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Microfold cells (or M cells) are found in the
gut-associated lymphoid tissue Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut. Owing to its physiological function in food absorption, the mucos ...
(GALT) of the
Peyer's patch Peyer's patches or aggregated lymphoid nodules are organized lymphoid follicles, named after the 17th-century Swiss anatomist Johann Conrad Peyer. * Reprinted as: * Peyer referred to Peyer's patches as ''plexus'' or ''agmina glandularum'' (cl ...
es in the
small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
, and in the
mucosa-associated lymphoid tissue The mucosa-associated lymphoid tissue (MALT), also called mucosa-associated lymphatic tissue, is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body, such as the gastrointestinal t ...
(MALT) of other parts of the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
. These cells are known to initiate mucosal immunity responses on the apical membrane of the M cells and allow for transport of
microbes A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...
and particles across the epithelial cell layer from the gut lumen to the
lamina propria The lamina propria is a thin layer of connective tissue that forms part of the moist linings known as mucous membranes or mucosae, which line various tubes in the body, such as the respiratory tract, the gastrointestinal tract, and the urogenital ...
where interactions with immune cells can take place. Unlike their neighbor cells, M cells have the unique ability to take up
antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
from the lumen of the
small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
via
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
,
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 ...
, or transcytosis. Antigens are delivered to
antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...
s, such as
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s, and B lymphocytes. M cells express the
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
cathepsin E Cathepsin E is an enzyme () that in humans is encoded by the ''CTSE'' gene. The enzyme is also known as ''slow-moving proteinase'', ''erythrocyte membrane aspartic proteinase'', ''SMP'', ''EMAP'', ''non-pepsin proteinase'', ''cathepsin D-like ac ...
, similar to other antigen-presenting cells. This process takes place in a unique pocket-like structure on their basolateral side. Antigens are recognized via expression of cell surface receptors such as glycoprotein-2 (GP2) that detect and specifically bind to bacteria. Cellular prion protein (PrP) is another example of a cell surface receptor on M cells. M cells lack microvilli but, like other epithelial cells, they are characterized by strong
cell junction Cell junctions or junctional complexes are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring Cell (biology), cells or between a cell and the extracellular matrix in animals. Th ...
s. This provides a physical barrier that constitutes an important line of defense between the gut contents and the immune system of the host. Despite the epithelial barrier, some antigens are able to infiltrate the M cell barrier and infect the nearby epithelial cells or enter the gut.


Structure

M cells are distinguished from other intestinal epithelial cells by their morphological differences. They are characterized by their short microvilli or lack of these protrusions on the cell surface. When they present microvilli, they are short, irregular, and present on the apical surface or pocket-like invagination on the basolateral surface of these cells. When they lack microvilli, they are characterized by their microfolds, and hence receive their commonly known name. These cells are far less abundant than
enterocyte Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase ...
s. These cells can also be identified by
cytoskeletal The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all Cell (biology), cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane ...
and
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
components expressed at the edge of cells or on their cell surfaces, such as
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
, villin, cytokeratin, and vimentin.


Development

Factors promoting the differentiation of M cells have yet to be elucidated, but they are thought to develop in response to signals from immune cells found in developing Peyer's patches. B cells have been implicated in the developmental of M cells, since they are also localized in high numbers in the follicular-associated epithelium (FAE). FAE lacking B cell populations results in a decrease in the number of M cell lining the Peyer's patches. Similarly, a human lymphoma cell line is also known to undergo transition from adenocarcinoma cells to M cells. Though many studies have shown various cell types directing the differentiation of M cells, new research characterizes the molecular pathways that guide M cell differentiation. More recently, through loss-of-function and rescue-phenotype studies,
RANKL Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiat ...
is shown to be a receptor activator of NF-κB ligand and play a role in differentiation of M cells. RANKL is expressed throughout the small intestine, facilitates uptake of pathogens such as Salmonella, and is the most critical factor M cell differentiation. Microbes found on intestinal epithelium are known to direct M cell development. For example, the type III secretion system effector protein SopB activates the transition of M cells from
enterocyte Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase ...
s. M cells undergo the differentiation process for up to four days before reaching full maturation. Recent studies have suggested they arise distinctly from the lymphoid and myeloid lineages. Pathogens can take advantage of cell differentiation pathways in order to invade host cells. This is done by inducing differentiation of enterocytes into M cell type in gut epithelium. In one case, the SopB effector protein mentioned above is secreted to trigger fast differentiation of enterocytes localized in the FAE by initiation of epithelial to mesenchymal transition in these cells. When SopB activates differentiation of enterocytes, it acts via the activation of the Wnt/ b-catenin signaling pathway and triggers the RANKL and its receptor, implicated in regulating cell
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
.


