Lewis Blood Group System

Lewis antigens and antibodies:
This group used to make me go cross-eyed because it can be confusing. The key to understanding Lewis antigens is at the molecular level. It’s all about the different types of fucosyltransferase enzymes! A fucosyltransferase is a specific type of glycosyltransferase. There are two genes that are important here (Le, FUT3) which codes for the Lewis enzyme, and (Se, FUT2) which codes for the secretor enzyme. FUT is an abbreviation of fucosyltransferase. There is another FUT gene (H, FUT1) which codes for the H enzyme (the same glycosyltransferase talked about in ABO blood groups).

Each of these genes produces a different fucosyltransferase enzyme that will attach a fucose to a specific molecule or part of a molecule. Both Le and Se enzymes (from FUT3 and FUT2) preferentially add fucose sugars to type 1 chains. What is a type 1 chain? A “chain” is basically a biochemical structure that sugars and antigens attach to. Type 2 chains are the predominant RBC chain, and type 1 chains are predominant in secretions, plasma, and certain tissue types. So the fucosyltransferases from the (Le, FUT3) and (Se, FUT2) genes prefer the type 1 chains. However, they add the fucose to different parts of the chain. The Lewis enzyme adds fucose to the subterminal portion of the N-Acetylglucosamine part of the chain and the secretor enzyme adds fucose to the terminal end of the galactose molecule.

The secretor enzyme and the H enzyme both add fucose to the terminal end of galactose. The difference is the secretor enzyme is preferential to type 1 chains, and the H enzyme is preferential to type 2 chains. Both can be referred to as “H antigen.” When it is said the H antigen is present in saliva they are referring to type 1 chains and the secretor enzyme.

Does your head hurt yet? The part that makes Lewis antigens confusing is that they are a bit counterintuitive. The A antigen isn’t one type of antigen and the B antigen another like in ABO groups. In fact the Lewis antigens aren’t created by the red cell, they’re created in excretions and adsorbed onto the red cell. In Lewis antigens, Lewis A is when fucose is attached to the subterminal portion of the N-Acetylglucosamine part of the type 1 chain, and Lewis B is when fucose is attached to the terminal end of the galactose molecule and fucose is attached to the subterminal portion of the N-Acetylglucosamine molecule.

Another crucial part to understanding Lewis antigens is that the secretor enzyme highly out competes the Lewis enzyme. Why is that important if they attach to different parts of the molecule? It’s important because once the Lewis enzyme attaches its fucose sugar the secretor enzyme can’t attach a fucose to the terminal end of the galactose. It doesn’t work the other way around though, for example the secretor fucose can attach first and the Lewis fucose can still attach.

There are three common phenotypes for Lewis antigens: Le (a+b-), Le (a-b+), and Le (a-b-). The alleles for Lewis are Le and le. Secretor alleles are Se and se. Le and Se code for the fucosyltransferases outlined above, le and se don’t code for anything.

1. Le (a+b-) will be seen in non-secretors (sese) who have at least one Le allele. There is no secretor enzyme to outcompete the Lewis enzyme so there is a significant amount of “Lewis A.” This phenotype will be a non-secretor and have no H antigen in the saliva.

2. Le (a-b+) will be seen in secretors (at least one Se) and who have at least one Le allele. In this case the secretor enzyme outcompetes the Lewis enzyme to attach first and then the Lewis enzyme attaches second creating “Lewis B.” (There will be a small amount of Lewis A in these patients because the Lewis enzyme does bind before the secretor enzyme in a small percentage of the reactions, however it is not a significant amount of “Lewis A.”) This phenotype indicates the person is a secretor and will have H antigen in the saliva.

3. Le (a-b-) will be seen in non-secretors (sese) who also don’t code for the Lewis enzyme (lele).

You might be asking what about Le (a+b+)? Le (a+b+) is a rare phenotype for two main reasons:

1. The presence of the secretor fucose and the Lewis fucose yields “Lewis B.” Lewis B and Lewis A don’t exist together in large quantities.

2. If there was a lot of Lewis A, there wouldn’t be any Lewis B because once Lewis A attaches, Lewis B can’t attach.

However there is a scenario where a mutation in the secretor enzyme causes the Lewis enzyme to be as competitive. In this scenario, the weakened secretor enzyme allows there to be a more equal competition resulting in sufficient quantities of Lewis A and Lewis B. This mutation is somewhat common in Asian people but rare in Caucasians.

Lewis antibodies:
Lewis antibodies are generally IgM antibodies that occur naturally, and are clinically insignificant. They’re also usually only seen in patients who are Le (a-b-). Why is this? This phenotype is the only one without both the Lewis enzyme and secretor enzyme which both attach a fucose just in a different place. The similarities keep your body form producing an antibody.