Blood Group Terminology and the Other Blood Groups

• Lewis antigens are carbohydrate structures on glycolipids
• They're not produced by erythroid cells; they're absorbed from plasma into the red cell membrane.
• Leª and Leᵇ are not allelic products; they are produced by the Lewis gene FUT3
• FUT3 encodes fucosyltransferase on chromosome 19, producing α-4-L-fucosyltransferase.
• Leᵇ appears with Le(FUT3) and Se(FUT2) genes.
• The FUT3 gene produces α-4-L-fucosyltransferase
• The FUT2 gene produce α-2-L-fucosyltransferase
• Lewis antigens exist on platelets and lymphocytes, not granulocytes or monocytes.
• The Lewis enzyme is found in saliva, milk, sub maxillary glands, gastric mucosa, kidney mucosa, and cyst fluids.
• There are four Lewis phenotypes.
• Le (a+b-) is only found in ABH non-secretors because type 1 H precursor isn't converted to type 1H without the FUT2 gene (essential for secretor status).
• Le (a-b+) is only found in ABH secretors because most type 1H precursor converts to type 1H, and also only Leᵇ adsorbs onto RBCs from plasma.
• Le (a+b+) is only found in ABH secretors with a weak secretor FUT2 Seʷ.
• Both Leª and Leᵇ are detected on red blood cells.
• Le (a-b-) results from homozygosity for inactive mutations in Lewis FUT3 or the Le gene, leading to non-functional or partially active (Leʷ) enzymes.
• The Lewis substance is present in secretions and as antigens on RBCs, depending on inherited Lele, Sese, and ABO genes.
• Lewis genes impact the concentration of H, A, and B type 1 chain substance in secretions without affecting type 2 chains.
• Leª and Leᵇ glycoproteins are found in newborn infants' saliva, but not in plasma at birth; cord blood and infant RBCs show an Le(a-b-) phenotype.
• Lewis glycosphingolipids become detectable in plasma after 10 days.
• Babies who inherit Le and Se genes will transition from Le(a+b-) to Le(a+b+) and finally to Le(a-b+) after 6-7 years
• Babies with Le and se genes will remain Le(a+b-).
• Pregnant women, patients with cancer, alcoholic cirrhosis, and viral/parasitic infections may show low expression or transformation of Lewis antigens due to abnormal lipid metabolism or genetic mutation.
• In such cases, one-third of the Lewis antigen adsorbs to RBCs, attaching to lipoproteins; increased lipoproteins can decrease Lewis antigen adsorption on RBCs.

Lewis Antibodies

• Lewis antibodies appear only in Le (a-b-) individuals
• Lewis antibodies are generally considered clinically insignificant and are mostly inactive above 37°C.
• Lewis antibodies are naturally occurring, usually IgM, and can bind complement and cause in vivo/vitro hemolysis.
• Lewis antibodies react better with enzyme-treated cells.

Anti-Leª

• IgM, may also be IgG.
• Can be detected at room temperature and AHG phase.
• Reacting at 37°C may cause hemolytic transfusion reactions.
• Le (a-b+) individuals lack anti-Leª.

Anti-Leᵇ

• Typically IgM and does not fix complement like Anti-Leª.
• Usually produced from those with Le(a-b-) phenotypes, and sometimes from individuals with Le(a+b-) phenotypes.
• Classified into categories anti-LeᵇH and anti-LeᵇL
  • Anti-LeᵇH reacts to positive Leᵇ and positive H antigen.
  • Anti-LeᵇL reacts to positive Leᵇ antigen regardless of ABH antigens.
• These antibodies aren't implicated in hemolytic transfusion reactions.

Anti-Leˣ

• It reacts to all Le(a+b-) and Le(a-b+) and 90% of cord blood Le(a-b-).
• Is produced from Le(a-b-) individuals.
• Leˣ and Leʸ (Type 1 precursor and type 1 H structure) are found in Lewis-negative individuals Le(a-b-)
• They can exist with ABH non-secretors and ABH secretors, respectively.
• Leˣ(X) is a type 2 isomer of Leª, formed by adding a Fucose-α(1-3)GlcNAc linkage on the type 2 chain.
• Leʸ(Y) is a type 2 isomer of Leᵇ formed by adding Fucose-α(1-3)GlcNAc linkage on type 2 H substance.
• Lewis antibodies are considered insignificant in blood transfusions for two reasons:
  • They can be neutralized by soluble Lewis antigens in plasma.
  • Lewis antigens dissociate from RBCs as readily as they bind.
• Lewis antibodies are IgM, unable to cause HDN, and Lewis antigens aren't fully developed at birth.
• If a patient with Lewis antibodies needs transfusion, Lewis-negative antigen blood is not required unless compatibility tests are positive at the AHG phase, or hemolysis is seen in vitro.
• Lewis antibodies can be inhibited by saliva or commercial Lewis substances in complicated antibody identification.

Biologic Significance of the Lewis System

• The Lewis system is associated with factors causing diseases like:
  • Peptic ulcers
  • Ischemic heart disease
  • Cancer
  • Kidney transplant rejection
• Leᵇ is a receptor for Helicobacter pylori, which can cause chronic diseases by expressing antigens.

