Kell Blood Group System and the McLeod Syndrome

The Kell blood group system was discovered in 1946 and was named after Mrs. Kellner, the mother of first baby discovered to be affected by Hemolytic Disease of the Newborn (HDN) due to Kell antibodies. The Kell blood group system is classified into subtypes according to the type of antigens on red cells (proteins and carbohydrate molecules on red blood cell membranes). The Antibodies found in the body that can fight against the kell antigens are call the Kell Antibodies. These kell antibodies can attack red blood cells having the Kell antigens on their membranes and destroy these cells leading to hemolytic transfusion reactions (HTR) and hemolytic disease of the fetus and newborn (HDFN); because of these conditions, the Kell blood group is highly clinically significant.

Kell Blood Group System

The Kell blood group system contains more than 25 antigens, but only two are considered as the major antigens. These two major kell antigens include: the first kell antigen represented by capital letter K (with the symbol K1 and named after the parent blood group system as Kell). The second kell antigen is represented by a small letter k(with the symbol K2 and named as Cellano). Therefore the two major kell antigens can be named as Kell (K1) and Cellano (K2). The k antigen is a high-frequency antigen that is present in more than 98% of whites and blacks while the K antigen is much less common.

Molecular and Genetic Composition of the Kell Antigen

The Kell protein is a glycoprotein (made of both carbohydrate and protein molecules) this glycoprotein is actually a zinc endopeptidase (that break peptide bonds of nonterminal amino acids within a molecule). This kell antigen contains multiple intra-chain disulfide bonds, this means it can be destroyed by reducing agents such as dithiothreitol (DTT), 2-mercaptoethanol (2-ME) and 2-aminoethylisothiouronium bromide (AET).

The KEL gene coding for the Kell protein is located on chromosome 7. Another protein called Kx is essential for the expression of Kell antigens. This Kx has its locus on the X chromosome and is linked by a disulfide bond to the Kell protein on chromosome 7 – this interaction shields the Kx protein such that antibodies against the Kx protein do not react with Red blood cells that carry the normal Kell antigens, the anti-Kx antibodies only react with red blood cells carrying abnormal kell antigens. Anyone who lacks the Kx protein has a phenotype called the McLeod phenotype which is characterized by a marked reduction of the Kell antigens and anemia as well as neuromuscular abnormalities.

The different types of Kell Antigens

The majority of the antigens of the kell blood group system arise as a result a variety of nucleotide mutations that cause single amino acid substitutions in the K protein.

Kell blood group system phenotypes and prevalence
Kell blood group system phenotypes and prevalence

 

List of the 23 Antigens of the Kell blood group systems

  • K
  • K
  • Kpa
  • Kpb
  • Ku
  • Jsa
  • Js b
  • Ula
  • K11
  • K12
  • K13
  • K14
  • K16
  • K17
  • K18
  • K19
  • Km
  • Kpc
  • K22
  • K23
  • K24
  • VLAN
  • TOU

The kell antigens are coded by a complex of genetic loci, known as the Kell locus, which is located on chromosome 7q33.The high incidence kell antigens include: k, Kpb , Jsb, K14 and K11. The lower frequency antigens include: K, Kpa, Kpc, Jsa and K17.K0 is a phenotype that lacks Kell antigens and results from an assortment of mutations, including nucleotide deletion, defective splicing and premature stop codons. The weak expression of Kell antigens results in Kell-mod phenotypes.

McLeod phenotype

The McLeod phenotype occurs as a result of deletions and mutations of the XK locus, resulting in depressed expression of the Kell system antigens in addition to decreased Red blood cells survival, deformability, and permeability to water, as well as deformed spiky cell membranes of the RBCs ( acanthocytic morphology). The McLeod syndrome has been reported in very few males (about 60 males).

McLeod syndrome symptoms

  1. RBCs defects such as spiky cell membranes
  2. Muscular defects including skeletal muscle wasting
  3. Neurological defects such as seizures
  4. Cardiomyopathy

These symptoms develop after the fourth decade of life. This phenotype has been found in individuals with chronic granulomatous disease, which results from a deletion of the X chromosome that includes both the XK and the X-CGD loci.

Kell Antibodies

K antigen is strongly immunogenic , hence, anti-K antibodies are frequently formed in K-negative individuals who are exposed to K-positive RBCs. Rare cases of naturally occurring anti-K have been reported, but most anti-K alloantibodies are identified in individuals who have received RBC transfusion or have been pregnant. All other Kell system antibodies also result from RBC exposure. Anti-K and other antibodies to the Kell system antigens are capable of producing immediate and delayed hemolytic transfusion reactions and hemolytic disease of the fetus and newborn.

Neither maternal antibody titer nor amniotic fluid bilirubin levels are good predictors of the severity of hemolytic disease of the fetus and newborn because Kell antigens are expressed very early during erythropoiesis this means that anti-Kell antibodies can cause destruction of these RBCs precursor cells and thereby suppress erythropoiesis. Therefore, these antibodies can cause anemia without hemolysis nor elevated bilirubin therefore, in pregnancy, the maternal antibody titer and amniotic fluid bilirubin levels are not good predictors of the severity of hemolytic disease of the newborn.

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