Gut-associated lymphoid tissue

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Gut-associated lymphoid tissue
Details
System Lymphatic system
Identifiers
Acronym(s)GALT
FMA 62820
Anatomical terminology

Gut-associated lymphoid tissue (GALT) [1] 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.

Contents

Owing to its physiological function in food absorption, the mucosal surface is thin and acts as a permeable barrier to the interior of the body. Equally, its fragility and permeability creates vulnerability to infection and, in fact, the vast majority of the infectious agents invading the human body use this route. [2] The functional importance of GALT in body's defense relies on its large population of plasma cells, which are antibody producers, whose number exceeds the number of plasma cells in spleen, lymph nodes and bone marrow combined. [3] GALT makes up about 70% of the immune system by weight; compromised GALT may significantly affect the strength of the immune system as a whole. [4]

Structure

The gut-associated lymphoid tissue lies throughout the intestine, covering an area of approximately 260–300 m2. [5] In order to increase the surface area for absorption, the intestinal mucosa is made up of finger-like projections (villi), covered by a monolayer of epithelial cells, which separates the GALT from the lumen intestine and its contents. These epithelial cells are covered by a layer of glycocalyx on their luminal surface so as to protect cells from the acid pH.[ citation needed ]

New epithelial cells derived from stem cells are constantly produced on the bottom of the intestinal glands, regenerating the epithelium (epithelial cell turnover time is less than one week). [2] [6] Although in these crypts conventional enterocytes are the dominant type of cells, Paneth cells can also be found. These are located at the bottom of the crypts and release a number of antibacterial substances, among them lysozyme, and are thought to be involved in the control of infections.[ citation needed ]

Underneath them, there is an underlying layer of loose connective tissue called lamina propria. There is also lymphatic circulation through the tissue connected to the mesenteric lymph nodes.

Both GALT and mesenteric lymph nodes are sites where the immune response is started due to the presence of immune cells through the epithelial cells and the lamina propria.

The GALT also includes the Peyer's patches of the small intestine, isolated lymphoid follicles present throughout the intestine, and the appendix in humans. [2]

The following examples comprise lymphoid tissues that act as interfaces between immune system and incoming antigens either as food antigens or as pathogenic or commensal microbiota's antigens:[ citation needed ]

GALT can be also divided into two categories considering the structure, from which the function arise. There can be found 1.) organised GALT made up from folicules – such as Peyer's patches, mesenteric lymph nodes and even more organised appendix. Its main function is to induce immune reaction. 2.) diffuse GALT with single T and B cells, macrophages, eosinophiles, basophiles and mast cells, preferentially found in lamina propria. This part of GALT is made up from mature effector cells ready to perform their actions.[ citation needed ]

The GALT has been described in the adult eastern grey kangaroo (Macropus giganteus), [7] tammar wallaby (Notamacropus eugenii), [8] stripe-faced dunnart (Sminthopsis macroura), [9] and red-tailed phascogale (Phascogale calura). [10] The adult northern brown bandicoot (Isoodon macrourus) has been described to have both organised and diffuse GALT. [11]

The development of the GALT has also been described in several marsupial species, [12] including tammar wallabies, [13] stripe-faced dunnarts (Sminthopsis macroura), [14] [15] and red-tailed phascogales [16]

Peyer's patches

The Peyer's patch is an aggregate of lymphoid cells projected to the lumen of the gut which acts as a very important site for the initiation of the immune response. It forms a subepithelial dome where large number of B cell follicles with its germinal centers, T cell areas between them in a smaller number and dendritic cells are found. In this area, the subepithelial dome is separated from the intestinal lumen by a layer of follicle-associated epithelium. This contains conventional intestinal epithelial cells and a small number of specialized epithelial cells called microfold cells (M cells) in between. Unlike enterocytes, these M cells present a folded luminal surface instead of the microvilli, do not secrete digestive enzymes or mucus and lack a thick surface of glycocalix, so it can be in contact with microbiota and antigens presented in the content of gut.[ citation needed ]

Function

Intestinal microenvironments and niches. Mucosal immunity.png
Intestinal microenvironments and niches.

Under normal circumstances, immune system of the whole organism needs intestinal source of antigens to train and regulate development of various immune cells. Without having such stimulation, many properties of immune systems do not develop, as it is shown on the case of germ-free animals. Because immune cells are in constant touch with bacterial and food antigens, the primary response is set up as tolerogenic. The complex interaction between these intestinal microbiota, the intestinal epithelial layer, and the local mucosal immune system is essential for maintaining gut health and systemic immunity because the nutrition level of a person’s diet contributes to the gut microbiota (a multispecies microbial community of bacteria, fungi, and viruses, all in a particular niche) that is in synergy with the host. [5] Still there must be a robust defence in a case that pathogens cross either the border line of epithelium or produce harmful substances like bacterial toxins. Such a walking on the edge of a knife is ensured by diverse types of immune cells:

