Lewis antigen system

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The Lewis antigen system is a human blood group system. It is based upon two genes on chromosome 19: FUT3, or Lewis gene; and FUT2, or Secretor gene. Both genes are expressed in glandular epithelia. FUT2 has a dominant allele which codes for an enzyme (designated Se) and a recessive allele which does not produce a functional enzyme (designated se). Similarly, FUT3 has a functional dominant allele (Le) and a non-functional recessive allele (le).

Contents

The proteins produced by the FUT2 and FUT3 genes modify type I oligosaccharide chains to create Lewis antigens. These oligosaccharide chains are similar to the type II chains of the ABO blood system, with a single bond in a different position. 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: [1] 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.

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-). [2]

The enzyme fucosyltransferase 3 (FUT3), encoded by Le gene, adds a fucose to the precursor oligosaccharide substrate, converting it to the Le-a antigen. People who have the Le allele and who are non-secretors (homozygous for the nonfunctional se allele) will express the Le-a antigen in their bodily fluids and on their erythrocytes.

If a person has both the Le and Se alleles, their exocrine cells will also have the enzyme fucosyltransferase 2 (FUT2). This adds fucose to the oligosaccharide precursor in a different position from the FUT3 enzyme. This produces the Le-b antigen. In most people having both Le and Se, it is difficult to detect the antigen Le-a. This is because the activity of the FUT2 enzyme is more efficient than the FUT3 enzyme, so the type I oligosaccharide chain is mostly converted into Le-b instead of Le-a. Therefore, people with readily detectable Lewis-a antigen are non-secretors; they do not have FUT2 activity. Lewis-b antigen is found only in secretors: people who possess the Se allele and thus have FUT2 activity. Lewis negative people (Le a-, Le b-) are homozygous for the recessive le allele and can be either secretors or non-secretors.

Distribution of Lewis antigens

Lewis antigens are expressed on the surface of red blood cells, endothelium, kidney, genitourinary and gastrointestinal epithelium. [3] [4] [5] Lewis antigens are red blood cell antigens which are not produced by the cell itself. Instead, Lewis antigens are components of exocrine epithelial secretions, and are subsequently adsorbed onto the surface of the red cell. [6]

Genetics/phenotypes

The three above-stated common Lewis phenotypes represent the presence or absence of Lewis and Secretor enzymes.[ citation needed ]

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. [7] 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-). [7] Le(a+b+) phenotype is transiently observed in infants (Secretor activity increases with age). [7] 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. [7]

Oligosaccharide precursors

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. [2]

In neonates, i antigen oligosaccharides predominate (high in cord blood samples). Oligosaccharide branching increases with age, thus adults have mostly I antigen. [2]

Background on ABO blood group system

The H gene of the ABO system encodes a fucosyltransferase that adds fucose to type 2 precursor substances on the surface of RBCs to make H antigen. The h allele is an amorphic form of the gene. 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. [2]

The Le gene

The Le gene encodes a fucosyltransferase 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. [2]

The Se gene

The Se gene encodes a fucosyltransferase that adds fucose to type 1 precursor generating H antigen. After this step, the Le gene product (FUT3) can add another fucose producing 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). [2]

In addition, the Se gene product is responsible for the presence of A, B and H substances in secretions.[ citation needed ]

Lewis antibodies

Lewis antibodies are naturally occurring antibodies, almost always IgM type, found almost exclusively in Le(a-b-) individuals. [7] Lewis antibodies may include a mixture of anti-Le(a), anti-Le(b) and anti-Le(a+). [7]

Transfusion medicine practice

Interpretation of antibody panel to detect patient antibodies towards the most relevant human blood group systems, including Lewis. .mw-parser-output .hatnote{font-style:italic}.mw-parser-output div.hatnote{padding-left:1.6em;margin-bottom:0.5em}.mw-parser-output .hatnote i{font-style:normal}.mw-parser-output .hatnote+link+.hatnote{margin-top:-0.5em} Further information: Blood compatibility testing Serology interpretation of antibody panel for blood group antigens.jpg
Interpretation of antibody panel to detect patient antibodies towards the most relevant human blood group systems, including Lewis.

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 and antibodies neonates/pregnant women

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). [2] Most newborns will type as Le(a-b-). [7]

Lewis antigen is often decreased on RBCs during pregnancy with some women transiently typing as Le(a-b-). [7] This is thought to be due in part to increased circulating plasma volume in pregnancy and increased lipoprotein. [5]

Disease associations

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). [7] [8] [9]

Le(b) and type 1 H antigens are also receptors for Norwalk virus (common cause of acute gastroenteritis). [10]

The Le(a-b-) phenotype is associated with an increased susceptibility to infections by Candida and uropathogenic Escherichia coli. [7] [11] [12]

In patients with pancreatic adenocarcinoma and not harbouring a functional Lewis enzyme (Lea-b- genotype: 7%–10% of the population), levels of CA 19-9 are typically undetectable or below 1.0 U/ml. [13]

Related Research Articles

<span class="mw-page-title-main">ABO blood group system</span> Classification of blood types

The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes. For human blood transfusions, it is the most important of the 44 different blood type classification systems currently recognized by the International Society of Blood Transfusions (ISBT) as of December 2022. A mismatch in this, or any other serotype, can cause a potentially fatal adverse reaction after a transfusion, or an unwanted immune response to an organ transplant. The associated anti-A and anti-B antibodies are usually IgM antibodies, produced in the first years of life by sensitization to environmental substances such as food, bacteria, and viruses.

