PIGR | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | PIGR , Pigr, polymeric immunoglobulin receptor | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 173880 MGI: 103080 HomoloGene: 1984 GeneCards: PIGR | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Polymeric immunoglobulin receptor (pIgR) is a transmembrane protein that in humans is encoded by the PIGR gene. [5] It is an Fc receptor which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A and immunoglobulin M (pIg) and immune complexes. pIgRs are mainly located on the epithelial lining of mucosal surfaces of the gastrointestinal tract. The composition of the receptor is complex, including 6 immunoglobulin-like domains, a transmembrane region, and an intracellular domain. [6] pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli. [6] [7]
pIgR is produced among others by intestinal epithelial cells (IECs) and bronchial epithelial cells. pIgR belongs to the family of type I transmembrane proteins. The extracellular portion of the protein contains 6 domains: 5 evolutionary conserved immunoglobulin-like domains, [8] and 1 non-homologous domain, which is involved in proteolytic cleavage of pIg-pIgR complex from the apical side of the IECs. The quite long intracellular domain of the receptor, along with the transmembrane region, is responsible for the transduction of highly conserved signals. [7] [9] During transcytosis, an essential part of pIgR, the secretory component, is attached to the ligand and later cleaved with the ligand to form fully functioning secreted IgA. [10]
Per Brandtzaeg showed that secretory component acts as a plasma membrane receptor on epithelial cells for polymeric immunoglobulin A and immunoglobulin M. [11] This was paradoxical, as secretory component is a soluble protein, whereas plasma membrane receptors are transmembrane proteins. Numerous models were proposed for how secretory component might work as a receptor, though none of these models resolved this paradox. [11] Keith Mostov and colleagues found that secretory component was a proteolytic fragment of a transmembrane precursor, the pIgR, which led them to propose the currently accepted model [12]
Polymeric immunoglobulin receptor is responsible for transcytosis of soluble dimeric IgA, pentameric IgM, and immune complexes from the basolateral to the apical mucosal epithelial cell surface. pIgR has a strong specificity to polymeric immunoglobulins and is not responsive to monomeric immunoglobulin. [13] The ligand’s J-chain is responsible for the binding of pIgR to its ligand. [7] [10]
The process of transporting polymeric immunoglobulins from the basolateral to apical side, known as transcytosis, is composed of several distinct steps. Transcytosis is initiated by either the binding of dimeric IgA to the receptor or the phosphorylation of Ser-664 residue of the receptor. [9] The internalization of both free and IgA-bound pIgR is mediated by clathrin coating. The internalized receptor is transported to basolateral early endosomes. The following step of transporting the pIgR across the cell (through tubulo-vesicular compartments to apical recycling endosome) is dependent on microtubules. [9] When pIgR reaches the apical membrane, proteolytic cleavage generates either a free secretory component of SC-IgA complex , which is released to the apical lumen. [7] Cleavage occurs at the junction of the transmembrane region of the receptor and domain 5. [6]
pIgRs are capable of capturing IgA bound to an antigen (Immune complexes (ICs)) with identical affinity as IgA and transport them to apical side. ICs result from the capture of an antigen by an antibody. IgA ICs are formed within the mucous membranes in response to foreign invasion. [14] The accumulation of ICs on the basolateral side of mucous layers can have detrimental effects. Transcytosis of IgA ICs from the formation sites represents an important mechanism of eliminating circulating antigens and minimizing their negative effects. [14] [15]
The expression of pIgR is critically regulated by the pro-inflammatory cytokines, such as IL-1, IL-4, TNF-α, and IFN-γ. The transcriptional regulation by different cytokines proceeds through similar pathways, involving the NF-kB feedback loop. Interaction of IL-1 and TNF-α with their receptors ultimately lead to transcriptional activation of PIGR gene due to nuclear translocation of NF-kB. NF-kB interacts with intron 1 of the PIGR gene to start pIgR mRNA synthesis. [6]
Besides NF-kB pathway, the transcriptional induction also proceeds in response to IFN-γ, upregulating the expression of pIgR. [6] [7]
Additionally, instead of the usual antagonistic behavior, IL-4 acts synergistically with IFN-γ to induce pIgR transcription. Their combination exhibits an upregulating effect in PIGR expression because of the presence of STAT6 enhancer, the main downstream effector of IL-4, binding site in PIGR's intron 1. [16]
The level of pIgRs in the mucosal reproductive tract is highly dependent on the activity of sex hormones and correlates with estrous cycle phases. The peaks of pIgR expression at proestrus and estrus phases are due to the dominant activity of estrogen, which acts as a pIgR agonist. The low levels of pIgR during the diestrus are linked to the downregulating activity of progesterone, which peaks during this phase and is able to reverse the activity of estrogen. [17] Androgens are the agonists of pIgR expression in both male and female reproductive tissues. [6]
5’-flanking region of the Pigr gene contains a response element to glucocorticoids. This class of hormones increases the steady mRNA expression levels of pIgR of intestinal cells. [16] [18]
Prolactin elevates the levels of IRF-1 via Jak-STAT pathway. IRF-1 is known to be a direct agonist of pIgR expression. Considering this linkage, prolactin is believed to exhibit indirect upregulation of pIgR levels during pregnancy and lactation. [6]
IECs express a variety of Toll-like receptors (TLRs), activation of which ultimately leads to the pIgR upregulation during the infection. [6] [7] The most prominent modulators of pIgR regulation consist of TLR4 and TLR3, which recognize bacterial lipopolysaccharide and viral dsRNA respectively. TLR4, like the majority of TLRs, transduce the signal though MyD88 adaptor and execute the function via NF-kB, which stimulates the expression of pIgR by binding to intron 1 of the gene. TLR3, on the other hand, involves the regulation by the means of IRF-1, which is able to promote the transcription of PIGR gene by binding to exon 1. [16] [18]
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.
