Immunoglobulin A

IgA1 vs. IgA2 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); the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body: • IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a predominance of IgA1-producing cells. • In IgA2, the heavy and light chains are not linked with disulfide, but with non-covalent bonds. In secretory lymphoid tissues (e.g., gut-associated lymphoid tissue, or GALT), the share of IgA2 production is larger than in the non-secretory lymphoid organs (e.g. spleen, peripheral lymph nodes). 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. (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. Serum vs. secretory IgA It is also possible to distinguish forms of IgA based upon their location – serum IgA vs. secretory IgA. In serum IgA is predominantly monomeric with a minor population of IgA polymers (dimers in healthy individuals). IgA has the unique ability to be secreted by B cells either as a monomer or as a covalently-linked polymer of multiple IgA subunits. Polymers of 2–4 IgA monomers, but most commonly 2, are covalently linked to one molecule of the J chain (joining chain) inside the B cell prior to secretion as a J chain-coupled polymeric IgA molecule. The J chain is a polypeptide with a backbone molecular mass of 15 kDa but typically ~18 kDa when glycosylated, rich with cysteine and structurally completely different from other immunoglobulin chains. As such, the molecular weight of a J chain-coupled dimer of IgA is ~340 kDa. The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kDa) called the secretory component that is produced by epithelial cells. This molecule originates from the poly-Ig receptor (130 kDa) that is responsible for the uptake and transcellular transport of J chain-containing polymeric (but not monomeric, which is devoid of J chain) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid. ==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. 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). 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) 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, 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. 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. In patients with acute-on-chronic liver failure (ACLF) syndrome characterized by multi-organ failure, elevated serum sIgA levels demonstrate a strong correlation with short-term mortality. ==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. 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. Microbial Neisseria species including Neisseria gonorrhoeae (which causes gonorrhea), Streptococcus pneumoniae, and Haemophilus influenzae type B 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. 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. 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 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. Drug-induced Vancomycin can induce a linear IgA bullous dermatosis in some patients. == See also ==