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

carbohydrate A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...

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. Sialyl-Lewis^X is also one of the most important blood group antigens 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 termi ...

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, that i ...

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 monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

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 T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...

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 T_h1 cells but not on T_h2 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" () was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is ''N''-acetylneuraminic acid ...

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) l ...

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, 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 ...

s: FUT3, FUT5, FUT6 and FUT7. The other three enzymes of the sialyltransferase family, ST3GAL3, ST3GAL4, and 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 endothelium before potentially exiting into the 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'' (Latin meaning "transparent zone") is the specialized area surrounding mammalian oocytes (eggs). It is also known as an egg coat. The ''zona pellucida'' is essential for oocyte growth and fertilization. The ''zona pelluc ...

(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. The human ZP is coated with 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'', reveals that 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 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 (biology), 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 ph ...

and

chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...

, found in neutrophils; it is expressed by cells present in 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, classicall ...

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

immunohistochemistry Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of Antibody, antibodies binding specifically to antigens in biological tissues. Alber ...

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 lymph nodes. The condition was named a ...

. Reed–Sternberg cells display a characteristic pattern of sialyl-Lewis^X 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 Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...

. Immunohistochemical panels for the diagnosis of Hodgkin's 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 for anaplastic large cell lymphoma. Function This receptor is expressed by activate ...

and CD45; 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, or ...

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 area most commonly affected is the lining of the lungs and chest wall. Less commonly the lini ...

, 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 when 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. There is frequent overexpression of sialyl-Lewis^X on cancer cells, and it 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. It is also 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

Sialyl-Lewis^X 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 is overexpressed 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 and COVID pandemic), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began with an disease outbreak, outbreak of COVID-19 in Wuhan, China, in December ...

, the receptor for sulfated sialyl-Lewis^X oligosaccharide (particularly with α2,3 linkages) 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 depending on age and risk level. Typi ...

), the sixth coronavirus to be described.

History

The term "Lewis" in the name comes from a family of people with 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 an important red blood cell antigen present on the glycolipids on the plasma membrane of the cell. Its localization to 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 immunophe ...

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

leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

identified via

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

. Sialyl-Lewis^X was assigned the name CD15.