Mucosal immunology

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Components of mucosal immune system Mucosal immunity March 18.jpg
Components of mucosal immune system

Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. [1] The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. [2] In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. [1] Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more. [2]

Contents

The mucosal immune system consists of a cellular component, 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, cilia function, intestinal peristalsis, etc.) and chemical factors (pH, antimicrobial peptides, etc.). [3]

Function

The mucosal immune system provides three main functions:

Physical barrier

Mucosal barrier integrity physically stops pathogens from entering the body. [4] Barrier function is determined by factors such as age, genetics, types of mucins present on the mucosa, interactions between immune cells, nerves and neuropeptides, and co-infection. Barrier integrity depends on the immunosuppressive mechanisms implemented on the mucosa. [3] The mucosal barrier is formed due to the tight junctions between the epithelial cells of the mucosa and the presence of the mucus on the cell surface. [4] The mucins that form mucus offer protection from components on the mucosa by static shielding and limit the immunogenicity of intestinal antigens by inducing an anti-inflammatory state in dendritic cells (DC). [5]

Active immunity

The nasal-associated lymphoid tissue and Peyer's patches of the small intestine generate IgA immunity. Both use M cells to transport antigen inside the body so that immune responses can be mounted . 2226 IgA Immunity.jpg
The nasal-associated lymphoid tissue and Peyer’s patches of the small intestine generate IgA immunity. Both use M cells to transport antigen inside the body so that immune responses can be mounted .

Because the mucosa surfaces are in constant contact with external antigens and microbiota many immune cells are required. For example, approximately 3/4 of all lymphocytes are found in the mucous membranes. [3] These immune cells reside in secondary lymphoid tissue, largely distributed through the mucosal surfaces. [3]

The mucosa-associated lymphoid tissue (MALT), provides the organism with an important first line of defense. Along with the spleen and lymph nodes, the tonsils and MALT are considered to be secondary lymphoid tissue. [7]

The MALT's cellular component is composed mostly of dendritic cells, macrophages, innate lymphoid cells, mucosal-associated invariant T cells, intraepithelial T cells, regulatory T cells (Treg), and IgA secreting plasma cells. [1] [3] [8]

Intraepithelial T cells, usually CD8+, reside between mucosal epithelial cells. These cells do not need primary activation like classic T cells. Instead, upon recognition of antigen, these cells initiate their effector functions, resulting in faster removal of pathogens. [8] Tregs are abundant on the mucous membranes and play an important role in maintaining tolerance through various functions, especially through the production of anti-inflammatory cytokines. [9] Mucosal resident antigen-presenting cells (APCs) in healthy people show a tolerogenic phenotype. [10] These APCs do not express TLR2 or TLR4 on their surfaces. In addition, only negligible levels of the LPS receptor CD14 are normally present on these cells. [10] Mucosal dendritic cells determine the type of subsequent immune responses by the production of certain types of cytokines and the type of molecules involved in the co-stimulation. [3] For example production of IL-6 and IL-23 induce Th17 response, [4] IL-12, IL-18 and INF-γ induce Th1 response, [3] [4] IL-4 induces Th2 response, [4] and IL-10, TGF-β and retinoic acid induce tolerance. [11] Innate lymphoid cells are abundant in the mucosa where via rapid cytokine production in response to tissue-derived signals, they act as regulators of immunity, inflammation, and barrier homeostasis. [12]

The adaptive mucosal immune system is involved in maintaining mucosal homeostasis through a mechanism of immune exclusion mediated by secretory antibodies (mostly IgA) that inhibit the penetration of invasive pathogens into the body's tissues and prevent the penetration of potentially dangerous exogenous proteins. [13] Another mechanism of adaptive mucosal immunity is the implementation of immunosuppressive mechanisms mediated mainly by Tregs to prevent local and peripheral hypersensitivity to harmless antigens, i.e. oral tolerance. [11]