B-lymphocytes

Plasma B cells residing at lamina propria produce high levels of specific secretory IgA (sIgA) antibodies. These IgA are secreted into the lumen of the gut through the epithelial layer by transcytosis. Firstly epithelial cell binds a dimer of IgA via polymeric Ig receptor at the basolateral side and transports it in a vesicle into the luminal space. Then the receptor is proteolytically cleaved and the dimer of IgA is released with a portion of the receptor called the secretory component. The secretory component protects secreted antibodies against the digestive milieu in the gut. [17]

A high level of secretory IgA results from the interaction of B cells and intestinal antigen presenting dendritic cell (DC) in cooperation with follicular T helper cell (Tfh) in the germinal centers (GCs) of Peyer's patches. [18] There are two main ways of IgA production 1) T-cell dependent resulting in sIgAs with high affinity and specificity and 2) T-cell independent generation of sIgA, which utilizes dendritic cells and their production of BAFF and APRIL cytokines. T-cell independently produced sIgAs have lower affinity and coat mainly commensals. [19] [20] General functions of secretory IgAs are to coat any of the intestinal bacteria (commensal or pathogenic ones) to impair their motility and to prevent them from getting in prolonged and direct contact with the intestinal epithelium and the host intestinal immune system. This is called immune exclusion. Secreted IgAs bind to bacterial toxins and neutralize them as well. [18] [19] [20]

T-lymphocytes

Naïve CD4+T cells differentiate into Treg or various helper T cell subsets (Th1, Th2, Th17 or Tfh). In the gut-associated lymphoid tissue, the process of differentiation occurs via presentation of antigens derived from gut microbiota by antigen presenting cells such as dendritic cells or M cells in Peyer's patches. [18] Typical process of an oral tolerance towards ingested food antigens can be described as continuous luminal sampling of antigens by DCs and their subsequent migration followed by priming of naïve T cells in mesenteric lymph nodes to become immunosuppressive T cells (Treg). [21] Antigens received in this way ensure tolerance against them. Commensal microbiota activates immune response as well - in a way that protects host intestinal tissue from damaging it by immune cell reactions. The outcome of T cell populations in healthy individuals differs from the spectrum of T cells resulting from acute infection or chronic inflammation. Inappropriate stimulation (typically by segmented filamentous bacteria - SFB) of chronic Th1 or Th17 cell response plays a crucial role in pathological damage to the host. [22]

Several novel gut-associated lymphoid cells have been described. They are of different origins and follow different maturation processes but share the same GALT role – to rapidly respond to pathogens and secrete effector cytokines. Such multi-layered protection systems highlights the susceptibility of mucosal sites to invading agents. The mucosal route is the most frequent way for entering of pathogenic infections into the host. [23] Robust engagement of a variety of lymphoid cells patrolling the epithelial layer also reflects evolutionary pressure and arms race between immune systems and pathogens escaping its control. [24]

Intraepithelial lymphocytes (IELs)

Long-lived and residential intraepithelial lymphocytes (IELs) are one of the largest populations of T-lymphocytes in the body. [24] In contrast to other peripheral lymphocytes, IEL do not circulate in the blood stream or lymphatic system but reside in the epithelial layer in intestine. [25] Such location in very special per itself – IELs patrol the condition within a single layer of cells and have dendritic look. [26] They provide the first line of defense in case of pathogen crossing the epithelial barrier. IELs encompass surprising diversity of origins and divide into two main categories – conventional and nonconventional. It is based on molecular surface properties and the place where they acquire their final effector cytotoxic program. [24]

Conventional IELs bear classical TCR receptor made up from α and β subunit together with CD4 or CD8 co-receptors. They represent a relative minority of the total intestinal IELs compared with unconventional IELs. They are derived from naïve T cells that encounter antigens in the periphery (typically antigens displayed by DC in the Peyer's patches). After this activation, conventional IELs express gut-tropic molecules allowing them to home in intestinal tissue after trafficking through lymph stream and subsequent blood stream. Conventional intraepithelial cells are thus tissue-resident effector memory T cells, capable of rapid respond with cytolytic activity and release of cytokines such as INFγ and TNF. [24]

Unconventional IELs present majority of IEL cells in intestinal epithelial layer and acquire their effector program after exiting thymus as naïve cells and encountering antigens in GALT. After such stimulation, unconventional IELs (mainly γδ T cells) reside in the intestinal epithelium. [24] γδ T cells express TCR receptor made of γ and δ subunit and do not recognize antigen peptides presented in the MHC-bound form. The process of their activation is still largely unknown. Main property of γδ T cells is formation of long-lived memory populations in barrier tissues such as intestinal epithelium or in the skin. They perform immune memory in particular tissue even after clearance of pathogen or retreat of inflammation. [25]

Innate lymphoid cells (ILCs)

