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The Lewis antigen system is a human blood group system based upon genes on chromosome 19 p13.3 (FUT3 or Lewis gene) and 19q13.3, (FUT2 or secretor gene). Both genes are expressed in glandular epithelia and have dominant alleles (Le and Se, respectively) coding for enzymes with fucosyltransferase activity and recessive alleles (le and se, respectively) that are not functional.
There are two main types of Lewis antigens, Lewis a (Le-a) and Lewis b (Le-b). There are three common phenotypes: Le(a+b-), Le(a-b+), and Le(a-b-). They are red cell antigens which are not produced by the erythrocyte itself. Instead, Lewis antigens are components of exocrine epithelial secretions, and are subsequently adsorbed onto the surface of the erythrocyte.
The enzyme fucosyltransferase 3 encoded by Le gene adds a fucose to the precursor oligosaccharide substrate in subterminal position, converting it to the Le-a antigen. If a person has Le allele and is non-secretor (homozygous for the se allele), the Le-a antigen will be present in his bodily fluids and on his erythrocytes.
If a person besides Le has the allele Se (i.e. is a secretor), his exocrine cells will have also the enzyme fucosyltransferase 2, adding fucose to the oligosaccharide precursor in terminal position. The combined action of the two enzymes will produce antigen Le-b. In most people having both Le and Se, it is difficult to detect antigen Le-a because it is converted to Le-b very efficiently. Therefore, people with readily detectable Lewis a antigen are non-secretors, i.e. do not secrete A, B or H antigens, while Lewis b antigen is found only in secretors. Lewis negative people (Le a-, Le b-) are homozygous for the recessive le allele and can be either secretors or non-secretors.
The link between the Lewis blood group and secretion of the ABO blood group antigens was possibly the first example of multiple effects of a human gene.: the same enzyme (fucosyltransferase2) which converts the Le-a antigen to Le-b is also responsible for the presence of soluble A, B and H antigens in bodily fluids.
The three above-stated common Lewis phenotypes represent the presence or absence of Lewis and Secretor enzymes.
Le(a+b-) individuals have at least one functional Lewis gene (Le) but are homozygous for nonfunctional Secretor alleles (sese). Thus, these individuals synthesize and secrete Le(a) antigen but lack Le(b) and type 1 chain ABH. Le(a-b+) individuals inherit both Le and Se alleles, leading to the synthesis of Le(a), Le(b), and type 1 chain ABH. Most type 1 chain precursor is converted to Le(b), therefore these individuals appear as if they are Le(a-). Le(a+b+) phenotype is transiently observed in infants (Secretor activity increases with age). This phenotype is also encountered in 16% of Japanese individuals (who inherit a weak Secretor gene- Se(w)).
In absence of a functional Lewis gene (lele), neither Le(a) nor Le(b) are synthesized, leading to the Le(a-b-) phenotype. This phenotype is more common in persons of African descent. <Roback JD et al. AABB Technical Manual, 16th Ed. Bethesda: AABB Press, 2008.</ref>
Two precursor oligosaccharides exist, type 1 and type 2. Type 1 is found in secretions and in the serum. Type 2 is found exclusively on the surface of red blood cells. No type 1 oligosaccharide is found on RBCs. Unbranched type 1 and 2 oligosaccharides represent i antigen. Branched type 1 and 2 oligosaccharides are I antigens.
In neonates, i antigen oligosaccharides predominate (high in cord blood samples). Oligosaccharide branching increases with age, thus adults have mostly I antigen.
The H gene of the ABO system encodes a fucosyl transferase that adds fucose to type 2 precursor substances on the surface of RBCs to make H antigen. The h gene is an amorph. If no further modifications are made to the H antigen, the person is type O. When the A gene product acts on the H antigen and adds an N-acetylgalactosamine, the A antigen results and the person is type A. When the B gene product acts on the H antigen to add a galactose, the B antigen results and the person is type B.
The Le gene encodes a fucosyl transferase that adds fucose to type 1 precursor substance (both free in serum and in secretions) to make the Le(a) antigen. The le gene is an amorph. The Lewis antigen produced on free type 1 precursor substance passively adsorbs onto the surfaces or red blood cells.
The Se gene encodes a fucosyl transferase that adds fucose to type 1 precursor only if a fucose has already been added by the Le gene product (i.e., the Se gene fucosyl transferase adds a fucose to the Le(a) antigen). Addition of this second fucose produces the Le(b) antigen. Thus, individuals with the Le gene but no Se gene will have red blood cells bearing only the passively-adsorbed Le(a) but no Le(b). Individuals with both the Le gene and the Se gene will have red blood cells bearing only the passively adsorbed Le(b) and no Le(a). Individuals with no Le gene have neither Le(a) nor Le(b).
In addition, the Se gene product is responsible for the presence of A, B and H substances in secretions.
Lewis antibodies are naturally occurring antibodies, almost always IgM type, found almost exclusively in Le(a-b-) individuals (commonly Blacks). Lewis antibodies may include a mixture of anti-Le(a), anti-Le(b) and anti-Le(a+).
Lewis antibodies are almost always clinically insignificant because:
Therefore, it is not necessary to transfuse antigen-negative blood components for most patients.
Lewis antibodies are generally reactive at room temperature and only occasionally at 37 C and AHG phase (antihuman globulin).
Lewis antibodies are not a cause of hemolytic disease of the fetus and newborn (HDFN), as stated below.
Lewis antigens cannot be reliably detected until the 2nd birthday. Lewis antibodies in a pregnant woman are essentially totally insignificant because they are IgM subtype (don't cross the placenta) and Lewis antigen is weakly expressed during pregnancy (Lewis Le(a-b-) phenotype is commonly seen during gestation). Most newborns will type as Le(a-b-).
Lewis antigen is often decreased on RBCs during pregnancy with some women transiently typing as Le(a-b-). This is thought to be due in part to increased circulating plasma volume in pregnancy and increased lipoprotein.
The Le(b) and H antigens are receptors for the bacteria Helicobacter pylori, a gram-negative bacterium that can cause gastritis and has been implicated in peptic ulcer disease, gastric adenocarcinoma, mucosa-associated lymphoma (or mucosal associated lymphatic tissue lymphoma- MALToma) and idiopathic thrombocytopenic purpura (ITP)., 
Le(b) and type 1 H antigens are also receptors for Norwalk virus (common cause of acute gastroenteritis).