IgA antibody IgA antibody.tif
IgA antibody

Basic immune response in the gut

In the gut, lymphoid tissue is dispersed in gut-associated lymphoid tissue (GALT). A large number of immune system cells in the intestines are found in dome-like structures called Peyer’s patches and in small mucosal lymphoid aggregates called cryptopatches. [14] Above the Peyer’s patches is a layer of epithelial cells, 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. [14] Specialized phagocytic cells, called M cells, which are found in the epithelial layer of the Peyer’s patches, can transport antigenic material across the intestinal barrier through the process of transcytosis. [15] The material transported in this way from the intestinal lumen can then be presented by the antigen-presenting cells present in Peyer’s patches. [14] [15] In addition, dendritic cells in Peyer’s patches can extend their dendrites through M cell-specific transcellular pores and they can also capture translocated IgA immune complexes. [16] Dendritic cells then present the antigen to naïve T cells in the local mesenteric lymph nodes. [17]

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 TGF-β and retinoic acid. [17] These Tregs further travel to the lamina propria of villi through lymphatic vessels. There, Tregs produce IL-10 and IL-35, which affects other immune cells in the lamina propria toward a tolerogenic state. [17]

However, damging the homeostasis of the intestinal barrier leads to inflammation. The epithelium in direct contact with bacteria is activated and begins to produce danger-associated molecular patterns (DAMPs). [17] Alarm molecules released from epithelial cells activate immune cells. [17] [18] Dendritic cells and macrophages are activated in this environment and produce key pro-inflammatory cytokines such as IL-6, IL-12, and IL-23 which activate more immune cells and direct them towards a pro-inflammatory state. [18] The activated effector cells then produce TNF, IFNγ, and IL-17. [18] Neutrophils are attracted to the affected area and begin to perform their effector functions. [1] After the ongoing infection has been removed, the inflammatory response must be stopped to restore homeostasis. [17] The damaged tissue is healed and everything returns to its natural state of tolerance. [17]

Neonatal

At birth, neonates' mucosal immune systems are relatively undeveloped and need intestinal flora colonies to promote development. [7] Microbiota composition stabilizes around the age of 3. [2] In the neonatal period and in early childhood interaction of host immunity with the microbiome is critical. During this interaction various immunity arms are educated. They contribute to homeostasis and determine the future immune system settings, i.e. its susceptibility to infections and inflammatory diseases. [2] [3] For example, the B cell line in the intestinal mucosa is regulated by extracellular signals from commensal microbes that affect the intestinal immunoglobulin repertoire. [19] Diversity of microbiota in early childhood protects the body from the induction of mucosal IgE, which is associated with allergy development. [20]

Mucosal vaccines

Because of its front-line status within the immune system, the mucosal immune system is being investigated for use in vaccines for various afflictions, including COVID-19, [21] [22] [23] [24] [25] HIV, [26] allergies, poliovirus, influenza A and B, rotavirus, vibrio cholerae and many others. [27] [28]

See also

Related Research Articles

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body.

<span class="mw-page-title-main">Peyer's patch</span> Lymphatic tissue in the lower small intestine

Peyer's patches are organized lymphoid follicles, named after the 17th-century Swiss anatomist Johann Conrad Peyer. They are an important part of gut associated lymphoid tissue usually found in humans in the lowest portion of the small intestine, mainly in the distal jejunum and the ileum, but also could be detected in the duodenum.

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 immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

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.

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 tract, nasopharynx, thyroid, breast, lung, salivary glands, eye, and skin. MALT is populated by lymphocytes such as T cells and B cells, as well as plasma cells, dendritic cells and macrophages, each of which is well situated to encounter antigens passing through the mucosal epithelium. In the case of intestinal MALT, M cells are also present, which sample antigen from the lumen and deliver it to the lymphoid tissue. MALT constitute about 50% of the lymphoid tissue in human body. Immune responses that occur at mucous membranes are studied by mucosal immunology.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissues that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Microfold cells are found in the gut-associated lymphoid tissue (GALT) of the Peyer's patches in the small intestine, and in the mucosa-associated lymphoid tissue (MALT) of other parts of the gastrointestinal tract. These cells are known to initiate mucosal immunity responses on the apical membrane of the M cells and allow for transport of microbes and particles across the epithelial cell layer from the gut lumen to the lamina propria where interactions with immune cells can take place.

