Mucosal immunology is the study of

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

responses that occur at mucosal membranes of the

intestines The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

, the urogenital tract, and the

respiratory system The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies ...

. The mucous membranes are in constant contact with

microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

s, food, and inhaled

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 respons ...

s. In healthy states, the mucosal immune system protects the

organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...

against infectious

pathogen In biology, a pathogen ( el, πάθος, "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 ...

s and maintains a tolerance towards non-harmful

commensal Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fro ...

microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as

food allergies A food allergy is an abnormal immune response to food. The symptoms of the allergic reaction may range from mild to severe. They may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressur ...

irritable bowel syndrome Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...

, susceptibility to

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...

s, and more. The mucosal immune system consists of a

cellular component Cellular components are the complex biomolecules and structures of which cells, and thus living organisms, are composed. Cells are the structural and functional units of life. The smallest organisms are single cells, while the largest organism ...

, humoral immunity, and defense mechanisms that prevent the invasion of microorganisms and harmful foreign substances into the body. These defense mechanisms can be divided into physical barriers ( epithelial lining,

mucus Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...

, cilia function, intestinal peristalsis, etc.) and chemical factors ( pH, antimicrobial peptides, etc.).

Function

The mucosal

provides three main functions: *First line of defense from harmful

ic structures and

. *Prevents systemic

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

s to

commensal bacteria Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fr ...

and food

s. *Regulates appropriate

s to

Physical barrier

Mucosal barrier integrity physically stops pathogens from entering the body. Barrier function is determined by factors such as age,

genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...

, types of

mucin Mucins () are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most ...

s present on the mucosa, interactions between immune cells, nerves and

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

s, and

co-infection Coinfection is the simultaneous infection of a host by multiple pathogen species. In virology, coinfection includes simultaneous infection of a single cell by two or more virus particles. An example is the coinfection of liver cells with hepatiti ...

. Barrier integrity depends on the immunosuppressive mechanisms implemented on the mucosa. The mucosal barrier is formed due to the

tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

s between the

epithelial cells 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 intercell ...

of the mucosa and the presence of the

on the cell surface. The

s that form

offer protection from components on the mucosa by static shielding and limit the

immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...

of intestinal

s by inducing an

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

state in dendritic cells (DC).

Active immunity

Because the mucosa surfaces are in constant contact with external

s and microbiota many

immune cells 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 mult ...

are required. For example, approximately 3/4 of all

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 are found in the mucous membranes. These immune cells reside in

secondary lymphoid tissue 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, lymphatic or lymphoid o ...

, largely distributed through the mucosal surfaces. 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 tr ...

(MALT), provides the organism with an important first line of defense. Along with the

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

and

lymph nodes 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 inclu ...

, the

tonsils The tonsils are a set of lymphoid organs facing into the aerodigestive tract, which is known as Waldeyer's tonsillar ring and consists of the adenoid tonsil, two tubal tonsils, two palatine tonsils, and the lingual tonsils. These organs play a ...

and MALT are considered to be

. The MALT's

is composed mostly of dendritic cells, macrophages,

innate lymphoid cell Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling mo ...

s, mucosal-associated invariant T cells, intraepithelial T cells,

regulatory T cells The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosu ...

(Treg), and IgA secreting plasma cells. Intraepithelial T cells, usually

CD8+ A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...

, reside between mucosal

. These cells do not need primary activation like classic T cells. Instead, upon recognition of

, these cells initiate their effector functions, resulting in faster removal of

s. Tregs are abundant on the

mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It i ...

s and play an important role in maintaining tolerance through various functions, especially through the production of

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s. Mucosal resident antigen-presenting cells (APCs) in healthy people show a tolerogenic phenotype. These APCs do not express

TLR2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sys ...

TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...

on their surfaces. In addition, only negligible levels of the LPS

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

CD14 CD14 (cluster of differentiation 14) is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP). ...

are normally present on these cells. Mucosal dendritic cells determine the type of subsequent

s by the production of certain types of

s and the type of molecules involved in the

co-stimulation Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activa ...

. For example production of IL-6 and IL-23 induce Th17 response, IL-12, IL-18 and INF-γ induce Th1 response, IL-4 induces Th2 response, and IL-10,

TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

and

retinoic acid Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...

induce tolerance.

Innate lymphoid cell Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling mo ...

s are abundant in the mucosa where via rapid

production in response to tissue-derived signals, they act as regulators of

immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity desc ...

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

, and barrier

homeostasis In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...

. The adaptive mucosal immune system is involved in maintaining

mucosal A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...

through a mechanism of immune exclusion mediated by secretory antibodies (mostly IgA) that inhibit the penetration of invasive

s into the body's tissues and prevent the penetration of potentially dangerous exogenous proteins. Another mechanism of adaptive mucosal immunity is the implementation of

immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...

mechanisms mediated mainly by Tregs to prevent local and peripheral

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

to harmless

s, i.e. oral tolerance.

Basic immune response in the gut

In the gut,

lymphoid tissue 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, lymphatic or lymphoid o ...

is dispersed in

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 mucosa ...

