HOME

TheInfoList



OR:

The Lewis antigen system is a
human blood group system The term human blood group systems is defined by the International Society of Blood Transfusion (ISBT) as systems in the human species where cell-surface antigens—in particular, those on blood cells—are "controlled at a single gene locus or by ...
. It is based upon two genes on
chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosome ...
:
FUT3 Galactoside 3(4)-L-fucosyltransferase is an enzyme that in humans is encoded by the ''FUT3'' gene. Function The Lewis histo-blood group system comprises a set of fucosylated glycosphingolipids that are synthesized by exocrine epithelial cells ...
, or Lewis gene; and
FUT2 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. Approximately 20% of Caucasians are non-secretors due to the G428A (rs601338) and C571T (rs4 ...
, 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). 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 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 43 different blood type (or group) classification system ...
, with a single bond in a different position. The link between the Lewis blood group and secretion of the ABO blood group
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s was possibly the first example of multiple effects of a human
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
: 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-).Mais DD. ASCP Quick Compendium of Clinical Pathology, 2nd Ed. Bethesda: ASCP Press, 2008. The enzyme fucosyltransferase 3 (FUT3), encoded by Le gene, adds a fucose to the precursor
oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...
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 cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s,
endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
, kidney, genitourinary and gastrointestinal epithelium.Issitt PD, Anstee DJ. Applied Blood Group Serology. 4th Ed. Durham, NC: Montgomery Scientific Publications, 1998. Lewis antigens are
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
antigens which are not produced by the cell itself. Instead, Lewis antigens are components of
exocrine Exocrine glands are glands that secrete substances on to an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of two ...
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
secretions, and are subsequently adsorbed onto the surface of the red cell.


Genetics/phenotypes

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.Roback JD et al. AABB Technical Manual, 16th Ed. Bethesda: AABB Press, 2008. 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.


Lewis-related genes


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


Background on ABO blood group system

The H gene of the ABO system encodes a
fucosyltransferase A fucosyltransferase is an enzyme that transfers an L-fucose sugar from a GDP-fucose (guanosine diphosphate-fucose) donor substrate to an acceptor substrate. The acceptor substrate can be another sugar such as the transfer of a fucose to a core G ...
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.


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.


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


Lewis antibodies

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


Transfusion medicine practice

Lewis antibodies are almost always clinically insignificant because: * transfused red cells shed their Lewis antigens and acquire the Lewis phenotype of the recipient * Lewis antibodies are quickly adsorbed by free serum Lewis antigens, 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 Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five ...
(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). 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.


Disease associations

The Le(b) and H antigens are receptors for the bacteria ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is though ...
'', a
gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
bacterium that can cause
gastritis Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
and has been implicated in
peptic ulcer disease Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...
,
gastric adenocarcinoma Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
, mucosa-associated lymphoma (or mucosal associated lymphatic tissue lymphoma – MALToma) and
idiopathic thrombocytopenic purpura Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of oth ...
(ITP). Le(b) and type 1 H antigens are also receptors for Norwalk virus (common cause of acute gastroenteritis). The Le(a-b-) phenotype is associated with an increased susceptibility to infections by Candida and uropathogenic ''Escherichia coli''. 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.


References


External links


Lewis
at
BGMUT The BGMUT (Blood Group antigen gene MUTation) Database documents allelic variations in the genes encoding for human blood group systems. It was set up in 1999 through an initiative of the Human Genome Variation Society ( HGVS). Since 2006, it has ...
Blood Group Antigen Gene Mutation Database at
NCBI The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health (NIH). It is approved and funded by the government of the United States. The ...
,
NIH The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
{{transfusion medicine Blood antigen systems Transfusion medicine