Function

M cells do not secrete mucus or digestive
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s, and have a thinner
glycocalyx The glycocalyx (: glycocalyces or glycocalyxes), also known as the pericellular matrix and cell coat, is a layer of glycoproteins and glycolipids which surround the cell membranes of bacteria, epithelial cells, and other cells. Animal epithe ...
, which allows them to have easy access to the intestinal lumen for
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
of antigens. The main function of M cells is the selective endocytosis of antigens, and transporting them to intraepithelial
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s and lymphocytes, which then migrate to
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s where an immune response can be initiated.


Passive immunity

M cells play a role in
passive immunity In immunology, passive immunity is the transfer of active humoral immunity of ready-made antibodies. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and it can also be induced arti ...
, or the transfer of active
humoral immunity Humoral immunity is the aspect of immunity (medical), immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is ...
during and post pregnancy. Infants rely on
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
specific to their mother's intestinal antigens, which move from the mother's gut and enter the breast milk. These antibodies are able to move into the milk supply through the
lymphatic system The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lympha ...
. Even though the mechanism of this transport is not fully understood, it is hypothesized that dendritic cells and macrophages play the role of transport vehicles. In females that are not lactating, when M cells recognize antigen in the gut, they stimulate production of many Immunoglobulin A ( IgA) antibodies. These antibodies are released into the gut mucosa,
salivary gland The salivary glands in many vertebrates including mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands ( parotid, submandibular, and sublingual), as well as hundreds of min ...
s, and
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s. However, in females that are lactating, M cells recognize antigen and IgA is directed from the gut to the mammary gland. IgA traveling from the gut to breast milk supply is controlled by hormones, chemokines, and cytokines. Thus, the
mammary gland A mammary gland is an exocrine gland that produces milk in humans and other mammals. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in primates (for example, human ...
and breast milk have critical roles alongside M cells in mucosal immune system.


Clinical significance

M cells are exploited by several
pathogenic In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ. The term ...
gram-negative bacteria Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the Crystal violet, crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelo ...
including ''
Shigella flexneri ''Shigella flexneri'' is a species of Gram-negative bacteria in the genus ''Shigella'' that can cause diarrhea in humans. Several different serogroups of ''Shigella'' are described; ''S. flexneri'' belongs to group ''B''. ''S. flexneri'' infect ...
'', ''
Salmonella typhimurium ''Salmonella enterica'' subsp. ''enterica'' is a subspecies of ''Salmonella enterica'', the rod-shaped, flagellated, aerobic, Gram-negative bacterium. Many of the pathogenic serovars of the ''S. enterica'' species are in this subspecies, includin ...
'', and '' Yersinia pseudotuberculosis'', as well as infectious
prion A prion () is a Proteinopathy, misfolded protein that induces misfolding in normal variants of the same protein, leading to cellular death. Prions are responsible for prion diseases, known as transmissible spongiform encephalopathy (TSEs), w ...
s, such as in bovine spongiform encephalitis (Mad-cow disease), as a way of penetrating the intestinal epithelium. Exploitation as a
virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in botany) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following: * c ...
depends upon the pathogen's ability to bind to M cells and thus guarantee penetration in that manner, as M cells sample intestinal contents. EPEC (see Pathogenic ''Escherichia coli'') containing plasmids with genes for EAF (''
Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
'' adherence factor) will adhere to M cells. They are also exploited by viruses such as Polio and Reovirus for dissemination.
CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha- chemo ...
tropic but not
CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 p ...
tropic HIV has been noted to be able to bind to M cells and get transported across the epithelium by them.


See also

*
List of human cell types derived from the germ layers This is a list of Cell (biology), cells in humans derived from the three embryonic germ layers – ectoderm, mesoderm, and endoderm. Cells derived from ectoderm Surface ectoderm Skin * Trichocyte (human), Trichocyte * Keratinocyte Anterior pi ...


References


External links


Slide at ucsd.edu
{{Authority control Immune system Animal cells Human cells Small intestine