Misplaced Pages

#268731

38-523: IgA has two subclasses ( IgA1 and IgA2 ) and can be produced as a monomeric as well as a dimeric form. The IgA dimeric form is the most prevalent and, when it has bound the Secretory component, is also called secretory IgA (sIgA). sIgA is the main immunoglobulin found in mucous secretions , including tears , saliva , sweat , colostrum and secretions from the genitourinary tract , gastrointestinal tract , prostate and respiratory epithelium . It

76-615: A chromosomal abnormality identified in multiple myeloma lines. The abnormality has been identified as a translocation event, where translocation between IGHA1 (found on chromosome 14), and FCRL4 (the gene sequence encoding for an inhibitory receptor, found on chromosome 1) leads to the production of a fusion protein . Polymeric immunoglobulin receptor 1XED , 2OCW , 3CHN , 3CM9 , 5D4K 5284 18703 ENSG00000162896 ENSMUSG00000026417 P01833 O70570 NM_002644 NM_011082 NP_002635 NP_035212 Polymeric immunoglobulin receptor (pIgR)

114-406: A protease that destroys IgA . Additionally, Blastocystis species have been shown to have several subtypes that generate cysteine and aspartic protease enzymes which degrade human IgA. IgA nephropathy is caused by IgA deposits in the kidneys. The pathogenesis involves the production of hypoglycosylated IgA1, which accumulates and subsequently leads to the formation of immune complexes and

152-400: A linear IgA bullous dermatosis in some patients. IGHA1 3493 n/a ENSG00000211895 n/a n a n/a n/a n/a n/a n/a Immunoglobulin heavy constant alpha 1 is a immunoglobulin gene with symbol IGHA1 . It encodes a constant (C) segment of Immunoglobulin A heavy chain . Immunoglobulin A is an antibody that plays a critical role in immune function in

190-426: A plasma membrane receptor on epithelial cells for polymeric immunoglobulin A and immunoglobulin M. 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. Keith Mostov and colleagues found that secretory component

228-468: A transmembrane region, and an intracellular domain. pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli. 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, and 1 non-homologous domain, which

266-482: Is a transmembrane protein that in humans is encoded by the PIGR gene . 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,

304-657: Is also found in small amounts in blood. The secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic enzymes; thus, sIgA can survive in the harsh gastrointestinal tract environment and provide protection against microbes that multiply in body secretions. sIgA can also inhibit inflammatory effects of other immunoglobulins. IgA is a poor activator of the complement system , and opsonizes only weakly. IgA exists in two isotypes , IgA1 and IgA2. They are both heavily glycosylated proteins. While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions);

342-442: Is expressed on immune effector cells, to initiate inflammatory reactions. Ligation of FcαRI by IgA containing immune complexes causes antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation of eosinophils and basophils , phagocytosis by monocytes , macrophages , and neutrophils , and triggering of respiratory burst activity by polymorphonuclear leukocytes . Unlike IgM and IgG , which activate complement through

380-417: Is free to diffuse throughout the lumen , with dimeric IgA and SC together forming the so-called secretory IgA (sIgA) In the gut, IgA can bind to the mucus layer covering the epithelial cells. In this way, a barrier capable of neutralizing threats before they reach the epithelial cells is formed. Secretory IgA levels fluctuate diurnally, with the highest levels found in the small intestine and feces around ZT6,

418-536: 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. 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. Per Brandtzaeg showed that secretory component acts as

SECTION 10

#1732781110269

456-401: 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 . When pIgR reaches the apical membrane, proteolytic cleavage generates either a free secretory component of SC-IgA complex , which

494-438: Is released to the apical lumen. Cleavage occurs at the junction of the transmembrane region of the receptor and domain 5. 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. The accumulation of ICs on

532-401: Is responsible for the binding of pIgR to its ligand. 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. The internalization of both free and IgA-bound pIgR

570-669: Is termed selective IgA deficiency and can produce a clinically significant immunodeficiency . Anti-IgA antibodies, sometimes present in individuals with low or absent IgA, can result in serious anaphylactic reactions when transfused with blood products that incidentally contain IgA. However, most persons with suspected IgA anaphylactic reactions had experienced acute generalized reactions that were from causes other than anti-IgA transfusion. Neisseria species including Neisseria gonorrhoeae (which causes gonorrhea ), Streptococcus pneumoniae , and Haemophilus influenzae type B all release

608-401: Is thought to allow IgA1 to adapt more effectively to varying epitope spacings on multivalent antigens, while also presenting less resistance to bacterial proteases. It is also possible to distinguish forms of IgA based upon their location – serum IgA vs. secretory IgA. In secretory IgA, the form found in secretions, polymers of 2–4 IgA monomers are linked by two additional chains; as such,

646-465: 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. Besides NF-kB pathway, the transcriptional induction also proceeds in response to IFN-γ, upregulating the expression of pIgR. Additionally, instead of

684-413: The binding site for this protein, with the binding site incorporating one antiparallel beta strand on either side of the helix. In addition to the binding sites, the opposite side of the beta-sandwich is connected by a series of loops, which define a hypervariable loop system, that may have a role in determining the specificity of an interaction between IgA and an antigen. IGHA1 has been implicated in

