89% female population express Xga where as only 66% of male population
express Xga .
Anti-Xga antibodies are predominantly IgG thus reactive in IAT testing but poor immunogen so
transfusion reaction or HDN not reported.
CD 99 had been added to system as gene that encode CD99,MIC2 gene have been found closely
linked to XG gene on short arm of x chromosome.
CD99 function as recptor and cell adhesion agent in most human cells.
The Sciana Blood Group system
Sc system is composed of: Sc1 and Sc2 antithetical alleles
Sc3 (high incidence antigen)
Randin(Rd) antigen
Sc1 & Sc2 Inherited as co-dominant character on chromosome 1.
Sc1 is High incidence antigen(100%) while Sc2 is low incidence antigen(<1%)
Anti Sc1 & Anti Sc2 are IgG and react in IAT testing.Anti Sc1 has been found to activate
compliment while Anti Sc2 not.
Sc3 antigen has high incidence .
Sc3 expressed on RBCs carrying Sc1 &Sc2 & corresponding anti Sc3 is found in Sc null or Sc;-1-
2 phenotype.
Anti Sc3 is IgG and thus react in IAT testing.
Rd is well developed in cord cells and Anti-Rd found to be stimulated through pregnancy.
Functional aspects
Neither Anti Sc1 nor Anti Sc2 has been implicated in transfusion reaction.
Anti Sc2 may cause mild HDN.
Anti Sc3 has been found to cause mild transfusion reaction but not associated with HDN.
Anti Rd is clinically important due to its association with HDN.

The Dombrock Blood Group System (ISBT 014)
Before1992, Dombrock considered as poly-morphic blood group system with two antigens,
Doa(DO1) and Dob (DO2), the products of alleles.
later on discovery of rare phenotype Gy(a) Hy Jo(a) were also Do(ab) led to Gya becoming
DO3 and the phenotypically and bio-chemically related antigens Hy and Joa becoming DO4 and
DO5.
DO is located on chromosome 12p13.Gene locus is ART4 (DO).
Protein product of this gene contains an arginine-glycine-aspartic acid (RGD) motif, commonly
involved in cell-to-cell interactions involving integrin binding.
A single amino acid substitution within this motif results in Doa versus Dob antigenicity.
All antigen of this system resides on a GPI-linked glycoprotein that resides on RBC membrane.
Thus null phenotype which lacks all the antigen has been found in PNH III(deficient in All GPI-
Linked glycoproteins).
The Dombrock glycoprotein could have a role in modication of proteins at the red
cell surface and might be involved in NAD+ clearance of the serum.The product of the Dob allele
contains an Arg-Gly-Asp motif, characteristic of adhesion molecules involved in cellular interaction.
Do antibodies are reported to cause acute to delayed transfusion reaction.

Colton blood Group system (ISBT 015)
Colton blood group system shows single polymorphism with two High & Low incidence alleles
coa and Cob respectively.
Single amino acid substitution from alanine to valine at 45 position of exon 1 accounts for the
Colton polymorphism
Coa and Cob are codominant.
CO Gene or (AQP1 gene)
Chromosomal location of AQP1 gene is 7p14.
Colton antigens are produced by alleles of a single gene that encodes one member (AQP1) of the
Aquaporin family of water channel proteins.
AQP1 and AQP3 are the only Aquaporins expressed in erythrocyte membranes.
Aquaporin Facilitates water-selective movement across the lipid bilayer in response to an
osmotic gradien
Subjects lacking or showing a deficiency of AQ1 (Co neg.) show no obvious clinical defect but
their red cell lifespan is slightly decreased and their membrane surface area is slightly reduced .

