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Lutheran

The Lutheran blood group system (ISBT 005)! While not always causing the dramatic reactions seen with ABO or Rh, Lutheran has some unique biochemical features and inheritance patterns that make it fascinating. Its main antigens, Lua and Lub, are carried on a protein involved in cell adhesion, and the system is known for its characteristic mixed-field agglutination in antibody testing and some interesting rare null phenotypes

Genetics: The BCAM Gene

  • The Lutheran antigens are encoded by the BCAM gene (Basal Cell Adhesion Molecule), also historically referred to as the LU gene
  • Location: This gene resides on chromosome 19, interestingly, in the same region as and closely linked to the Secretor (FUT2) and Lewis (FUT3) genes

Biochemistry: The Lutheran Glycoprotein (B-CAM/LU)

Lutheran antigens are located on a specific protein with important biological functions:

  • Structure: The BCAM gene codes for the Lutheran glycoprotein (B-CAM/LU). This is a Type I transmembrane glycoprotein, meaning it passes through the red cell membrane once, with its N-terminus outside and C-terminus inside the cell
  • Family: B-CAM/LU belongs to the Immunoglobulin Superfamily (IgSF), a large group of cell surface proteins involved in recognition, binding, or adhesion
  • Function: B-CAM/LU functions as an adhesion molecule. Its primary known ligand (binding partner) is laminin, a major component of the extracellular matrix (the “scaffolding” outside cells). This interaction is thought to play a role in:
    • Red blood cell development and maturation
    • Maintaining membrane integrity
    • Pathophysiology: Notably, B-CAM/LU mediates the adhesion of sickle red blood cells to the endothelium (lining of blood vessels), contributing to the vaso-occlusive events characteristic of sickle cell disease

The Major Lutheran Antigens: Lua and Lub

These are the two primary, antithetical antigens of the system:

  • Biochemical Difference: The difference between Lua and Lub arises from a single nucleotide polymorphism (SNP) in the BCAM gene. This SNP results in a single amino acid substitution at position 77 of the mature protein:
    • Lua (LU1): Has Histidine (His) at position 77
    • Lub (LU2): Has Arginine (Arg) at position 77
  • Prevalence: This is a key difference!
    • Lua: Low prevalence antigen, found in about 8% of Caucasians and less frequently in other populations
    • Lub: High prevalence antigen, found in over 99% of most populations
  • Inheritance: An individual inherits one BCAM allele from each parent, leading to three possible genotypes:
    • LU*A/LU*A (Homozygous Lua) → Phenotype: Lu(a+b-) (Rare)
    • LU*B/LU*B (Homozygous Lub) → Phenotype: Lu(a-b+) (Common)
    • LU*A/LU*B (Heterozygous) → Phenotype: Lu(a+b+) (Uncommon, ~8%)

Other Lutheran Antigens

There are about 20 antigens identified within the Lutheran system. Another important one is:

  • Lu3: This is a very high-prevalence antigen present on all red cells that express either Lua or Lub (or both). It is absent only on the cells of individuals with the rare recessive Lu(a-b-) null phenotype

Lutheran Null Phenotypes: Lu(a-b-)

Individuals lacking both Lua and Lub are rare, and their phenotype can arise from different genetic mechanisms:

