Sialyl Lewis^X (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ...

which is usually attached to O-

glycans The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrat ...

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. The discovery of the essential role that this tetrasaccharide plays in the fertilization process was reported in August 2011. Sialyl Lewis ^X is also one of the most important

blood group antigens 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 b ...

and is displayed on the terminus of glycolipids that are present on the cell surface. The sialyl Lewis ^X determinant, E-

selectin The selectins (cluster of differentiation 62 or CD62) are a family of cell adhesion molecules (or CAMs). All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminu ...

ligand carbohydrate structure, is constitutively expressed on

granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ...

s and

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...

s and mediates inflammatory extravasation of these cells. Resting T- and B-

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

s lack its expression and are induced to strongly express sialyl Lewis ^X upon activation. The sialyl Lewis ^X determinant is expressed preferentially on activated

Th1 cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...

s but not on Th2 cells.

Structure

Sialyl-Lewis X is a tetrasaccharide composed of a

sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this ...

fucose Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on ''N''-linked glycans on the mammalian, insect and plant cell surface. Fucose is the fundamental sub-unit of the seaweed polysaccharide fucoidan. The α(1→3) li ...

and an N-acetyllactosamine. Its systematic name is 5-acetylneuraminyl-(2-3)-galactosyl-(1-4)-(fucopyranosyl-(1-3))-N-acetylglucosamine (Neu5Acα2-3Galβ1-4 ucα1-3lcNAcβ). In humans, according to Table 1 and Fig.1 it is synthesized by four

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 ...

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 cel ...

, FUT5,

FUT6 Alpha-(1,3)-fucosyltransferase is an enzyme that in humans is encoded by the ''FUT6'' gene. The alpha-1,3-fucosyltransferases constitute a large family of glycosyltransferases with a high degree of homology. The enzymes of this family comprise 3 ...

and FUT7. The other three enzymes of the sialyltransferase family ST3GAL3,

ST3GAL4 is an enzyme that in humans is encoded by the ''ST3GAL4'' 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' ...

, an
ST3GAL6
participate in the synthesis of the Sialyl-Lewis ^X precursor.

Function

Leukocyte homing

Sialyl-Lewis^x is important in leukocyte tethering and rolling. Leukocytes move through the blood stream and then tether themselves to the endothelial wall and roll along the endothelial tissue to determine if they want to leave the bloodstream to get to necessary tissue. Sialyl-Lewis^x is a necessary partner for the three selectins that bind the leukocyte and endothelial cells. When sialyl-Lewis^x is part of an O-glycan and attached to CD34 it can then bind to L-selectin. For the binding to L-selectin to occur sialyl-Lewis^x must undergo sulfation. For sialyl-Lewis^x to bind to P-selectin, an O-linked glycan near the N-terminus of P-Selectin Glycoprotein Ligand-1 (PSGL-1) is modified with sialyl-Lewis^x and in combination with nearby tyrosine residues modified with sulfate, forms the binding contact for P-selectin. For sialyl-Lewis^x to bind to E-selectin it can be part of either an N-linked or O-linked glycan attached to cell surface glycoproteins such as PSGL-1, CD43 or CD44. This sialyl-Lewis^x mediated binding to selectins allows circulating leukocytes to stick to and roll along endothelial cells lining blood vessels thereby enabling the leukocytes to accumulate at a site of vascular inflammation.

Fertilization

Sialyl-Lewis^x allows a sperm cell to recognize and fertilize an egg cell. For fertilization to occur, human sperm must bind to the

zona pellucida The zona pellucida (plural zonae pellucidae, also egg coat or pellucid zone) is a specialized extracellular matrix that surrounds the plasma membrane of mammalian oocytes. It is a vital constitutive part of the oocyte. The zona pellucida first a ...

(ZP), the translucent matrix covering the human egg composed of four glycoproteins ZP1, 2, 3, and 4, and transit through the matrix in order to fuse with the oocyte. Human ZP is coated with highly dense N- and O-glycans that are terminated with the sialyl-Lewis^x sequence. The hemizona assay, which assesses sperm-ZP binding by counting the number of sperm bound to hemispheres of bisected nonliving human eggs ''in vitro'', revealed that as little as 0.5 mM sialyl-Lewis^x inhibits sperm-ZP binding by 63%. Furthermore, adding purified and solubilized ZP3 or ZP4 from the human oocyte dose-dependently inhibits sperm-ZP binding in the hemizona assay. Such evidence suggest that the early steps of human sperm-egg binding may be mediated by lectins for sialyl-Lewis^x present on human sperm.

