Kell

Clinically, Kell blood group system (ISBT 006) is a major player, right behind ABO and Rh, primarily because the K antigen (KEL1) is highly immunogenic and the resulting anti-K is relatively common and can cause significant transfusion reactions and Hemolytic Disease of the Fetus and Newborn (HDFN). Unlike systems like ABO or Lewis, Kell antigens are located on a specific transmembrane protein (a zinc endopeptidase) encoded by the KEL gene. The presence or absence of key amino acids on this protein defines the various Kell antigens, most notably the antithetical K (KEL1) and k (Cellano, KEL2) pair. Proper expression of Kell antigens also relies on its structural link to another protein, Kx, which has its own implications when absent (McLeod phenotype)

Genetics: The KEL Gene

• The Kell system antigens are encoded by the KEL gene, located on chromosome 7
• This single gene is responsible for the main Kell protein that carries most of the common Kell antigens

Biochemistry: The Kell Protein

Unlike ABO, Lewis, P1PK, or Ii which involve carbohydrates, Kell antigens are located on a protein

• Structure: The KEL gene codes for a Type II transmembrane glycoprotein (approx. 93 kDa). It passes through the red cell membrane only once, with its short N-terminal end inside the cell and the large C-terminal end (carrying the antigenic sites) outside the cell
• Function: The Kell protein is a zinc-dependent endopeptidase (a metalloprotease). It’s known to cleave a substance called endothelin-3, suggesting a role in vasoactive peptide metabolism, although its exact physiological role on RBCs isn’t fully established
• Crucial Linkage: The Kell protein is covalently linked via a disulfide bond to another integral membrane protein called Kx (XK protein). This linkage is vital for the proper expression and stability of Kell antigens in the membrane

Major Kell Antigens: K and k (Kell and Cellano)

These are the most commonly encountered antithetical pair in the Kell system:

• K Antigen (KEL1)
  • Biochemistry: Defined by the presence of Threonine at amino acid position 193 of the Kell protein
  • Prevalence: Relatively low prevalence antigen, found in about 9% of the Caucasian population, and even less frequent in individuals of African descent (around 2%)
  • Immunogenicity: Highly immunogenic! It’s considered the third most potent antigen at stimulating antibody production after A, B, and D. This is why anti-K is one of the most common non-ABO antibodies encountered
• k Antigen (Cellano, KEL2)
  • Biochemistry: Defined by the presence of Methionine at amino acid position 193 (a single nucleotide polymorphism in the KEL gene causes this Thr -> Met swap)
  • Prevalence: Very high prevalence antigen, found in over 98% of most populations
  • Immunogenicity: Rarely encountered as an antibody (anti-k) because most people possess the k antigen and won’t make antibodies against it
• Inheritance: An individual can be homozygous (KK - very rare, kk - common) or heterozygous (Kk)

Other Important Kell Antigen Pairs

There are over 30 antigens in the Kell system, but two other antithetical pairs are particularly noteworthy:

• Kp Antigens
  • Kp^a (KEL3) / Kp^b (KEL4): Result from an amino acid change at position 281 (Arg -> Trp)
  • Kp^a: Low prevalence (~2% Caucasians)
  • Kp^b: High prevalence (>99.9%)
  • Anti-Kp^a is sometimes seen; anti-Kp^b is rare
• Js Antigens
  • Js^a (KEL6) / Js^b (KEL7): Result from an amino acid change at position 597 (Leu -> Pro)
  • Js^a: Low prevalence in Caucasians (<0.1%) but significantly higher prevalence in individuals of African descent (~20%)
  • Js^b: High prevalence (>99.9% in Caucasians, ~99% in African descent)
  • Anti-Js^a is sometimes seen, particularly in Caucasian populations; anti-Js^b is rare

The Kx Blood Group System (ISBT 019) and its Link to Kell

The Kx system is intrinsically linked to Kell expression:

• Kx Protein (XK protein): Encoded by the XK gene, located on the X chromosome (important for inheritance pattern!)
• Structure: A multi-pass transmembrane protein, distinct from the Kell protein
• Function: Precise function unknown, but thought to be involved in membrane transport and structural integrity
• Relationship: As mentioned, Kx is disulfide-linked to the Kell protein. Proper Kx expression is necessary for normal Kell antigen expression. Absence or reduction of Kx protein leads to reduced Kell antigen density