α-Galactosidase Enzyme

α-Galactosidase is a glycoside hydrolase enzyme that catalyses the following reaction:

A fucosyltransferase is an enzyme that transfers an L-fucose sugar from a GDP-fucose donor substrate to an acceptor substrate. The acceptor substrate can be another sugar such as the transfer of a fucose to a core GlcNAc (N-acetylglucosamine) sugar as in the case of N-linked glycosylation, or to a protein, as in the case of O-linked glycosylation produced by O-fucosyltransferase. There are various fucosyltransferases in mammals, the vast majority of which, are located in the Golgi apparatus. The O-fucosyltransferases have recently been shown to localize to the endoplasmic reticulum (ER).

The Kidd antigen system are proteins found in the Kidd's blood group, which act as antigens, i.e., they have the ability to produce antibodies under certain circumstances. The Jk antigen is found on a protein responsible for urea transport in the red blood cells and the kidney. They are important in transfusion medicine. People with two Jk(a) antigens, for instance, may form antibodies against donated blood containing two Jk(b) antigens. This can lead to hemolytic anemia, in which the body destroys the transfused blood, leading to low red blood cell counts. Another disease associated with the Jk antigen is hemolytic disease of the newborn, in which a pregnant woman's body creates antibodies against the blood of her fetus, leading to destruction of the fetal blood cells. Hemolytic disease of the newborn associated with Jk antibodies is typically mild, though fatal cases have been reported.

hh, or the Bombay blood group, is a rare blood type. This blood phenotype was first discovered in Bombay by Dr. Y. M. Bhende in 1952. It is mostly found in the Indian sub-continent and Iran.

Sialyl-Lewis <sup>X</sup> Chemical compound

Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means by which an egg attracts sperm; first, to stick to it, then bond with it and eventually form a zygote.

<span class="mw-page-title-main">Ii antigen system</span> Human blood group system

The Ii antigen system is a human blood group system based upon a gene on chromosome 6 and consisting of the I antigen and the i antigen. The I antigen is normally present on the cell membrane of red blood cells in all adults, while the i antigen is present in fetuses and newborns.

In enzymology, a 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Fucosyltransferase 3</span> Protein and coding gene in humans

Galactoside 3(4)-L-fucosyltransferase is an enzyme that in humans is encoded by the FUT3 gene.

<span class="mw-page-title-main">FUT2</span> Protein and coding gene in humans

Galactoside 2-alpha-L-fucosyltransferase 2 is an enzyme that in humans is encoded by the FUT2 gene. It affects the secretor status of ABO antigens.

<span class="mw-page-title-main">FUT1</span> Protein and coding gene in humans

Galactoside 2-alpha-L-fucosyltransferase 1 is an enzyme that in humans is encoded by the FUT1 gene.

<span class="mw-page-title-main">FUT6</span> Protein-coding gene in the species Homo sapiens

Alpha-(1,3)-fucosyltransferase is an enzyme that in humans is encoded by the FUT6 gene.

<span class="mw-page-title-main">FUT8</span> Protein-coding gene in the species Homo sapiens

Alpha-(1,6)-fucosyltransferase is an enzyme that in humans is encoded by the FUT8 gene.

<span class="mw-page-title-main">FUT9</span> Protein-coding gene in the species Homo sapiens

Alpha-(1,3)-fucosyltransferase is an enzyme that in humans is encoded by the FUT9 gene.

<span class="mw-page-title-main">ABO (gene)</span> Protein-coding gene in the species Homo sapiens

Histo-blood group ABO system transferase is an enzyme with glycosyltransferase activity, which is encoded by the ABO gene in humans. It is ubiquitously expressed in many tissues and cell types. ABO determines the ABO blood group of an individual by modifying the oligosaccharides on cell surface glycoproteins. Variations in the sequence of the protein between individuals determine the type of modification and the blood group. The ABO gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">TSTA3</span> Protein-coding gene in the species Homo sapiens

GDP-L-fucose synthetase is an enzyme that in humans is encoded by the TSTA3 gene.

Fucosyltransferase 4 , also known as FUT4, is an enzyme which in humans is encoded by the FUT4 gene.

<span class="mw-page-title-main">Congenital disorder of glycosylation type IIc</span> Medical condition

Congenital disorder of glycosylation type IIc or Leukocyte adhesion deficiency-2 (LAD2) is a type of leukocyte adhesion deficiency attributable to the absence of neutrophil sialyl-LewisX, a ligand of P- and E-selectin on vascular endothelium. It is associated with SLC35C1.