Immune dysregulation is any proposed or confirmed breakdown or maladaptive change in molecular control of immune system processes. For example, dysregulation is a component in the pathogenesis of autoimmune diseases and some cancers. Immune system dysfunction, as seen in IPEX syndrome leads to immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX typically presents during the first few months of life with diabetes mellitus, intractable diarrhea, failure to thrive, eczema, and hemolytic anemia. unrestrained or unregulated immune response.

<span class="mw-page-title-main">Intraepithelial lymphocyte</span>

Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).

Lymphocyte homing receptors are cell adhesion molecules expressed on lymphocyte cell membranes that recognize addressins on target tissues. Lymphocyte homing refers to adhesion of the circulating lymphocytes in blood to specialized endothelial cells within lymphoid organs. These diverse tissue-specific adhesion molecules on lymphocytes and on endothelial cells contribute to the development of specialized immune responses.

Interleukin-22 receptor subunit alpha-2 (IL-22RA2), also known as interleukin-22 binding protein (IL-22BP) is a naturally secreted monomeric protein acting as an interleukin-22 (IL-22) antagonist with inhibitory effects on IL-22 activity in vivo. IL-22BP is in humans encoded by the IL22RA2 gene located on chromosome 6, and in mice is encoded by the il22ra2 gene located on chromosome 10. IL-22BP belongs to the class II cytokine receptor family and it is a soluble receptor homolog of IL-22R.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

<span class="mw-page-title-main">Microbial symbiosis and immunity</span>

Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

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 molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Gut-specific homing is the mechanism by which activated T cells and antibody-secreting cells (ASCs) are targeted to both inflamed and non-inflamed regions of the gut in order to provide an effective immune response. This process relies on the key interaction between the integrin α4β7 and the addressin MadCAM-1 on the surfaces of the appropriate cells. Additionally, this interaction is strengthened by the presence of CCR9, a chemokine receptor, which interacts with TECK. Vitamin A-derived retinoic acid regulates the expression of these cell surface proteins.

<span class="mw-page-title-main">Intestinal mucosal barrier</span>

The intestinal mucosal barrier, also referred to as intestinal barrier, refers to the property of the intestinal mucosa that ensures adequate containment of undesirable luminal contents within the intestine while preserving the ability to absorb nutrients. The separation it provides between the body and the gut prevents the uncontrolled translocation of luminal contents into the body proper. Its role in protecting the mucosal tissues and circulatory system from exposure to pro-inflammatory molecules, such as microorganisms, toxins, and antigens is vital for the maintenance of health and well-being. Intestinal mucosal barrier dysfunction has been implicated in numerous health conditions such as: food allergies, microbial infections, irritable bowel syndrome, inflammatory bowel disease, celiac disease, metabolic syndrome, non-alcoholic fatty liver disease, diabetes, and septic shock.

Nasal- or nasopharynx- associated lymphoid tissue (NALT) represents immune system of nasal mucosa and is a part of mucosa-associated lymphoid tissue (MALT) in mammals. It protects body from airborne viruses and other infectious agents. In humans, NALT is considered analogous to Waldeyer's ring.

<span class="mw-page-title-main">ILC2</span>

ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell receptor because of the lack of recombination activating gene. ILC2s produce type 2 cytokines and are involved in responses to helminths, allergens, some viruses, such as influenza virus and cancer.

<span class="mw-page-title-main">Type 3 innate lymphoid cells</span>

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

References

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