(GALT). A large number of immune system cells in the

are found in dome-like structures called Peyer’s patches and in small mucosal lymphoid aggregates called cryptopatches. Above the Peyer’s patches is a layer of

, which together with the mucus form a barrier against microbial invasion into the underlying tissue. Antigen sampling is a key function of Peyer’s patches. Above the Peyer’s patches is a much thinner mucus layer that helps the antigen sampling. Specialized

phagocytic cells Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ' ...

, called M cells, which are found in the

epithelial layer 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 ...

of the Peyer’s patches, can transport antigenic material across the intestinal barrier through the process of

transcytosis Transcytosis (also known as cytopempsis) is a type of transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ...

. The material transported in this way from the

intestinal lumen The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

can then be presented by the antigen-presenting cells present in Peyer’s patches. In addition, dendritic cells in Peyer’s patches can extend their dendrites through M cell-specific

transcellular Transcellular transport involves the transportation of solutes by a cell ''through'' a cell. Transcellular transport can occur in three different ways active transport, passive transport, and transcytosis. Active Transport Main article: Active ...

pores and they can also capture translocated IgA

immune complex An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen o ...

es. Dendritic cells then present the antigen to naïve T cells in the local

mesenteric lymph nodes The superior mesenteric lymph nodes may be divided into three principal groups: * mesenteric lymph nodes * ileocolic lymph nodes * mesocolic lymph nodes Structure Mesenteric lymph nodes The mesenteric lymph nodes or mesenteric glands are one of ...

. If mucosal barrier homeostasis has not been violated and invasive pathogens are not present, dendritic cells induce tolerance in the gut due to induction of Tregs by secretion of

and

. These Tregs further travel to the lamina propria of villi through

lymphatic vessel The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph ve ...

s. There, Tregs produce IL-10 and

IL-35 Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the develo ...

, which affects other immune cells in the lamina propria toward a tolerogenic state. However, damging the

of the

intestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

barrier leads to

. The epithelium in direct contact with

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...

is activated and begins to produce danger-associated molecular patterns (DAMPs). Alarm molecules released from epithelial cells activate immune cells. Dendritic cells and macrophages are activated in this environment and produce key

pro-inflammatory Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

s such as IL-6, IL-12, and IL-23 which activate more immune cells and direct them towards a

state. The activated

effector cell In cell biology, an effector cell is any of various types of cell that actively responds to a stimulus and effects some change (brings it about). Examples of effector cells include: * The muscle, gland or organ cell capable of responding to ...

s then produce

TNF Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

IFNγ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

, and IL-17.

Neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

s are attracted to the affected area and begin to perform their effector functions. After the ongoing infection has been removed, the

inflammatory response Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

must be stopped to restore

. The damaged tissue is healed and everything returns to its natural state of tolerance.

Neonatal

At birth,

neonates An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

s are relatively undeveloped and need

intestinal flora Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mi ...

colonies to promote development. Microbiota composition stabilizes around the age of 3. In the neonatal period and in

early childhood Early childhood is a stage in human development following infancy and preceding middle childhood. It generally includes toddlerhood and some time afterward. Play age is an unspecific designation approximately within the scope of early childhood. ...

interaction of host

with the

microbiome A microbiome () is the community of microorganisms that can usually be found living together in any given habitat. It was defined more precisely in 1988 by Whipps ''et al.'' as "a characteristic microbial community occupying a reasonably wel ...

is critical. During this interaction various

arms are educated. They contribute to

and determine the future immune system settings, i.e. its susceptibility to

s and

inflammatory diseases Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

. For example, the B cell line in the

intestinal mucosa The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are: # Mucosa # Submucosa # Muscular layer # Serosa or adventitia The muco ...

is regulated by extracellular signals from commensal microbes that affect the intestinal immunoglobulin repertoire. Diversity of microbiota in

protects the body from the induction of mucosal IgE, which is associated with

allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

development.

Mucosal vaccines

Because of its front-line status within the

, the

is being investigated for use in

vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.

s for various afflictions, including COVID-19,

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

allergies Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermat ...

poliovirus A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species '' Enterovirus C'', in the family of ''Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3. Poliovirus is composed of a ...

influenza A '' A virus'' (''IAV'') causes influenza in birds and some mammals, and is the only species of the genus ''Alphainfluenzavirus'' of the virus family ''Orthomyxoviridae''. Strains of all subtypes of influenza A virus have been isolated from wild ...

and B,

rotavirus ''Rotavirus'' is a genus of double-stranded RNA viruses in the family ''Reoviridae''. Rotaviruses are the most common cause of diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus ...

vibrio cholerae ''Vibrio cholerae'' is a species of Gram-negative, facultative anaerobe and comma-shaped bacteria. The bacteria naturally live in brackish or saltwater where they attach themselves easily to the chitin-containing shells of crabs, shrimps, and oth ...

and many others.

Function

Physical barrier

Active immunity

Basic immune response in the gut

Neonatal

Mucosal vaccines

See also

References

Further reading