6.2 ABO & Lewis Systems
Key Takeaways
- A2 red cells carry both fewer A antigen sites and a qualitatively different (less branched) antigen structure than A1, which is why 1-8% of A2 and a higher share of A2B individuals form anti-A1.
- The Bombay phenotype (Oh) arises from homozygous inactivation of FUT1 (h/h), producing red cells with no detectable H, A, or B antigen and a serum antibody that reacts with nearly every red cell except other Bombay cells.
- Para-Bombay differs from true Bombay because the FUT2 secretor gene remains functional, so trace H (and sometimes weak A or B) substance appears in saliva even though red cell H expression is absent or markedly reduced.
- Lewis antigens are not intrinsic red cell membrane components; they are glycosphingolipids synthesized by secretor tissue and passively adsorbed from plasma onto the red cell surface.
- Secretor (FUT2) and Lewis (FUT3) genotype together determine Le(a-b+), Le(a+b-), or Le(a-b-) red cell phenotype, and Lewis antibodies are almost always benign, naturally occurring, cold-reactive IgM.
ABO & Lewis Systems
Quick Answer: ABO antigens are built by adding sugar residues onto the H antigen substrate, so ABO expression depends on a functional H gene as much as on the A or B allele itself. Weak ABO subgroups (A2, A3, Ax, Ael, and their B counterparts), the cis-AB and acquired B phenomena, and the Bombay/para-Bombay phenotypes all represent variations on this shared biosynthetic pathway. Lewis antigens are a separate story entirely: they are not made by red cells at all, but are synthesized by secretor tissue and adsorbed passively from plasma, with expression governed jointly by the secretor (FUT2) and Lewis (FUT3) genes.
ABO Biosynthesis Depends on H Substance
The ABO gene does not create the A or B antigen from nothing — it modifies a precursor structure, the H antigen, that is itself the product of a separate gene (FUT1, covered structurally in 6.1). The A allele encodes glycosyltransferase A (GTA), which adds N-acetylgalactosamine to H substance; the B allele encodes glycosyltransferase B (GTB), which adds galactose instead. Because the O allele is amorphic and adds nothing, group O red cells display unmodified H antigen at full density — which is exactly why anti-H (weak, naturally occurring, and clinically insignificant in almost everyone with normal H expression) reacts most strongly against group O cells among typical ABO phenotypes, and why H expression itself becomes the limiting factor in Bombay individuals discussed below.
A1 versus A2 and Weaker ABO Subgroups
About 80% of group A individuals are A1; the remainder are A2 or rarer weak subgroups. The distinction is both quantitative and qualitative: A1 red cells carry roughly 800,000 to 1,000,000 antigen sites per cell versus roughly 250,000 to 500,000 for A2, and the A1 transferase also creates additional branched-chain antigen structures that the A2 transferase cannot. Dolichos biflorus lectin agglutinates A1 cells but not A2 cells, making it the classic reagent for resolving an ABO forward/reverse discrepancy caused by unexpected reverse-typing reactivity. Because A2 cells lack the A1-specific branched epitope, roughly 1-8% of A2 individuals and a considerably higher proportion of A2B individuals produce anti-A1 in their own serum — clinically insignificant at 37 degrees Celsius but a frequent cause of ABO discrepancies that specialists must recognize rather than mistake for a genuine ABO typing error.
| Subgroup | Anti-A Reaction | Anti-A,B Reaction | Anti-H Reaction | Serum Anti-A1? |
|---|---|---|---|---|
| A1 | 4+ | 4+ | Weak/negative | No |
| A2 | 4+ | 4+ | Moderate | Sometimes (1-8%) |
| A3 | Mixed field | Mixed field | Strong | Sometimes |
| Ax | Weak/negative | Weak positive | Strong | Usually yes |
| Aend | Very weak, mixed field | Very weak | Strong | Variable |
| Am | Negative (adsorption/elution positive) | Negative | Strong | No |
| Ael | Negative (adsorption/elution positive) | Negative | Strong | Usually |
B subgroups follow a parallel hierarchy — B3 (mixed field), Bx (weak), Bel (adsorption/elution only) — governed by weak or structurally altered B-transferase alleles rather than by any change to the underlying H pathway.