Chido/Rodgers Blood group system (ISBT 017)
The antigens for the Chido/Rogers (Ch/Rg) blood group system are the two isoforms C4A (acidic)
and C4B (basic) of the 4th component of complement, part of the classical activation pathway.
Upon complement activation the protein is cleaved into several fragments, one of which,
fragment C4d, contains the Ch/Rg epitopes.
Chido and Rodgers antigens are not located on intrinsic red cell structures, but on the fourth
component of complement (C4), whichbecomes bound to the red cells from the plasma.
Gene locus of C4A and C4B are on major histocompatibility complex class III region on
chromosome 6.
Inherited absence of genes of C4 may be a predisposing factor for diseases such as insulin-
dependent diabetes and autoimmune chronic active hepatitis.
Specific C4 allotypes or absence of genes have been associated with other autoimmune
disorders including Grave's disease and rheumatoid arthritis.

Gerbich Blood group system (ISBT 020)
The antigens for the Gerbich blood group system reside on Glycophorin C (GPC) or Glycophorin
D (GPD) glycoproteins.
Both proteins are encoded by the same gene but arise through an alternative use of two AUG
initiator codons, at positions 1 and 66 of the mRNA sequence.
Both, GPC and GPD glycophorins are type 1 membrane glycoproteins.
Both proteins are expressed on the erythocyte surface
The Gerbich blood group system is characterized by three high incidence antigens, Ge2,Ge3,
Ge4.
Absence of these antigens may result in absence or reduced expression of GPC and GPD,
resulting in Ge negative phenotype "Yus","Ge" or/and "Leach.
maintenance of red cell integrity via interaction with protein 4.1.
GPC can participate in the invasion of the red cell by Plasmodium falciparum, serving as the
receptor for its PfEBP-2 (EBA-140) binding ligand. Reduction of GPC and GPD in protein 4.1-
deficient red cells can beGPC and GPD play a role in associated with hereditary elliptocytosis.
GPC and GBD serve as red cell receptors for influenza A and B.

Cromer Blood group system (ISBT 021)
Cromer system antigens reside on the decay-accelerating factor (known as DAF, CD55), a
glycosylphosphatidylinositol (GPI) -anchored membrane glycoprotein.
The physiological role of DAF is to inhibit the complement cascade at the level of the critical C3
convertase step.
By this mechanism,DAF acts to protect autologous cells and tissue from complement-mediated
damage and hence can play a role in preventing or modulating autoimmune disease and
inflammation.
The epitopes for the Cromer system antigens have been shown to reside at various sites of the
sequence of the DAF glycoprotein and most have been shown to result from single nucleotide
substitutions in SCR domains of DAF.
The null Inab phenotype results from the absence of DAF on the membrane surface.
DAF is one member of the complement regulatory proteins and it down-regulates the
complement cascade.
It also acts as receptor for adhesion of certain microorganisms and enteroviruses.
DAF play role in Complement regulation; it protects host cells and tissues from complement-
mediated damage by inhibiting assembly and accelerating decay of C3 and C5 convertases of
both classical and alternative pathways.
Erythocytes of patients with PNH III (paroxysmal nocturnal hemoglobinuria) are deficient in DAF.
Antibodies with specificities in Cromer blood group system have not
been reported to cause hemolytic disease of the newborn.

