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2336 Part XIII: Transfusion Medicine Chapter 136: Erythrocyte Antigens and Antibodies 2337

b
a
a
Do , Do , and Kn antigen expression is considerably weaker on cord Antigens in ABO, LE, P1PK, and GLOB blood group systems
b
a
RBCs than on RBCs from adults. Le , sometimes Le , Ch/Rg, AnWj, depend on an immunodominant sugar, usually terminally located, the
a
and Sd , are not readily detectable, although 50 percent of cord sam- polysaccharide to which the sugar is attached, and the type of linkage
ples type Le(a+) with more sensitive test methods. Full expression of involved. I/i specificity is defined by a series of sugars on the inner
A, B, H, I, and Lewis antigens usually is present by age 3 years, whereas portion of ABH saccharide chains. The presence of at least two repeat-
full expression of P1 and Lutheran antigens may not occur until ing Gal(β1–4)GlcNAc(β1–3)Gal units in a linear structure defines i
age 7 years. activity. I activity involves these same sugars in branched form (see
Table 136–3). The gene for I (GCNT2) encodes the transferase respon-
sible for branching (β(1–6) glucosaminyltransferase). During the first
VARIATION IN ANTIGEN EXPRESSION years of a child’s life, linear chains are modified into branched chains,
32
RBCs from individuals who are homozygous for an allele typically have resulting in the appearance of I antigens. The I antigen is reduced on
a greater number of antigen sites than do RBCs from individuals who RBCs from fetuses and infants. A rare i phenotype occurs in adults
are heterozygous. Consequently, their RBCs can react more strongly (see “I-Negative Phenotype [i Adult]” below).
with antibody. This difference in expression and antigen–antibody reac- Polysaccharide chains are attached to glycoproteins in secretions
tivity because of zygosity is known as dosage. For example, RBCs from (on type 2 chains), to glycolipids in plasma (on type 1 chains), and to
a homozygous MM individual carry a double dose of M antigen and both on the RBC membrane. Approximately 70 percent of A, B, H, and I
react more strongly with anti-M than do RBCs from a MN heterozygous antigens on the RBC membrane are carried on glycoproteins, primarily
individual carrying only a single dose of M. Antithetical antigens C/c, on the anion transporter, but also on the glucose transporter, the RhAG,
E/e, M/N, S/s, and Jk /Jk commonly show dosage effect. Dosage is less and others. Approximately 10 percent of these antigens are on NeuAc-
b
a
obvious with D, K/k, and Lu /Lu antigens. It typically is more apparent rich glycoproteins, 5 percent on simple glycolipids, and the remainder
a
b
16
k
within a family than between families. Dosage within the Duffy system on polyglycosylceramide. P1, P , and P antigens are found on glycolip-
also may not be serologically obvious because Fy(a+b–) or Fy(a–b+) ids both on the membrane and in plasma. 33
phenotypes are seen in either homozygous (Fy Fy or Fy Fy ) or hemizy- Lewis antigens are unique because they occur only on type 1
a
b
a
b
gous (Fy Fy or Fy Fy) individuals. polysaccharide chains, which are found in plasma and secretions but
b
a
Some blood group antigens are inherited as closely linked genes not made by RBCs. Hence, they exist on RBCs only by adsorption
or haplotypes. Haplotype pairings and gene interaction (either cis or of Lewis substance from plasma. The Le (or FUT3) gene encodes an
a
b
trans) also can affect phenotypic expression. For example, the pairing α(1–4)fucosyltransferase. Whether the resulting antigen is Le or Le
of RHCE*C in trans position to RHD can result in weak expression of D depends on the secretor gene Se (or FUT2), which encodes an α(1–2)
(see “Rh Blood Group System” above), whereas RHCE*E in cis position fucosyltransferase.
with RHD is associated with strong expression of D. Among the com-
mon phenotypes, R R RBCs carry the strongest expression of D. In the PROTEIN ANTIGENS
2
2
Kell system, Kp is associated with weakened expression of in cis k and
a
Js antigens. Protein structures that carry blood group antigens can be grouped
b
Still other antigens are affected by regulator genes. The dominant into three categories: (1) those that make a single pass through the
29
type of the Lu(a–b–) phenotype [In(Lu)] results from heterozygosity for erythrocyte membrane, (2) those that make multiple passes through
an allele of the KLF1 gene, the gene that encodes erythroid Krüppel-like the membrane, and (3) those that are attached to the membrane
factor (EKLF). The dominant inhibitor gene KLF1 suppresses expres- through a covalent linkage to lipid (GPI-linked; see Fig. 136–1).
sion of Lutheran, P1, i, and many other antigens. The dominant inhib- Single-pass proteins include GPA with M and N antigens, gly-
30
itor In(Jk) suppresses expression of Jk and Jk antigens. Rare variants cophorin B (GPB) with S, s, and U antigens, GPC and glycophorin D
a
b
31
of the RHAG gene depress or prevent expression of the Rh antigens (see (GPD) with Gerbich antigens, and the Lutheran, LW, Indian, Knops,
“Rh Syndrome” below). Xg, Ok, and Scianna proteins (see Fig. 136–1). These proteins have an
null
extracellular amino-terminus and an intracellular carboxyl-terminus
(referred to as type I). In contrast, the Kell glycoprotein has an extracel-
BIOCHEMISTRY OF ERYTHROCYTE lular carboxyl-terminus and an intracellular amino-terminus (referred
to as type II).
ANTIGENS Most proteins that carry blood group antigens and make multi-
ple passes through the erythrocyte membrane have both carboxyl- and
An antibody typically recognizes an epitope consisting of four to five amino-terminal ends that are intracellular, are hydrophobic, and have a
amino acids on linear proteins or one to seven sugars. Alternatively, the transport function. Rh, RhAG, Diego, Colton, Kidd, Kx, GIL, and Raph
antibody-binding site may encompass a more complex three-dimensional proteins are included in this category. Duffy and Lan are multipass pro-
structure with branches or folds, and recognition may depend on teins, but they have an extracellular amino-terminus. Duffy has homol-
both amino acids and sugars. Tables 136–2 and 136–3 and Fig. 136–1 ogy with a family of cytokine receptors and the Lan protein belongs to
summarize blood group biochemistry and antigen structure. 4,6,16 the family of ATP-binding cassettes. 4,6,34
Lipid-linked proteins have their carboxyl-terminus attached to
the lipid GPI and are said to be GPI-linked or anchored. Cromer, Yt,
CARBOHYDRATE ANTIGENS Dombrock, and JMH proteins belong to this category. GPI-linked
Polysaccharides with blood group activity are made by sequential addition proteins are of special interest to hematologists because defective
of specific sugars (or sugar derivatives) to specific precursors in specific synthesis of the GPI anchor is responsible for paroxysmal noctur-
linkages by specific transferases. Sugars commonly involved are galactose nal hemoglobinuria (PNH). Thus, PNH-III RBCs lack all proteins
35
(Gal), N-acetyl-D-galactosamine (GalNAc), N-acetylglucosamine (Glc- attached by a GPI anchor, including those carrying blood groups
NAc), fucose (Fuc), and N-acetylneuraminic acid (NeuAc). (Chap. 40).
Kaushansky_chapter 136_p2327-2352.indd 2337 9/21/15 4:30 PM