  1. Recessive Type Lu(a-b-)
    • Genetics: Caused by inheriting two rare, non-functional (amorph) BCAM alleles. The BCAM gene itself is defective
    • Biochemistry: Results in the complete absence of the B-CAM/LU protein from the red cell membrane
    • Antibodies: These individuals can produce anti-Lu3 if immunized. Anti-Lu3 reacts with all cells except other recessive-type Lu(a-b-) cells
    • Clinical: Usually clinically healthy, RBCs function normally
  2. Dominant Inhibitor Type Lu(a-b-) (In(Lu))
    • Genetics: Caused by inheriting a dominant suppressor gene, unrelated to the BCAM locus. The most common inhibitor is called In(Lu), which results from mutations in the EKLF (or KLF1) gene. EKLF codes for an erythroid transcription factor crucial for the expression of many genes in red cell development
    • Biochemistry: The BCAM gene is usually normal, but its expression is severely reduced (suppressed) by the faulty EKLF transcription factor. These individuals have trace amounts of Lutheran protein and other affected antigens (like P1, i, AnWj) on their RBCs
    • Antibodies: Because they have trace amounts of Lutheran protein, they do not make anti-Lu3. They are generally non-responsive to Lutheran antigens
    • Clinical: Usually healthy, but may have subtle RBC abnormalities
  3. X-linked Inhibitor Type Lu(a-b-)
    • Genetics: An extremely rare mechanism involving an inhibitor gene on the X chromosome (XS2 locus)
    • Biochemistry: Suppresses Lutheran expression

Antigen Expression

  • Lutheran antigens are poorly developed at birth, with cord blood cells often showing weaker reactivity than adult cells
  • Expression strength can vary among adults

Effect of Reagents on Lutheran Antigens

  • Proteolytic Enzymes (Ficin, Papain): Lutheran antigens are generally RESISTANT to treatment with common enzymes
  • Sulfhydryl Reagents (DTT, 2-ME): Lutheran antigens are also generally RESISTANT to DTT and 2-ME

Lutheran Antibodies (Anti-Lua, Anti-Lub, Anti-Lu3)

Lutheran antibodies often display a characteristic reactivity pattern:

  • Mixed-Field Agglutination: This is a hallmark! Lutheran antibodies often cause agglutination where there are clumps of cells mixed with unagglutinated free cells in the test tube. This appearance can be subtle and easily missed
  • Anti-Lua
    • Type: Can be IgM, IgG, or IgA, or a mixture. Often “naturally occurring” but can be immune stimulated
    • Reactivity: Often reacts best at room temperature (IS) but may persist to 37°C and AHG. Frequently shows mixed-field agglutination
    • Clinical Significance: Generally considered not clinically significant or only mildly significant. Rarely causes mild HTRs or HDFN
  • Anti-Lub
    • Type: Usually IgG, immune stimulated
    • Reactivity: Reacts best at the AHG phase. Can show mixed-field agglutination
    • Clinical Significance: Clinically significant! Although rare (due to the high prevalence of Lub antigen), anti-Lub can cause HTRs (usually mild to moderate) and mild HDFN
  • Anti-Lu3
    • Type: IgG, immune stimulated
    • Reactivity: Reacts at AHG with all cells except recessive Lu(a-b-) cells
    • Clinical Significance: Clinically significant. Requires rare Lu(a-b-) blood for transfusion

Key Terms

  • BCAM Gene: Gene on chromosome 19 encoding the Lutheran glycoprotein
  • B-CAM/LU: Lutheran glycoprotein; Basal Cell Adhesion Molecule
  • Immunoglobulin Superfamily (IgSF): Large family of cell surface proteins involved in adhesion and recognition
  • Laminin: Extracellular matrix protein that binds to B-CAM/LU
  • Lua/Lub: Major antithetical Lutheran antigens differing by His/Arg at position 77
  • Antithetical Antigens: Antigens coded by alleles at the same locus
  • Lu3: High-prevalence antigen absent only on recessive Lu(a-b-) cells
  • Lu(a-b-) Null Phenotype: Absence of Lua and Lub; can be recessive (due to BCAM mutations) or dominant (due to In(Lu)/ EKLF mutations)
  • In(Lu): Dominant inhibitor gene (usually mutation in EKLF) suppressing Lutheran expression
  • EKLF (KLF1): Erythroid transcription factor gene; mutations cause In(Lu) phenotype
  • Mixed-Field Agglutination: Characteristic pattern of agglutination with clumps and free cells, common with Lutheran antibodies