Immunoglobulin M (IgM) is one of several isotypes of antibody that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antigen. that's why it is also called acute phase antibody.In humans and other mammals that have been studied, plasmablasts residing in the spleen are the main source of specific IgM production.
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.
Transcytosis 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 ejected on the other side. Examples of macromolecules transported include IgA, transferrin, and insulin. While transcytosis is most commonly observed in epithelial cells, the process is also present elsewhere. Blood capillaries are a well-known site for transcytosis, though it occurs in other cells, including neurons, osteoclasts and M cells of the intestine.
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.
Chemokine ligand 28 (CCL28), also known as mucosae-associated epithelial chemokine (MEC), CCK1 and SCYA28, is a chemokine. CCL28 regulates the chemotaxis of cells that express the chemokine receptors CCR3 and CCR10. CCL28 is expressed by columnar epithelial cells in the gut, lung, breast and the salivary glands and drives the mucosal homing of T and B lymphocytes that express CCR10, and the migration of eosinophils expressing CCR3. This chemokine is constitutively expressed in the colon, but its levels can be increased by pro-inflammatory cytokines and certain bacterial products implying a role in effector cell recruitment to sites of epithelial injury. CCL28 has also been implicated in the migration of IgA-expressing cells to the mammary gland, salivary gland, intestine and other mucosal tissues. It has also been shown as a potential antimicrobial agent effective against certain pathogens, such as Gram negative and Gram positive bacteria and the fungus Candida albicans.
Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map in a 150-kb region of the leukocyte receptor complex (LRC) on human chromosome 19q13.4.
The neonatal Fc receptor is a protein that in humans is encoded by the FCGRT gene. It is an IgG Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin. In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother's milk, leading to its name as the neonatal Fc receptor. In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus. FcRn has also been shown to play a role in regulating IgG and serum albumin turnover. Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF, and down-regulated by IFN-γ.
In immunology, antibodies are classified into several types called isotypes or classes. The variable (V) regions near the tip of the antibody can differ from molecule to molecule in countless ways, allowing it to specifically target an antigen . In contrast, the constant (C) regions only occur in a few variants, which define the antibody's class. Antibodies of different classes activate distinct effector mechanisms in response to an antigen . They appear at different stages of an immune response, differ in structural features, and in their location around the body.
The Joining (J) chain is a protein component that links monomers of antibodies IgM and IgA to form polymeric antibodies capable of secretion. The J chain is well conserved in the animal kingdom, but its specific functions are yet to be fully understood. It is a 137 residue polypeptide, encoded by the IGJ gene.
The secretory component is a component of immunoglobulin A (IgA). Secretory component is a proteolytic cleavage product of the polymeric immunoglobulin receptor which remains associated with dimeric IgA in sero-mucus secretions. Polymeric IgA binds to the polymeric immunoglobulin receptor on the basolateral surface of epithelial cells and is taken up into the cell via transcytosis. The receptor-IgA complex passes through the cellular compartments before being secreted on the luminal surface of the epithelial cells, still attached to the receptor. Proteolysis of the receptor occurs and the dimeric IgA molecule, along with the secretory component, are free to diffuse throughout the lumen.
CD83 is a human protein encoded by the CD83 gene.
Killer cell immunoglobulin-like receptor 2DL4 is a protein that in humans is encoded by the KIR2DL4 gene.
Leukocyte immunoglobulin-like receptor subfamily B member 4 is a protein that in humans is encoded by the LILRB4 gene.
Hepatitis A virus cellular receptor 1 (HAVcr-1) also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a protein that in humans is encoded by the HAVCR1 gene.
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Fc fragment of IgA receptor (FCAR) is a human gene that codes for the transmembrane receptor FcαRI, also known as CD89. FcαRI binds the heavy-chain constant region of Immunoglobulin A (IgA) antibodies. FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils, though it is notably absent from intestinal macrophages and does not appear on mast cells. FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound. Inside-out signaling primes FcαRI in order for it to bind its ligand, while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain.
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.
Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.