CHAPTER- FOUR

Other Blood Group

Systems
 Learning objectives
At the end of this chapter, the student should be able to:
 Briefly explain the characteristics and biochemistry
of other blood group antigen.
 Name the type of immunoglobulin class produced in
other blood group system and their reactivity.
 Compare and contrast the characteristics of
antibodies in other blood group system.
Major Blood Group Systems
 Lewis
I
P
 MNSs
 Kell
 Kidd
 Duffy
 lutheran
Basic terms to remember
 Clinical significance: antibodies that are associated
with decreased RBC survival
 Transfusion reactions

 HDN

 Not clinically significant: antibodies that do not cause

red cell destruction
 Cold reacting antibodies: agglutination best observed
at or below room temp.
 Warm reacting antibodies: agglutination best
observed at 37°C
 Systems that Produce
Cold-Reacting Antibodies
1. Lewis Antigens
 Identified in 1946
 Lele locus is on chromosome 19.
 Soluble antigens produced by tissues and found in body
fluids (plasma) Lewis substance
 Adsorbed on the RBC
adheres to RBC
becoming an antigen
RBC

Le substance in
Le genes plasma
 Difference of Lewis blood group from the others

 Lewis antigens are not intrinsic to the RBC membrane

produced during cell development
An individual’s Lewis phenotype is not determined solely
by genes at the Lele locus but also by the action of genes at
the Hh and Sese loci.
 The amount of Lewis antigen expressed on the RBC
varies according to the cell’s ABO phenotype.
 Lewis inheritance
 Lewis system depends on Hh, Se, and Le genes
 le, h, and se do not produce products
 If the Le gene is inherited, Lea substance is produced
 Le, H, and Se genes must ALL be inherited to convert Le a
to Leb. Examples:
 Le se H  Le(a+b-)
 Le Se H  Le(a-b+)
 le H se  Le(a-b-)
 le hh se  Le(a-b-)
Lewis Antibodies
 Usually occur naturally in those who are Le(a-b-)
 Other phenotypes RARELY produce the antibody
 IgM (may fix complement, becoming hemolytic)
 Enzymes enhance activity
 May be detected soon after pregnancy because pregnant
women may temporarily become Le(a-b-)
No clinical significance…Why?
 Le antibodies in a patient can be neutralized by the
Lewis antigens in the donor’s plasma (cancel each other
out)
 do not cause HDN because they do not cross placenta
(antigens not developed well in cord blood) Le(a-b-)
 2. I antigens
 These antigens may be I or i
 They form on the precursor chain of RBC
 Newborns have i antigen
 Adults have I antigen
 i antigen (linear) converts to I (branched) as the child
matures (precursor chain is more linear at birth) at about
18 months
I antibodies
 Most people have autoanti-I (RT or 4°C)
 Alloanti-I is very rare
 Cold-reacting (RT or below) IgM antibody
 Clinically insignificant
 Can attach c’ (no hemolysis unless it reacts at 37°)
 Pre-warming the tests can eliminate reactivity
 Enzymes can enhance detection
I antibodies
 Anti-I often occurs as anti-IH
 This means it will react at different strengths with
reagent cells (depending on the amount of H antigen
on the RBC)
 O cells would have a strong reaction
 A cells would have a weaker reaction
Anti-I antibodies
 Anti-I:
 Associated as a cause of Cold Agglutinin Disease
(similar to PCH)
 May be secondary to M. pneumoniae infections

 Anti-i:
 rare and is sometimes associated with infectious
mononucleosis
3. P Antigen
 Similar to the ABO system
 The most common phenotypes are P1 and P2
 P1 – consists of P1 and P antigens
 P2 – consists of only P antigens
 Like the A2 subgroup, P2 groups can produce anti-P1
 75% of adults have P1
P1 Antigen
 Strength of the antigen decreases upon storage
 Found in secretions like plasma and hydatid cyst fluid
 Cyst of a dog tapeworm
 P antibodies
 Anti-P1
Naturally occurring IgM
 Not clinically significant
 Can be neutralized by hydatid cyst fluid to reveal more
clinically significant antibodies
 Anti-P

Produced in individuals with PCH

 PCH – IgG auto-anti-P attaches complement when cold
(fingers, toes). As the red cells circulate, they begin to
lyse (releasing Hgb)
 This PCH Ab is also called the DonathLandsteiner Ab
4. MNSs Blood System
 4 important antigens (more exist):
M
N
S
s
 U (ALWAYS present when S & s are inherited)
 M & N located on Glycophorin A
 S & s and U located on Glycophorin B
 Remember: Glycophorin is a protein that carries
many RBC antigens
MNSs Antigens