Knop Blood group system (ISBT022)
The protein carrying the Knops blood group antigens is complement receptor 1 (CR1), the
product of the complement receptor 1 (CR1) gene.
Gene locus - CR1 (CD35)
CR1 was identified as the protein carrying the KNa, McCa, Sla and Yka blood group antigens.
The CR1 gene exists in four forms giving rise to four different molecular weight protein isoforms,
that differ by approximately 30kD.
The basis for this molecular weight polymorphism is the deletion or duplication, by unequal
crossover events
The CR1 gene exhibits three kinds of polymorphisms:
1) DNA variation reflected in amino acid polymorphisms.
The most common blood group phenotypes among Asians and Caucasians is Kn(a+b-),
McC(a+b), Sl(a+)Vil-; in Blacks, the Sl(a-)Vil+ type predominates.
2) structural polymorphism as reflected by molecular weight polymorphism of the CR1 protein, based on
deletion or duplication, by unequal crossover events, of sequences encoding the SCRs
The most common size allele in all populations studied is CR1*1, whereas the smallest size, i.e.,
CR1*3 is found most frequently in those of African descent.
3) level of expression on the erythrocyte surface
The H (high expression) and L (low expression) alleles are associated with the restriction
fragment length polymorphism in Caucasians and Asians but not in Blacks.
The major functions of CR1 are the binding of C4b/C3b opsonized complexes as well as
complement regulation.
Also play role in Binding and removal of circulating immune complexes; decay acceleration of
C3, C5 and C3bBb convertases.
cofactor for Factor I cleavage of C3b; rosetting receptor for Plasmodium falciparum erythrocyte
membrane protein one (PfEMP-1).
No individual completely deficient in CR1 has been reported to date, although 1-2% of
Caucasians may have low level of erythrocyte CR1 (E-CR1).
Acquired low levels of E-CR1 are observed in patients with systemic lupus erythromatosis, AIDS,
glomerulonephritis, autoimmune hemolytic anemia and other syndromes featuring immune
complexes.
The serological null (Helgeson phenotype) may also be due to low E-CR1 but is not associated
with a disease state.

Indian Blood group system (ISBT023 )
The epitopes for the Indian system reside on a membrane glycoprotein, known as CD44 antigen
(also known as the lymphocyte homing receptor, human hyaluronate receptor).
Gene locus - CD44
Different isofoms, resulting from alternative splicing have been observed in different tissues, but
the major form is the 80 kDa species expressed predominantly in hematopoietic and lymphoid
tissues.
So far only two antithetical antigenic specificities have been documented Ina and Inb.
only two antigens in addition to Ina and Inb have been documented. The occurrence of the Inb is
universally common in the population whereas Ina has a relatively high frequency in some
Middle Eastern and Indian populations only.
Thus, the highest frequency is among Arabs (11.8%), Iranians (10.6%)
and South Asian Indians (4%), with only 0.1% frequency among
Caucasians, Asians and Blacks.
It is an adhesion molecule that can bind to various extracellular matrix components.
It is involved in immune stimulation and signaling between cells.
play a role in metastatic spreading of tumor cells.
Serum CD44 is elevated in some patients with lymphoma.
Joint fluid from patients with inflammatory synovitis has higher than normal levels of soluble
CD44.

John Milton Hagen Blood group system (ISBT026)
Semaphorin 7A, the antigen for the JMH blood groups system, is an 80 kd glycoprotein, bound to
the cell membrane via a glycosylphosphatidylinositol (GPI) linkage.
Chromosomal location of SEMA7A is 15q22.3-q23
Four alleles of SEMA7A gene were recently documented based on variant JMH serological
phenotypes .
It is expressed on the surface of erythrocytes and activated lymphocytes and is a member of
semaphorin family of proteins that play a major role in regulation of the immune response and
certain neuronal functions.
The deduced sequence of the protein consists of 666 amino acids, showing a signal peptide, a
GPI anchor motif and 5 potential glycosylation sites.
An immunoglobulin-like and an RGD motifs are also present.
In the immune system, Sema7A expressed on activated T cells stimulates macrophages to
produce proinflammatory cytokines through the alpha1beta1 integrin.
Thus, integrin-mediated signaling is a common mechanism by which Sema7A functions in both
the nervous and immune systems.

Rh-associated glycoprotein Blood Group System (ISBT 030)
Gene locus RHAG, chromosome 6p11-21
Absence or severely reduced expression of all Rh30 polypeptides and/or their associated Rh
antigens is referred to as Rhnull or Rhmod and is classified as amorph or regulator type.
The amorph type defines mutations in the RHCED antigen locus proper, whereas the regulator
type defines mutations in the RHAG locus that supresses the expression of Rh antigens.
Rh incompatibility is still the leading cause of hemolytic disease of the newborn (HDN) .