Immunoglobulin A

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Schematic of immunoglobulin A dimer showing H-chain (blue), L-chain (red), J-chain (magenta) and secretory component (yellow). Dimeric IgA schematic 01.svg
Schematic of immunoglobulin A dimer showing H-chain (blue), L-chain (red), J-chain (magenta) and secretory component (yellow).
Two views, one rotated 90 degrees with respect to the other, of the amino acid chains comprising secretory IgA1. Colors are: H-chains (blue and light blue), L-chains (red and light red), J-chain (magenta) and the secretory component (yellow). Coordinates of each backbone carbon atom were derived PDB entry 3CHN. 3D structure of secretory IgA1.png
Two views, one rotated 90 degrees with respect to the other, of the amino acid chains comprising secretory IgA1. Colors are: H-chains (blue and light blue), L-chains (red and light red), J-chain (magenta) and the secretory component (yellow). Coordinates of each backbone carbon atom were derived PDB entry 3CHN.
Two views, one rotated 90 degrees with respect to the other, of the amino acid chains comprising secretory IgA2. Colors are: H-chains (blue and light blue), L-chains (red and light red), J-chain (magenta) and the secretory component (yellow). Coordinates of each backbone carbon atom were derived PDB entry 3cm9. 3D structure of secretory IgA2.png
Two views, one rotated 90 degrees with respect to the other, of the amino acid chains comprising secretory IgA2. Colors are: H-chains (blue and light blue), L-chains (red and light red), J-chain (magenta) and the secretory component (yellow). Coordinates of each backbone carbon atom were derived PDB entry 3cm9.

Immunoglobulin A (Ig A, also referred to as sIgA in its secretory form) 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. [3] In absolute terms, between three and five grams are secreted into the intestinal lumen each day. [4] This represents up to 15% of total immunoglobulins produced throughout the body. [5]

Contents

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 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. [6] sIgA can also inhibit inflammatory effects of other immunoglobulins. [7] IgA is a poor activator of the complement system, and opsonizes only weakly.[ citation needed ]

Forms

IgA1 vs. IgA2

IgA exists in two isotypes, IgA1 and IgA2. They are both heavily glycosylated proteins. [8] While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions); [9] the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body: [10]

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. [9] Polysaccharide antigens tend to induce more IgA2 than protein antigens. [10]

Both IgA1 and IgA2 can be in membrane-bound form. [12] (see B-cell receptor )

The heavy chain of IgA1, in contrast to IgA2, features an extended hinge region. This is thought to allow IgA1 to adapt more effectively to varying epitope spacings on multivalent antigens, while also presenting less resistance to bacterial proteases. [13]

Serum vs. secretory IgA

It is also possible to distinguish forms of IgA based upon their location – serum IgA vs. secretory IgA.[ citation needed ]

In secretory IgA, the form found in secretions, polymers of 2–4 IgA monomers are linked by two additional chains; as such, 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.[ citation needed ]

The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kD) called 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.[ citation needed ]

Physiology

Serum IgA

In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89), which is expressed on immune effector cells, to initiate inflammatory reactions. [14] 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. [14] Unlike IgM and IgG, which activate complement through the classical pathway, IgA can activate complement via the alternative and lectin pathways. [15]

Secretory IgA

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). [14] Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent to mucosal surfaces. It binds to 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), is free to diffuse throughout the lumen, with dimeric IgA and SC together forming the so-called secretory IgA (sIgA) [16] 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.[ citation needed ]

Secretory IgA levels fluctuate diurnally, with the highest levels found in the small intestine and feces around ZT6, the middle of the light period. [17] The regulation of IgA secretion is related to the microbiota, and IgA is known to control specific members of oscillating microbes through direct interactions. [17] 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 the small intestine. [18]

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. [18] 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 the component of IgA can associate with the mucus layer that sits atop epithelial cells. [18] 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. [18]

Clearance of IgA is mediated at least in part by asialoglycoprotein receptors, which recognizes galactose-terminating IgA N-glycans. [8]

Pathology

Genetic

Decreased or absent IgA due to an inherited inability to produce IgA is termed selective IgA deficiency and can produce a clinically significant immunodeficiency. [19]

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. [20]

Microbial

Neisseria species including Neisseria gonorrhoeae (which causes gonorrhea), [21] Streptococcus pneumoniae , [22] and Haemophilus influenzae type B [23] all release 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. [24]

Autoimmune and immune-mediated

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 the production of IgA-specific IgG, further leading to tissue inflammation. [25]

Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies. [26] [27] 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. [28] [29]

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 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. [30]

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. [31]

Drug-induced

Vancomycin can induce a linear IgA bullous dermatosis in some patients. [32]

See also

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. Antigen literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems 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 splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is the largest of several isotypes of antibodies that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.

<span class="mw-page-title-main">Plasma cell</span> White blood cell that secretes large volumes of antibodies

Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen, where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell.

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.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

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.

<span class="mw-page-title-main">Isotype (immunology)</span>

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.

<span class="mw-page-title-main">J chain</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Polymeric immunoglobulin receptor</span> Protein-coding gene in the species Homo sapiens

Polymeric immunoglobulin receptor (pIgR) 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, a transmembrane region, and an intracellular domain. pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli.

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

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.

<span class="mw-page-title-main">FCAR</span> Mammalian protein found in Homo sapiens

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.

The following outline is provided as an overview of and topical guide to immunology:

<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">Ocular immune system</span> Immune system of the human eye

The ocular immune system protects the eye from infection and regulates healing processes following injuries. The interior of the eye lacks lymph vessels but is highly vascularized, and many immune cells reside in the uvea, including mostly macrophages, dendritic cells, and mast cells. These cells fight off intraocular infections, and intraocular inflammation can manifest as uveitis or retinitis. The cornea of the eye is immunologically a very special tissue. Its constant exposure to the exterior world means that it is vulnerable to a wide range of microorganisms while its moist mucosal surface makes the cornea particularly susceptible to attack. At the same time, its lack of vasculature and relative immune separation from the rest of the body makes immune defense difficult. Lastly, the cornea is a multifunctional tissue. It provides a large part of the eye's refractive power, meaning it has to maintain remarkable transparency, but must also serve as a barrier to keep pathogens from reaching the rest of the eye, similar to function of the dermis and epidermis in keeping underlying tissues protected. Immune reactions within the cornea come from surrounding vascularized tissues as well as innate immune responsive cells that reside within the cornea.

<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.

<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.

References

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  32. ↑ Go JR, Abu Saleh OM (October 2020). "Vancomycin-Induced Linear IgA Bullous Dermatosis". The New England Journal of Medicine. 383 (16): 1577. doi:10.1056/NEJMicm2003334. PMID   33053287. S2CID   222420540.
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