Kell System Null Phenotypes

• K₀ (Kell Null)
  • Phenotype: Individuals lack expression of all Kell system antigens (K, k, Kp^a, Kp^b, Js^a, Js^b, etc.) on their RBCs
  • Genetics: Usually due to inheriting two rare, non-functional (amorph) KEL alleles
  • Kx Expression: These individuals have elevated levels of Kx antigen on their RBCs (because it’s not linked to/masked by the Kell protein)
  • Antibodies: If exposed to normal Kell-positive cells, K₀ individuals can produce a potent antibody called anti-Ku (KEL5), which reacts with a “universal” Kell epitope present on all cells except K₀ cells. Finding compatible (K₀) blood is extremely difficult
• McLeod Phenotype
  • Genetics: Caused by mutations or deletions in the XK gene on the X chromosome (X-linked recessive inheritance)
  • Biochemistry: Results in absent or severely deficient Kx protein
  • Kell Expression: Leads to a marked depression (weakening) of all Kell system antigens, as Kx is needed for proper Kell expression/stability
  • RBC Morphology: Associated with acanthocytosis (spiky red cells)
  • Clinical Syndrome (McLeod Syndrome): A multi-system disorder primarily affecting males, characterized by:
    • Late-onset neurological problems (chorea, psychiatric issues)
    • Skeletal myopathy (muscle weakness)
    • Cardiomyopathy
    • Compensated hemolytic anemia (due to the acanthocytosis)
  • Antibodies: McLeod individuals may produce anti-Kx and/or anti-Km (KEL20) (another high-prevalence Kell antigen). Transfusion requires rare McLeod phenotype or K₀ blood

Effect of Reagents on Kell Antigens

This is a key feature used in antibody identification!

• Sulfhydryl Reagents (DTT, 2-ME, AET): Reagents like Dithiothreitol (DTT), 2-mercaptoethanol (2-ME), or ZZAP (which contains DTT) DESTROY Kell system antigens. They work by breaking the disulfide bonds that are critical for maintaining the structure of the Kell protein and its link to Kx
• Proteolytic Enzymes (Ficin, Papain): Kell antigens are generally RESISTANT to treatment with common enzymes like ficin and papain

Kell Antibodies

• Type: Usually IgG (primarily IgG1), reacting best at the AHG (Coombs) phase
• Stimulation: Typically immune stimulated (require exposure through transfusion or pregnancy)
• Clinical Significance: Clinically significant! Capable of causing:
  • Hemolytic Transfusion Reactions (HTRs): Often extravascular, can be severe
  • Hemolytic Disease of the Fetus and Newborn (HDFN): Anti-K is a notorious cause of severe HDFN, sometimes through suppression of fetal erythropoiesis in addition to hemolysis
• Dosage: Kell antibodies generally do not show dosage (react similarly with homozygous and heterozygous cells)

Key Terms

• KEL Gene: Gene on chromosome 7 encoding the Kell glycoprotein
• Kell Protein: Transmembrane zinc endopeptidase carrying Kell antigens
• XK Gene: Gene on the X chromosome encoding the Kx protein
• Kx Protein: Membrane protein linked to Kell protein, essential for normal Kell expression
• K/k (KEL1/KEL2): Major antithetical Kell antigens resulting from Thr193Met substitution
• Kp^a/Kp^b (KEL3/KEL4): Antithetical Kell antigens (Arg281Trp)
• Js^a/Js^b (KEL6/KEL7): Antithetical Kell antigens (Leu597Pro), Js^a more common in African descent
• K₀ (Kell Null): Phenotype lacking all Kell antigens but with increased Kx
• McLeod Phenotype/Syndrome: X-linked condition due to XK defect, causing absent Kx, weakened Kell antigens, acanthocytosis, and multi-system clinical features
• Sulfhydryl Reagents (DTT, ZZAP): Chemicals that destroy Kell antigens by breaking disulfide bonds
• Immunogenicity: Ability to provoke an immune response (K antigen is highly immunogenic)