Clinical significance

Leukocyte adhesion deficiency

Defective synthesis of the sialyl Lewis ^X antigen results in immunodeficiency (

leukocyte adhesion deficiency Leukocyte adhesion deficiency (LAD) is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also kno ...

type 2). Defective synthesis can be caused by the loss of fucosyltransferase, impairing the glycosylation of the glycosphingolipid. Sialyl Lewis x is being researched for detection and treatment of immune disorders because of its presence on leukocytes.

Blood cancers

Sialyl-Lewis^x mediates

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis i ...

and chemotaxis, found on neutrophils; expressed in patients with Hodgkin disease, some B-cell chronic lymphocytic leukemias, acute lymphoblastic leukemias, and most acute nonlymphocytic leukemias. CD15 is present on almost all

Reed–Sternberg cell Reed–Sternberg cells (also known as lacunar histiocytes for certain types) are distinctive, giant cells found with light microscopy in biopsies from individuals with Hodgkin lymphoma. They are usually derived from B lymphocytes, classically ...

s, including their rare mononuclear variants, and, as such, can be used in

immunohistochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to a ...

to identify the presence of such cells in biopsies. The presence of these cells is diagnostic of

Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition w ...

. Reed-Sternberg cells display a characteristic pattern of Sialyl-Lewis^x (CD15) positivity, with membranous staining combined with staining of the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ...

. Immunohistochemical panels for the diagnosis of Hodgkins disease typically employ CD15 along with

CD30 CD30, also known as TNFRSF8 ( TNF receptor superfamily member 8), is a cell membrane protein of the tumor necrosis factor receptor family and a tumor marker. Function This receptor is expressed by activated, but not by resting, T and B cel ...

and

CD45 Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the ''PTPRC'' gene. PTPRC is also known as CD45 antigen (CD stands for cluster of differentiation), which was originally called leukocy ...

; the latter does not stain Reed-Sternberg cells, but does stain almost all other lymphoid cells. Sialyl-Lewis^x is also present in about 50% of

adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, o ...

cells and can be used to distinguish such conditions from

mesothelioma Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The most common area affected is the lining of the lungs and chest wall. Less commonly the lining ...

, which is typically negative.

Cancer metastasis

Sialyl-Lewis^x plays a critical role in cancer metastasis, facilitating the extravasation of cancer cells out of the bloodstream while they are moving through the body. Its expression is related to tumor stage, recurrence, and overall patient survival. Therefore, sialyl Lewis x is being used as a target in studies to fight tumors and cancer cell growth. It has been shown that there is frequent overexpression of sialyl Lewis x on cancer cells and is found on both N-glycan and O-glycans. Sialyl Lewis x is being researched with CD markers to find new ways to create biosensors for cancer cells. Also, it is being used in new ways to target cancer cells specifically for cancer treatment.

In vitro fertilization

Sialyl-Lewis^x is being used to achieve greater rates of fertilization of eggs in women by coating the eggs with sialyl Lewis x.

Immunity and inflammation

It plays a key role in the inflammatory response and may be used to increase the leukocyte response to infections. Sialyl Lewis x is also an inflammation-associated antigen on liver cells. It becomes over expressed on diseased liver cells and can be used as a way to detect liver disease in a patient.

MERS coronavirus binding

In June 2019, before the onset of the

COVID-19 pandemic The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identified ...

, the sulfated sialyl-Lewis X oligosaccharide (particularly with α2,3 linkages) receptor was found to be the preferred binding site, both in humans and in dromedary camels, for the coronavirus causing Middle East Respiratory Syndrome (

MERS Middle East respiratory syndrome (MERS) is a viral respiratory infection caused by '' Middle East respiratory syndrome–related coronavirus'' (MERS-CoV). Symptoms may range from none, to mild, to severe. Typical symptoms include fever, cough, ...

), the sixth coronavirus to be described.

History

The term ''Lewis'' in its name comes from the name of a family of people who suffered from a red blood cell incompatibility. The studies done on these individuals' red blood cells led to the discovery of sialyl Lewis X. Sialyl Lewis x is a very important red blood cell antigen present on the glycolipids on the plasma membrane of the cell. Its localization on the cell surface of cells led to its alternative nomenclature as a

cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...

. Clusters of differentiation are a naming system devised in 1982 to classify cell-surface antigens on

leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...

identified via

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...

. Sialyl Lewis X was assigned the name CD15.