Cis-AB, B(A), and Acquired B
Cis-AB (introduced in 6.1) places both A- and B-transferase activity on a single inherited chromosome rather than on two independently segregating alleles, producing family pedigrees that violate ordinary ABO expectations. The B(A) phenomenon is a distinct, genuinely inherited variant in which certain ABO*A alleles encode a transferase with weak, promiscuous B-like activity, causing true group A red cells to react weakly with some anti-B reagents even though no B allele is present. Acquired B, in contrast, is not genetic at all: bacterial deacetylase enzymes — most often associated with colon cancer, intestinal obstruction, or gram-negative sepsis — strip the acetyl group from the terminal N-acetylgalactosamine of the A antigen, converting it to galactosamine, a structure that cross-reacts with some anti-B reagents. Acquired B is distinguished from a genuine B antigen by lowering reagent pH (most monoclonal anti-B reagents lose reactivity with acquired B at pH 6 to 6.5, but not with true B antigen), by the patient's ABO history, and by resolution once the underlying gastrointestinal condition is treated.
Bombay and Para-Bombay Phenotypes
The Bombay phenotype (Oh) results from homozygous inactivation of FUT1 (genotype h/h). Without a functional H gene, no H substance is made, so the ABO gene — regardless of whether it is A, B, or O — has no substrate to modify. Bombay red cells therefore type serologically as group O with routine anti-A and anti-B reagents, but the serum contains a potent, naturally occurring anti-A,B,H that reacts with essentially every red cell phenotype except other Bombay cells, including ordinary group O cells. This makes Bombay patients dependent on autologous donation or on rare Bombay-compatible donor blood; ordinary group O blood is not compatible.
Para-Bombay differs in one critical respect: the FUT2 secretor gene remains functional even though FUT1 is inactivated or severely impaired. Because secretor tissue can still synthesize small amounts of H substance through alternate pathways, para-Bombay individuals show trace H (and occasionally weak A or B, detectable only by adsorption/elution) in saliva, distinguishing them from true Bombay on saliva secretor testing even when red cell serology looks identical.
Secretor Status and the Lewis System
Lewis antigens are unusual among red cell blood groups because red cells do not synthesize them at all. FUT3 (the Lewis gene) is expressed in secretory epithelium, not in erythroid tissue, and its product is released into plasma as a soluble glycosphingolipid that is then passively adsorbed onto the red cell membrane. Expression depends on an interaction between the Lewis gene and the secretor gene:
| Secretor (FUT2) | Lewis (FUT3) | Red Cell Phenotype | Approximate Frequency |
|---|---|---|---|
| Se present | Le present | Le(a-b+) | Most common (roughly 70% in people of European ancestry) |
| Se absent | Le present | Le(a+b-) | Roughly 20% |
| Se present or absent | Le absent (le/le) | Le(a-b-) | Roughly 10% |
| Weak Se allele | Le present | Le(a+b+) | Uncommon overall, more frequent in some Asian populations |
Because Lewis substance is passively adsorbed rather than intrinsically synthesized, Lewis phenotype can change during life: pregnancy commonly causes a transient shift toward Le(a-b-) due to hemodilution and altered plasma lipoprotein handling, and transfused donor plasma can transiently alter a recipient's apparent Lewis typing. Lewis antibodies (anti-Le-a and anti-Le-b) are almost always naturally occurring, cold-reactive IgM that rarely cause clinically significant hemolysis and essentially never cause hemolytic disease of the fetus and newborn, both because IgM does not cross the placenta and because fetal red cells do not yet express adsorbed Lewis antigen. They remain worth recognizing because they can complicate antibody panel interpretation and, in rare reported cases involving complement-binding IgM, have been associated with immediate hemolytic transfusion reactions.
Which ABO subgroup characteristically shows mixed-field agglutination with anti-A reagent rather than a uniform reaction?
The Bombay phenotype results from a homozygous inactivating genotype at the ____ gene, leaving red cells with no detectable H, A, or B antigen despite a normal ABO genotype.
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A patient's red cells type as Le(a+b-). What does this most directly indicate about her secretor and Lewis genotype?
Which statements correctly describe Lewis blood group antibodies? Select all that apply.
Select all that apply