Important points to summarize:

• Lewis blood group antigens aren't synthesized by RBCs
• They are made in tissue cells, secreted into body fluids and plasma, and then adsorbed onto the RBC membrane.
• Lewis antigens in secretions are glycoproteins, while cell-bound antigens (absorbed from plasma onto RBC membranes) are glycolipids.
• The Le gene codes for L-fucosyltransferase, which adds L-fucose to the type 1 chain.
• The Le gene is needed for Leª substance expression; Le and Se genes required for Leᵇ substance.
• Leª antigen forms when L-fucose is added to carbon 4 of N-acetylglucosamine on a type 1 precursor structure.
• Le(a+b-) persons are ABH nonsecretors with only Leª substance in secretions.
• Leᵇ antigen forms when a second L-fucose is added to carbon 4 of the subterminal N-acetyl-D-glucosamine of type 1 H.
• Le(a-b+) persons are ABH secretors with both Leª and Leᵇ substances in secretions.
• The most common Lewis phenotype in whites and blacks is Le (a-b+).
• The lele genotype is more common in blacks than in whites and will phenotype as Le (a-b-).
• Lewis antigens are poorly expressed at birth.
• Lewis antigens do not show dosage in serologic reactions.
• Lewis antibodies are generally IgM (naturally occurring).
  • Capable of binding complement
  • Enhanced by enzymes
  • Lewis substance in secretions can neutralize Lewis antibodies.
• Lewis antibodies are often encountered in pregnant women.
• Considered insignificant in transfusion medicine.

MNS Blood Group System

• The MNS blood group system (002) involves M (MNS1) and N (MNS2) antigens and their corresponding antibodies, Anti-M and Anti-N consisting of 45 antigens.
• MN antigens are well-developed at birth.
• Anti-M is a common, naturally occurring antibody.
• Most Anti-M and Anti-N are inactive at 37°C, considered clinically insignificant, and do not bind complement.
• Anti-M reacts better with MM genotype than MN, and sometimes not react at all with MN genotype. Anti-N reacts better with NN than MN, and sometimes not at all with the MN.
• The antibody reactivity to M/N antigens can be enhanced by increasing serum, the incubation time, or decreasing the temperature.
• Anti-M and anti-N are clinically significant if active above 37°C and can cause IHTRs and DHTRs.
• Anti-M very rarely causes HDFN
• MN antigens are not present on WBCs or platelets.
• M and N are located at the N-terminus of Glycophorin A (GPA) and are easily destroyed, especially by enzymes like ficin, papain, and bromelin, and ZZAP
• They not affected are affected by DTT, AET, α-chymotrypsin, choroquine, or glycine-acid-EDTA.
• M-active GPA has serine at position 1 and glycine at position 5.
• N-active GPA has leucine at position 1 and glutamic acid at position 5.
• Some people express the N antigen on GPB.
• Some Anti-N does not detect the N antigen on GPB.
• Dialysis patients treated with formaldehyde can alter the M and N antigens, producing Anti-Nf, which does not react at 37°C and is not clinically significant in transfusion.
• Antibodies to k, Kpb, Jsb, and other high-incidence Kell antigens are rare but can mask other alloantibodies.
• These are denatured by DTT or AET treated cells.

Ko Phenotype

• Homozygosity for a type of nonsense mutation, missense mutation, and splice site mutation that has been associated with the Ko null phenotype.
• Ko produce Anti Ku (Anti – KEL5) if immunized, resulting in HDFN and HTR.

Mcleod syndrome

• Is associated with acanthocytosis and muscular/ neurological defects.
• The syndrome is X-linked.
• They are found usually in boys.
• Results from homozygosity for inactivating mutation and deletion of the XK gene.
• Results in the absence of XK protein to expresses Kx antigen.
• It shows weakly expressed Kell system, no Km (KEL20), and no Kx.
• Chronic granulomatous disease (CGD) is also related to deletion of X–chromosome included XK gene.
• CGD patients with Mcleod syndrome usually produce Anti–Kx & Anti–Km so CGD & Mcleod syndrome should avoid transfusion.
• There is an unclear relationship between Kell antigens and the Gerbich-negative.
• These have caused hemolysis in vivo.
• High-incidence Kell antigens have antibodies that may be detected due to rare or masked other alloantibodies, or denatured by DTT or AET treatment.

Duffy system (008)

• The antigens reside on glycoprotein of 336 amino acids encoded by Duffy gene (DARC)
• DARC consist of two exons, and exon 1 encodes for the first seven amino acids of the glycoprotein.

Fyª (FY1) and Fyb (FY2)

• These are found in 3 alleles in the systems.
• One codes for Glu42, one codes for Asp42.
• One has some sort of regulatory effect

Kidd(009) antigens

• They encode for transporters on the RBC
• They allow the cell to transport urea in and out of the ell to carry the molecule to other organs

Lutheran blood group system(005)

• Lutheran genes code for Lu3, Lu6, Lu8 and AB
• Recessive inheritance results in the expression of anti-ab and not the antigen

Anti-Dia, -Dib, and Anti-Wra

• Generally considered clinically significant
• Have caused severe HTRs and HDFN
• Anti-Wra is relatively common.

Wrb

• Expression requires a normal GPA (MNS system)
• Alloanti-Wrb is extremely rare.
• There are few reactions with Anti-Yta.

The Diego system

• The antigens are located on a major RBC protein.

Cromer antigens

• Carried on the decay accelerating factor and are distributed in body fluids.

The in a antigen

• The in B is more prevelent
• Expression is more depressed on Lu(a-b-)

LW antigens

• Has a relationship with D antigen
• RHnull RBCs are LW(a-b-) cells
• Cannot anti-LW with DTT treated RBCs, must be AB cells.

Cold autoantibodies that can use IgM or IgG at all temperatures

IgM reactions

• Are usually at below 37 and are less serious

IGG reactions

• Are serious at above and can cause warm destruction of the cells

Codyminant alelles

• Means the genes are not silent and they produce antibodies and antigens

Autoantibodies

• Can mask results and also cause warm or cold destruction of RBCs.