M & N only differ in

M their amino acid sequence
Glycophorin A N
at positions 1 and 5
RBC

Glycophorin B
U
S
s S & s only differ in
their amino acid
sequence at position 29
COOH end ….. …. 5, 4, 3, 2, 1 (NH2 end)
MNSs antigens
 all show dosage
 M & N give a stronger reaction when homozygous,
(M+N-) or (M-N+)
 Weaker reactions occur when in the heterozygous state
(M+N+)
 Antigens are destroyed by enzymes (i.e. ficin, papain)
U (Su) antigen
 The U antigen is ALWAYS present when S & s are
inherited
 About 85% of S-s- individuals are U-negative (RARE)
 U-negative cells are only found in the Black population
Frequency of MNSs antigens
Phenotypes Blacks Whites
(%) (%)
M+ 74 78
N+ 75 72
S+ 30.5 55
s+ 94 89
U+ 99 99.9
High-incidence antigen
Thought…..
 Can a person have NO MNSs antigens?
 Yes, the Mk allele produces no M, N, S, or s
antigens
 Frequency of 0.00064 or .064%
Anti-M and anti-N antibodies
 Demonstrate dosage
 Anti-M and anti-N
 IgM (rarely IgG)
 Clinically insignificant
 If IgG, could be implicated in HDN (RARE)
 Will not react with enzyme treated cells
 Anti-S, Anti-s, and Anti-U
 Clinically significant
 IgG
 Can cause RBC destruction and HDN
 Anti-U
 will react with S+ or s+ red cells
 Usually occurs in S-s- cells
 Can only give U-negative blood units found in <1%
of Black population
 Contact rare donor registry
MNSs Antibody Characteristics
Antibody IgG Class Clinically
significant
Anti-M IgM (rare IgG) No
Anti-N IgM No
Anti-S IgG Yes
Anti-s IgG Yes
Anti-U IgG Yes
 Systems that Produce
Warm-Reacting Antibodies
5. Kell System
 Discovered in 1946
 Includes 22 high and low frequency antigens (k1-k25)
and 3 Ag removed from the system
 well developed at birth
 Kell (KEL) locus is found on chromosome 7 and has 4
sub locus – Kpa/Kpb, K/k, Jsa/Jsb, KELL11/KELL17
 High frequency antigens – k, Kpb, Jsb, KELL11

Similar to the Rh system
2 major antigens (over 2 exist)
K (Kell), <9% of population
k (cellano), >90% of population
The K antigen is very immunogenic (2nd to the D antigen)
in stimulating antibody production
1:10 negative for k Ag =develop anti-k in response to
transfusion
Other Kell antigens
 Other sets of alleles also exist in the Kell system:
 Analogous to the Rh system: C/c and E/e
 Kp antigens
 Kpa is a low frequency antigen (only 2%)
 Kpb is a high frequency antigen (99.9%)
 Js antigens
 Jsa (20% in Blacks, 0.1% in Whites)
 Jsb is high frequency (80-100%)
 Kell antigens
 Kell antigens have disulfide-bonded regions on the
glycoprotein's(integrated to the RBC membrane except
k24)
 This makes them sensitive to sulfhydryl reagents:
 2-mercaptoethanol (2-ME)
 Dithiothreitol (DTT)
 2-aminoethylisothiouronium bromide (AET)
Kellnull or K0
 No expression of Kell antigens except a related antigen
called Kx
 As a result of transfusion, K0 individuals can develop
anti-Ku (Ku is on RBCs that have Kell antigens)
=alloantibody
 Rare Kell negative units should be given
Kell antibodies
 IgG (react well at AHG)
 Produced as a result of immune stimulation (transfusion,
pregnancy)
 Ab don’t bind the c’
 Clinically significant
 Enzyme phase no enhancement or depression of Ab
reactivity
 Kell antibodies
 Anti-K is most common because the K antigen is
extremely immunogenic
 k, Kpb, and Jsb antibodies are rare (many individuals
have these antigens and won’t develop an antibody)
 The other antibodies are also rare since few donors have
the antigen
 Kx antigen
 Not a part of the Kell system, but is related
 Kx antigens are present in small amounts in
individuals with normal Kell antigens
 Kx antigens are increased in those who are K0
 McLeod Syndrome
 The XK1 gene (on the X chromosome) codes for the Kx
antigen
 When the gene is not inherited, Kx is absent (almost
exclusive in White males)
 Causes abnormal red cell morphologies and decreased red
cell survival:
 Acanthocytes – spur cells (defected cell membrane)
 Reticulocytes – immature red cells
 Associated with chronic granulomatous disease
 WBCs engulf microorganisms, but cannot kill (normal
flora)
6. Kidd Blood Group
2 antigens
 Jka and Jkb (codominant alleles)
 Show dosage