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells and term “innate” means they do not need antigen receptor gene rearrangement. Due to the development of novel method, such as single cell RNA sequencing, subtypes of innate lymphoid cells are described. Based on their transcriptional profile set by main transcription factors ILCs are divided into five distinct subsets: NK cells, ILC1s, ILC2s, ILC3s, and LTi cells. ILCs are prevalent at mucosal surfaces, playing a key role in mucosal immunity and homeostasis due to their ability of rapid secretion of immunoregulatory cytokines and thus communicating with other immune cells. [27]

Innate immunity

Beside adaptive specific immunity, an innate immunity plays a significant role in GALT because it provides more rapid response. Recognition of microbial non-self signature occurs by pattern recognition receptors (PRR) that can be found on dendritic cells, macrophages, monocytes, neutrophils and epithelial cells. PRRs bind to conserved microbial pattern like cell walls components (LPS, teichoic acid, flagellin, peptidoglycan) or viral or bacterial nucleic acid. PRRs are localized extracellularly as membrane-bound receptors (Toll-like receptors) or intracellularly (NOD-like and RIG-like receptors). [22] Varied palette of pattern recognition receptors is activated by various signals named PAMP (pathogen associated molecular patterns) or by signals connected to tissue damage named DAMP (damage associated molecular patterns).

Macrophages

Majority of antigen presenting cells (APCs) in intestine is derived from macrophages, which have very quick turnover. Macrophages are prevalent in lamina propria and submucosal deeper layers like muscularis layer. Macrophages can use their trans-epithelial dendrites (long cytoplasmic extensions) and directly contact epithelial layer and sample luminal bacteria. [26] Under healthy conditions macrophages engulf commensal bacteria and surrounding cellular debris, secrete IL-10, drive maturation of Treg and contribute to tissue homeostasis. Because of low expression of innate response receptors and co-stimulatory surface molecules, intestinal macrophages do not initiate inflammation. But upon infection or inflammation, the profile of macrophages changes and they start to secrete large amounts of TNF-α and become proinflammatory effector cells. [28]

Dendritic cells

DCs present less than 10% of lamina propria APC and typically do not reside in lower layers. Inherent production of retinoic acid and TGF-β (typical for gut-associated DCs) induces expression of gut-homing molecules and favor IgA switch during maturation of B cells in folicules. DCs also direct Treg and conventional IELs to receive their final phenotype of mature effector cells in intestine. [26]

Other animals

The adaptive immunity, mediated by antibodies and T cells, is only found in vertebrates. Whereas all of them have a gut-associated lymphoid tissue and the vast majority have a version of spleen and thymus, not all vertebrates show bone marrow, lymph nodes or germinal centers, what means that not all vertebrates can generate lymphocytes in bone marrow. [3] This different distribution of the adaptive organs in the different groups of vertebrates suggests GALT as the very first part of the adaptive immune system in vertebrates. It has been suggested that from this existing GALT, and due to the pressure put by commensal bacteria in gut that coevolved with vertebrates, later specializations as thymus, spleen or lymph nodes appeared as part of the adaptive immune system. [2]

Additional images

Related Research Articles

<span class="mw-page-title-main">Lamina propria</span> Thin connective layer forming part of the mucous membranes

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 tract.

<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.

Dr George Gordon MacPherson was Reader in Experimental Pathology, Turnbull Fellow, Tutor in Medicine, and Senior Tutor at Oriel College, Oxford. He held a Bachelor's degree (B.M.), Master's degree (M.A.) and a doctorate (D.Phil.). His research interests were in Cell Biology, Pathology, and Immunology. Medically qualified, he researched in the field of cellular immunology at the Sir William Dunn School of Pathology, University of Oxford.

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.

Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances from leaving the intestine and migrating to the body more widely. In a healthy human intestine, small particles can migrate through tight junction claudin pore pathways, and particles up to 10–15 Å can transit through the paracellular space uptake route. There is some evidence abnormally increased intestinal permeability may play a role in some chronic diseases and inflammatory conditions. The most well understood condition with observed increased intestinal permeability is celiac disease.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

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.

High endothelial venules (HEV) are specialized post-capillary venules characterized by plump endothelial cells as opposed to the usual flatter endothelial cells found in regular venules. HEVs enable lymphocytes circulating in the blood to directly enter a lymph node.

<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.

<span class="mw-page-title-main">Lymphotoxin alpha</span> Protein found in humans

Lymphotoxin-alpha (LT-α) formerly known as tumor necrosis factor-beta (TNF-β) is a protein that in humans is encoded by the LTA gene. Belonging to the hematopoietic cell line, LT-α exhibits anti-proliferative activity and causes the cellular destruction of tumor cell lines. As a cytotoxic protein, LT-α performs a variety of important roles in immune regulation depending on the form that it is secreted as. Unlike other members of the TNF superfamily, LT-α is only found as a soluble homotrimer, when found at the cell surface it is found only as a heterotrimer with LTβ.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorption, and secretion. Useful substances are absorbed into the body, and the entry of harmful substances is restricted. Secretions include mucins, and peptides.

<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.

<span class="mw-page-title-main">Mucosal immunology</span> Field of study

Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. 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. 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.

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">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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