Metabolic and Immunologic Consequences of ABH Secretor and Lewis Subtype Status

Alternative Medicine Review, August, 2001 by Peter J. D'Adamo, Gregory S. Kelly

Abstract

Determining ABH secretor phenotype and/or Lewis (Le) blood group status can be useful to the metabolically-oriented clinician. For example, differences in ABH secretor status drastically alter the carbohydrates present in body fluids and secretions; this can have profound influence on microbial attachment and persistence. Lewis typing is one genetic marker which might help identify subpopulations of individuals genetically prone to insulin resistance, autoimmunity, and heart disease. Understanding the clinical significance of ABH secretor status and the Lewis blood groups can provide insight into seemingly unrelated aspects of physiology, including variations in intestinal alkaline phosphatase activity, propensities toward blood clotting, reliability of some tumor markers, the composition of breast milk, and several generalized aspects of the immune function. Since the relevance of ABH blood group antigens as tumor markers and parasitic/bacterial/viral receptors and their association with immunologically important proteins is now well established, the prime biologic role for ABH blood group antigens may well be independent and unrelated to the erythrocyte.

(Altern Med Rev 2001;6(4):390-405)

Functional and Genetic Factors Involved in AB H Secretion

The term "ABH secretor," as used in blood banking, refers to secretion of ABO blood group antigens in fluids such as saliva, sweat, tears, semen, and serum. A person who is an ABH secretor will secrete antigens according to their blood group; for example, a group O individual will secrete H antigen, a group A individual will secrete A and H antigens, etc. Soluble (secreted) antigens are called substances. To test for secretor status, an inhibition or neutralization test is done using saliva. The principle of the test is that if ABH antigens are present in a soluble form in a fluid (e.g., saliva) the antigens will neutralize their corresponding antibodies, and the antibodies will no longer be able to agglutinate red cells possessing the same antigens.

One of the primary differences in physiology between secretors and non-secretors involves qualitative and quantitative differences in components of their saliva, mucus, and other bodily secretions. ABH secretion is controlled by two alleles, Se and se. Se is dominant and se is recessive (or amorphic). Approximately 80 percent of people are secretors (SeSe or Sese).

In the most rudimentary sense, it is the secretor gene (FUT2 at 19q13.3) that codes for the activity of the glycosyltransferases needed to assemble aspects of both the ABO and Lewis (Le) blood groups. This is accomplished in concert with the gene for group O, or H (FUT1) and the gene for the Lewis phenotype. These enzymes are then active in places like goblet and mucous gland cells, resulting in the presence of the corresponding antigens in bodily fluids.[1]

The H antigens are indirect gene products expressed as fucose-containing glycan units, residing on glycoproteins or glycolipids of erythrocyte membranes or on mucin glycoproteins in secretions. They serve as the fucosylated-glycan substrates for glycosyltransferases that give rise to the epitopes for the A, B, and Lewis blood group antigens. The major difference between the two genes is in their pattern of expression. The FUT1 (H) gene is expressed predominantly in erythroid tissues giving rise to FUT1 (H enzyme) whose products reside on erythrocytes, whereas the FUT2 (Secretor) gene is expressed predominantly in secretory tissues giving rise to FUT2 (Secretor enzyme) and to products that reside on mucins in secretions.[2]

When alleles of both genes fail to express active enzymes, individuals bearing them in homozygous state lack the substrates for the A or B glycosyltransferases and do not express the A and B epitopes.

Relationship of ABH Secretor Status and Lewis System

Two broad categories of Lewis blood type exist. These are the Lewis positive (either Le (a+b-) or Le (a-b+)) and Lewis negative (Le (a-b-)) phenotypes. Since FUT1 provides the glycans necessary for glycosyltransferase conversion into the Lewis antigen in addition to ABH, the Lewis blood group determinants are structurally related to determinants of the ABO and the H/h blood group systems and the outcome of Lewis typing can be used for the de facto determination of ABH secretor status among Lewis positive individuals (Table 1). In the presence of FUT2 alleles that express type 1 H determinants, the phenotype will be Le (a-b+), but individuals in whom the FUT2 gene is not expressed will be Le(a+b-).

Table 1. Lewis Blood Types and their Relationship to ABH
Secretors/Non-secretor Status

LEWIS PHENOTYPE                        ABH SECRETOR STATUS

Le (a+b-) which has Lewis a antigen    Always ABH non-secretor
but not Lewis b
Le (a-b+) which has Lewis b antigen    Always ABH secretor
but not Lewis a
Le (a-b-) having neither Lewis a       Lewis outcome not a
nor Lewis b                            determinant of ABH secretor
                                       status. However, this variant is
                                       associated with its own unique
                                       metabolic consequences.