Genotype Phenotype Whites Blacks

(%) (%)
JkaJka Jk(a+b-) 26.3 51.1
JkaJkb Jk(a+b+) 50.3 40.8
JkbJkb Jk(a-b+) 23.4 8.1
JkJk Jk(a-b-) rare rare
Kidd Antigens
 Well developed at birth
 Enhanced by enzymes
 Not very accessible on the RBC membrane
Kidd antibodies
 Anti-Jka and Anti-Jkb
 IgG
 Clinically significant
 Implicated in HTR and HDN
 Common cause of delayed HTR
 Usually appears with other antibodies when detected
Kidd antibodies
 Anti-Jk3
 Found in some individuals who are Jk(a-b-)
 Far East and Pacific Islanders (RARE)
 7. Duffy Blood Group(fy)
 discovered in 1950(hemophilic, [Link])
 Predominant genes (codominant alleles):
 is a single locus system with two antigens, Fya and Fyb
on chromosom-1 but have total of six Ag fy3Ag and
other fy4,fy5 and fy6 Ag
 Fy locus is syntenic with Rh locus
 well developed at birth
 not identified on granulocyte, lymphocyte, monocyte
and platelets
 Antigens are destroyed by enzymes
 Show dosage
 Phenotypes Blacks Whites
Fy(a+b-) 9 17
Fy(a+b+) 1 49
Fy(a-b+) 22 34
Fy(a-b-) 68 RARE(anti-
fy3)
biochemistry of Duffy Ag
 Mapped to the glycoprotein of the RBC membrane
 Gycoprotien spans the lipid bilayer of the membrane
multiple times
Duffy antibodies
 Common characteristics of anti-fy3 and anti-fyb
 IgG (rxn observed best in AHG phase)
 Do not bind complement
 Clinically significant
 Stimulated by transfusion or pregnancy (but not a
common cause of HDN)
 Do not react with enzyme treated RBCs
 The Duffy and Malaria Connection
 Most African-Americans are Fy(a-b-)
 Interestingly, certain malarial parasites (P. knowlesi and P.
vivax) will not invade Fya and Fyb negative cells
 It seems either Fya or Fyb are needed for the merozoite to
attach to the red cell
 The Fy(a-b-) phenotype is found frequently in West and
Central Africans, supporting the theory of selective
evolution
Other Blood Group
Antigens…
8. Lutheran Blood Group System
 Identified in 1945
 Single locus (on chromosome 19) system comprises of 18
Ags from Lu1-Lu20)
 2 codominant alleles: Lua and Lub
 Weakly expressed on cord blood cells
 Most individuals (92%) have the Lub antigen, Lu(a-b+)
 The Lu(a-b-) phenotype is RARE
 Lutheran antibodies
 Anti-Lua
 IgM and IgG
 Not clinically significant
 Reacts at room temperature
 Mild HDN
 Naturally occurring or immune stimulated
 Anti-Lub
 Rare because Lub is high incidence antigen
 IgG
 Associated with transfusion reactions (rare HDN)
Bg Antigens
 Three (Bennett-Goodspeed) Bg antigens:
 Bga
 Bgb
 Bgc
 Related to human leukocyte antigens (HLA) on RBCs
 Antibodies are not clinically significant
Sda Antigens
 High incidence antigens found in tissues and body fluids
 Antibodies are not clinically significant
 Antibodies characteristically cause mixed field
agglutination with reagent cells
 Xg Blood Group
 Only one exists (Xga)
 Inheritance occurs only on the X chromosome
 89% Xga in women
 66% in males (carry only one X)
 Men could be genotype Xga or Xg
 Women could be XgaXga, XgaXg, or XgXg

 Example: Xg(a+) male with Xg(a-) woman would only

pass Xg(a+) to daughters, but not sons
 The antigen is not a strong immunogen (not attributed to
transfusion reactions); but antibodies may be of IgG class
HTLA Antigens
 High Titer Low Avidity (HTLA)
 Occur with high frequency
 Antibodies are VERY weak and are not clinically
significant
 Do not cause HDN or HTR
Review
Cold Antibodies (IgM)
 Anti-Lea
 Anti-Leb
 Anti-I
 Anti-P1
 Anti-M
 Anti-A, -B, -H
 Anti-N

LIiPMABHN
Naturally Occurring
Warm antibodies (IgG)

 Rh antibodies
 Kell
 Duffy
 Kidd
 S,s
Remember enzyme activity:
Papain, bromelin,
ficin, and trypsin Enhanced by Destroyed
enzymes by enzymes
Kidd Fya and Fyb
Rh M, N
Lewis S, s
I
P
Remembering Dosage:
 Kidds
and Duffy the Monkey (Rh) eat lots of
M&Ns

M&Ns
M&Ns

Jka, Jkb, Fya, Fyb, C, c, E, e (no D), M, N, S, s

MNSs
Kidd Duffy Rh

adapted from Clinical Laboratory Science Review: A Bottom Line Approach (3rd Edition)