Secretor status refers to the presence or absence of water-soluble ABO blood group antigens in a person's bodily fluids, such as saliva, tears, breast milk, urine, and semen. People who secrete these antigens in their bodily fluids are referred to as secretors, while people who do not are termed non-secretors. Secretor status is controlled by the FUT2 gene, and the secretor phenotype is inherited in an autosomal dominant manner, being expressed by individuals who have at least one functioning copy of the gene. The non-secretor phenotype (se) is a recessive trait. Approximately 80% of Caucasian people are secretors, while 20% are non-secretors. Non-secretors have reduced susceptibility to the most common strains of norovirus. Expression of the antigens in the Lewis blood group is also affected by secretor status: non-secretors cannot produce the Le(b) antigen.

Human milk oligosaccharides (HMOs), also known as human milk glycans, are short polymers of simple sugars that can be found in high concentrations in human breast milk. Human milk oligosaccharides promote the development of the immune system, can reduce the risk of pathogen infections and improve brain development and cognition. The HMO profile of human breast milk shapes the gut microbiota of the infant by selectively stimulating bifidobacteria and other bacteria.

References

  1. ↑ GRUBB R (1948). "Correlation between Lewis blood group and secretor character in man". Nature. 162 (4128): 933. Bibcode:1948Natur.162..933G. doi: 10.1038/162933a0 . PMID   18104581. S2CID   4104311.
  2. 1 2 3 4 5 6 7 8 Mais DD. ASCP Quick Compendium of Clinical Pathology, 2nd Ed. Bethesda: ASCP Press, 2008.
  3. ↑ Marionneau, S.; Cailleau-Thomas, A.; Rocher, J.; Le Moullac-Vaidye, B.; Ruvoën, N.; Clément, M.; Le Pendu, J. (2001). "ABH and Lewis histo-blood group antigens, a model for the meaning of oligosaccharide diversity in the face of a changing world". Biochimie. 83 (7): 565–73. doi:10.1016/s0300-9084(01)01321-9. PMID   11522384.
  4. ↑ Holgersson, J.; Breimer, M. E.; Samuelsson, B. E. (1992). "Basic biochemistry of cell surface carbohydrates and aspects of the tissue distribution of histo-blood group ABH and related glycosphingolipids". APMIS. Supplementum. 27: 18–27. PMID   1520526.
  5. 1 2 Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th Ed. Durham, NC: Montgomery Scientific Publications, 1998.
  6. ↑ Harmening, [edited by] Denise M. (2005). Modern blood banking and transfusion practices (5th ed.). Philadelphia: F.A. Davis. ISBN   978-0-8036-1248-8.{{cite book}}: |first= has generic name (help)
  7. 1 2 3 4 5 6 7 8 9 10 11 Roback JD et al. AABB Technical Manual, 16th Ed. Bethesda: AABB Press, 2008.
  8. ↑ Boren, T.; Falk, P.; Roth, K. A.; Larson, G.; Normark, S. (1993). "Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens". Science. 262 (5141): 1892–5. Bibcode:1993Sci...262.1892B. doi:10.1126/science.8018146. PMID   8018146.
  9. ↑ Franchini, M.; Veneri, D. (2004). "Helicobacter pylori infection and immune thrombocytopenic purpura: An update". Helicobacter. 9 (4): 342–6. doi:10.1111/j.1083-4389.2004.00238.x. PMID   15270749. S2CID   36822965.
  10. ↑ Hutson, A. M.; Atmar, R. L.; Marcus, D. M.; Estes, M. K. (2003). "Norwalk virus-like particle hemagglutination by binding to h histo-blood group antigens". Journal of Virology. 77 (1): 405–15. doi:10.1128/jvi.77.1.405-415.2003. PMC   140602 . PMID   12477845.
  11. ↑ Hilton, E.; Chandrasekaran, V.; Rindos, P.; Isenberg, H. D. (1995). "Association of recurrent candidal vaginitis with inheritance of Lewis blood group antigens". The Journal of Infectious Diseases. 172 (6): 1616–9. doi:10.1093/infdis/172.6.1616. PMID   7594730.
  12. ↑ Stapleton, A.; Nudelman, E.; Clausen, H.; Hakomori, S.; Stamm, W. E. (1992). "Binding of uropathogenic Escherichia coli R45 to glycolipids extracted from vaginal epithelial cells is dependent on histo-blood group secretor status". The Journal of Clinical Investigation. 90 (3): 965–72. doi:10.1172/JCI115973. PMC   329952 . PMID   1522244.
  13. ↑ Ducreux, M.; Cuhna, A. Sa.; Caramella, C.; Hollebecque, A.; Burtin, P.; Goéré, D.; Seufferlein, T.; Haustermans, K.; Van Laethem, J.L.; Conroy, T.; Arnold, D. (September 2015). "Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology. 26: v56–v68. doi: 10.1093/annonc/mdv295 . PMID   26314780.
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