722-482: The molecular weight of slgA is 385kD. One of these is the J chain (joining chain), which is a polypeptide of molecular mass 15kD, rich with cysteine and structurally completely different from other immunoglobulin chains. This chain is formed in the IgA-secreting cells. The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kD) called

760-405: The mucous membranes . IgA shows the same typical structure of other antibody classes, with two heavy chains and two light chains, and four distinct domains: one variable region, and three variable regions. As a major class of immunoglobulin in body secretions, IgA plays a role in defending against infection , as well as preventing the access of foreign antigens to the immunologic system. IGHA1

798-403: The secretory component that is produced by epithelial cells . This molecule originates from the poly-Ig receptor (130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid. In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89 ), which

SECTION 20

#1732781110269

836-456: 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. 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

874-453: The classical pathway, IgA can activate complement via the alternative and lectin pathways . The high prevalence of IgA in mucosal areas is a result of a cooperation between plasma cells that produce polymeric IgA (pIgA), and mucosal epithelial cells that express polymeric immunoglobulin receptor (pIgR). Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent to mucosal surfaces. It binds to

912-511: The component of IgA can associate with the mucus layer that sits atop epithelial cells. Since sIgA is a poor opsonin and activator of complement, simply binding a pathogen isn't necessarily enough to contain it—specific epitopes may have to be bound to sterically hinder access to the epithelium. Clearance of IgA is mediated at least in part by asialoglycoprotein receptors , which recognizes galactose -terminating IgA N- glycans . Decreased or absent IgA due to an inherited inability to produce IgA

950-495: The constant regions of IgA, and is composed of an amino acid sequence 353 residues long. The secondary structure contained within this region is dominated by beta strands , which define four antiparallel beta sheets . These antiparallel beta-sheets are then sandwiched to form two beta-sandwiches, a typical tertiary structure of the immunoglobulin fold class. The two beta sheets that comprise each beta-sandwich are joined by an alpha helix on one side. These alpha helices define

988-518: 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. Androgens are the agonists of pIgR expression in both male and female reproductive tissues. 5’-flanking region of the Pigr gene contains a response element to glucocorticoids . This class of hormones increases

1026-401: The genes were contained in three exons , each of which encodes a single region of the protein domain. The genes encoding IGHA1 are found on human chromosome 14 . The sequence encoding IGHA1 is 1,497 nucleotides long and is found between loci 105,707,168 and 105,708,664. The annotated chromosome location is also given as 14q32.33. The Ig alpha-1 chain C region is contained on the first of

1064-621: The middle of the light period. The regulation of IgA secretion is related to the microbiota, and IgA is known to control specific members of oscillating microbes through direct interactions. However, the underlying cause of the rhythmic secretion of IgA is not completely understood and may differ from one region of the body to another. Production of sIgA against specific antigens depends on sampling of M cells and underlying dendritic cells , T cell activation, and B cell class switching in GALT, mesenteric lymph nodes , and isolated lymphoid follicles in

1102-423: The pIgR on the basolateral surface of epithelial cells, and is taken up into the cell via endocytosis . 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 a portion of the receptor known as the secretory component (SC),

1140-399: The pIgR upregulation during the infection. 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

1178-537: The production of IgA-specific IgG, further leading to tissue inflammation. Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies. Additional testing has been conducted using IgA trans-glutaminase autoantibodies which has been identified as a specific and sensitive for the detection of celiac disease. Henoch–Schönlein purpura (HSP) is a systemic vasculitis caused by deposits of IgA and complement component 3 (C3) in small blood vessels. HSP occurs usually in small children and involves

Immunoglobulin A - Misplaced Pages Continue

1216-503: The ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body: Both IgA1 and IgA2 have been found in external secretions like colostrum , maternal milk, tears and saliva , where IgA2 is more prominent than in the blood. Polysaccharide antigens tend to induce more IgA2 than protein antigens. Both IgA1 and IgA2 can be in membrane-bound form. ( see B-cell receptor ) The heavy chain of IgA1, in contrast to IgA2, features an extended hinge region. This

1254-475: The skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys. It usually follows an upper respiratory infection and resolves within a couple weeks as the liver clears out the IgA aggregates. Linear IgA bullous dermatosis and IgA pemphigus are two examples of IgA-mediated immunobullous diseases. IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab. Vancomycin can induce

1292-428: The small intestine. sIgA primarily acts by blockading epithelial receptors (e.g. by binding their ligands on pathogens), by sterically hindering attachment to epithelial cells, and by immune exclusion. Immune exclusion is a process of agglutinating polyvalent antigens or pathogens by crosslinking them with antibody, trapping them in the mucus layer, and/or clearing them peristaltically . The oligosaccharide chains of

1330-416: The steady mRNA expression levels of pIgR of intestinal cells. 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. IECs express a variety of Toll-like receptors (TLRs), activation of which ultimately leads to

1368-511: 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. 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

1406-457: Was a proteolytic fragment of a transmembrane precursor, the pIgR, which led them to propose the currently accepted model 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. The ligand’s J-chain

1444-442: Was first described in detail in 1975, when the primary structure (the amino acid sequence) of IgA was elucidated through the sequencing of tryptic and chymotryptic peptides. Similarly, the primary sequence was determined independently for the alpha-2 chain of the protein in 1979. Complete nucleotide sequences for the alpha-1 heavy chain constant region and the allelic alpha-2 heavy chain regions were published in 1984, and showed

#268731