Lewis, I, P1PK, FORS, and GLOB Blood Group Systems

Antigens and Genetic Basis

Lewis antigens (Le ^a and Le ^b ) are not intrinsic to RBC membrane, but are synthesized by intestinal epithelial cells, circulate in plasma either free or bound to lipoproteins, and are then passively adsorbed onto the RBC membrane. Le ^a and Le ^b are synthesized in a stepwise fashion by fucosyltransferases, which add fucose moieties onto type I glycoprotein chains; these enzymes are encoded by LE(FUT3), which adds fucose to GlcNAC ( N -acetylglucosamine) and SE(FUT2) , which adds fucose on the Gal (galactose) moiety. The enzyme encoded by LE(FUT3) is responsible for synthesis of Le ^a resulting in Le(a+b−) phenotype. The enzyme encoded by SE(FUT2) converts Le ^a to Le ^b by the addition of another fucose molecule, resulting in Le(a−b+) phenotype. Individuals who have mutations in LE(FUT3) do not make Le ^a and therefore cannot synthesize Le ^b , regardless of SE(FUT2) enzyme activity, resulting in Le(a−b−) phenotype. Individuals who have mutations in SE(FUT2) have reduced activity of fucosyltransferase and reduced conversion of Le ^a to Le ^b , which can result in weak expression of both Le ^a and Le ^b , resulting in uncommon Le(a+b+) phenotype principally found in Taiwanese and Asian individuals ( Table 29.1 ).

Expression

Lewis antigens are adsorbed onto RBCs, platelets, and lymphocytes from plasma glycolipids. Lewis antigens are also widely distributed on human tissues, are present in soluble form in body fluids, and serve as receptors for some pathogenic bacteria. The antigens are not expressed on cord RBCs, and Le ^a appears before Le ^b and usually within the first few months of life. Antigen expression does not reach adult levels until 6 years of age. Antigen levels on RBCs are often diminished during pregnancy and various diseases; diminished antigens on RBCs are likely to be secondary to changes in endothelial secretion or changes in plasma lipoprotein content.

Antibodies

Lewis antibodies are predominantly found in persons with Le(a−b−) RBCs, and are often identified in plasma of pregnant women with depressed antigen expression. Antibodies are primarily IgM and reactive at temperatures below 37°C; however, mixtures of IgM/IgG or pure IgG, which are reactive at 37°C, do exist. Most Lewis antibodies are naturally occurring (present without previous exposure to antigen-positive RBCs) and are not usually clinically significant ( Table 29.2 ). Rare cases of antibodies causing hemolytic transfusion reaction (HTR) have been reported and are more commonly due to antibodies against Le ^a than Le ^b . Importantly, soluble Lewis antigens present in donor plasma neutralize the antibody, and Lewis antigens can also elute from RBCs into the plasma. Antibodies do not cause hemolytic disease of the fetus and newborn (HDFN) because Lewis antigens are not expressed on fetal RBCs and most anti-Le ^a and -Le ^b are IgM and do not cross the placenta. Patients with Lewis antibodies may be transfused with RBCs that are crossmatch-compatible at 37°C.

Antigens and Genetic Basis

I and i antigens differ in their branching structure. The i antigen is found predominantly on fetal and infant RBCs, where a disaccharide unit ( N -acetyllactosamine) is linked in linear chain. During the first 6 years of life, increased expression of acetylglucosamine transferase, encoded by GCNT2 (IGnT) , results in increased branching of carbohydrate structure leading to expression of I antigen. In some adults, i antigen is not converted to branched chain I antigen secondary to gene mutations leading to lack of transferase activity and rare i (“adult little i”) phenotype. Congenital cataracts are associated with a lack or marked reduction of I antigen on RBCs and lens.

The gene responsible for I antigen is GCNT2 (or IGnT ), and the reference allele is designated GCNT2 ^∗ 01 . GCNT2 is organized into three exons, but here are three versions of exon 1: 1A, 1B, or 1C. As a result, three alternative mRNA transcripts may be synthesized: GCNT2A, GCNT2B, or GCNT2C. GCNT2C-transcript is present in erythroid cells and encodes 6-β- N -acetylglucosaminyltransferase; branching enzyme for I expression. The I+ ^W phenotypes are due to homozygous or compound heterozygous single nucleotide changes in GCNT2 . The i _adult (or I null phenotype) is due to homozygosity or compound heterozygosity for missense or nonsense mutations or deletion of the GCNT2 coding region.

Expression

RBCs from newborns predominately express i, while RBCs from adults have predominantly I antigen. Adult RBCs vary in amount of I antigen expressed. Ii antigens are found on the surface of most cells and on soluble glycoproteins in saliva, plasma, and other fluids.