The dimeric IgA molecule
1 H-chain
2 L-chain
3 J-chain
4 secretory component
Immunoglobulin A (IgA, also referred to as sIgA) is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined;[1] between three and five grams are secreted into the intestinal lumen each day.[2] This accumulates up to 15% of the total immunoglobulin produced in the entire body.[3]
IgA has two subclasses (IgA1 and IgA2) and can exist in a dimeric form called secretory IgA (sIgA). In its secretory form, IgA 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.[4] sIgA can also inhibit inflammatory effects of other immunoglobulins.[5] IgA is a poor activator of the complement system, and opsonises only weakly. Its heavy chains are of the type α.
Contents
- 1 Forms
- 1.1 IgA1 vs. IgA2
- 1.2 Serum vs. secretory IgA
- 2 IgA activity
- 3 Transport
- 4 Pathology
- 4.1 Genetic
- 4.2 microbial
- 4.3 autoimmune/immune-mediated
- 4.4 drug-induced
- 5 See also
- 6 References
- 7 External links
Forms
IgA1 vs. IgA2
IgA exists in two isotypes, IgA1 and IgA2. They are both heavily glycosylated proteins.[6] While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions);[7] the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body:[8]
- IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a predominance of IgA1-producing cells.[9]
- In IgA2, the heavy and light chains are not linked with disulfide, but with noncovalent 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.[7] Polysaccharide antigens tend to induce more IgA2 than protein antigens.[8]
Serum vs. secretory IgA
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, the molecular weight of slgA is 385,000D. 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 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.
IgA activity
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 an immunoglobulin receptor called the polymeric Ig receptor (pIgR). pIgA is released from the nearby activated plasma cells and binds to pIgR. This results in transportation of IgA across mucosal epithelial cells and its cleavage from pIgR for release into external secretions.[10]
In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89), which is expressed on immune effector cells, to initiate inflammatory reactions.[10] 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.[10]
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.[11] 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.[11]
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 sIgA’s secretory component can associate with the mucus layer that sits atop epithelial cells.[11]
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.[11]
Transport
Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent to mucosal surfaces. It binds to the polymeric immunoglobulin receptor 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, are free to diffuse throughout the lumen.[12] In the gut, it can bind to the mucus layer on top of the epithelial cells to form a barrier capable of neutralizing threats before they reach the cell.
Clearance of IgA is mediated at least in part by asialoglycoprotein receptors, which recognizes galactose-terminating IgA N-glycans.[13]
Pathology
Genetic
Decreased or absent IgA, termed selective IgA deficiency, can be a clinically significant immunodeficiency.
microbial
Neisseria species including Neisseria gonorrhœae (which causes gonorrhea),[14] Streptococcus pneumoniae,[15] and Haemophilus influenzae type B[16] all release a protease which destroys IgA.
autoimmune/immune-mediated
IgA nephropathy is caused by IgA deposits in the kidneys. It is not yet known why IgA deposits occur in this chronic disease. Some theories suggest an abnormality of the immune system results in these deposits.[17]
Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies.[18][19]
Henoch–Schönlein purpura (HSP) is a systemic disorder caused by deposits of IgA and complement component 3 (C3) in the small 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.[20]
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.[21]
drug-induced
Vancomycin can induce a linear IgA bullous dermatosis in some patients.
See also
- List of target antigens in pemphigus
- TGF beta
References
- ^ S Fagarasan and T Honjo (2003). "Intestinal IgA Synthesis: Regulation of Front-line Body Defenses". Nature Reviews Immunology 3 (1): 63–72. doi:10.1038/nri982. PMID 12511876.
- ^ P. Brandtzaeg, R. Pabst (2004). "Let's go mucosal: communication on slippery ground". Trends Immunology 25 (11): 570–577. doi:10.1016/j.it.2004.09.005. PMID 15489184.
- ^ AJ Macpherson and E Slack. (2007). "The functional interactions of commensal bacteria with intestinal secretory IgA.". Current Opinion in Gastroenterology 23 (6): 673–678. doi:10.1038/nrmicro2114. PMID 17906446.
- ^ Junqueira, Luiz C.; Jose Carneiro (2003). Basic Histology. McGraw-Hill. ISBN 0-8385-0590-2.
- ^ Holmgren, J; Czerkinsky, C (April 2005). "Mucosal immunity and vaccines". Nature Medicine 11 (4s): S45–S53. doi:10.1038/nm1213. PMID 15812489.
- ^ Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMID 25578468.
- ^ a b Delacroix, DL; Dive, C; Rambaud, JC; Vaerman, JP (Oct 1982). "IgA subclasses in various secretions and in serum.". Immunology 47 (2): 383–5. PMC 1555453. PMID 7118169.
- ^ a b Simell, B; Kilpi, T; Käyhty, H (Mar 2006). "Subclass distribution of natural salivary IgA antibodies against pneumococcal capsular polysaccharide of type 14 and pneumococcal surface adhesin A (PsaA) in children". Clinical and experimental immunology 143 (3): 543–9. doi:10.1111/j.1365-2249.2006.03009.x. PMC 1809616. PMID 16487254.
- ^ http://www.nature.com/mi/journal/v1/n1/pdf/mi20076a.pdf
- ^ a b c Snoeck V, Peters I, Cox E (2006). "The IgA system: a comparison of structure and function in different species". Vet. Res. 37 (3): 455–67. doi:10.1051/vetres:2006010. PMID 16611558.
- ^ a b c d Mantis, Nicholas, Rol, Nicolas, Corthésy, Blaise (Nov 2011). "Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut". Mucosal Immunology 4 (6): 603–11. doi:10.1038/mi.2011.41. PMC 3774538. PMID 21975936.
- ^ CS Kaetzel, JK Robinson, KR Chintalacharuvu, JP Vaerman, and ME Lamm (1991). "The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA". Proc Natl Acad Sci USA 88 (19): 8796–8800. doi:10.1073/pnas.88.19.8796. PMC 52597. PMID 1924341.
- ^ Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMID 25578468.
- ^ Halter, R; Pohlner, J; Meyer, TF (Jul 1984). "IgA protease of Neisseria gonorrhoeae: isolation and characterization of the gene and its extracellular product". The EMBO Journal 3 (7): 1595–601. PMC 557564. PMID 6430698.
- ^ Proctor, M; Manning, PJ (Sep 1990). "Production of immunoglobulin A protease by Streptococcus pneumoniae from animals". Infection and immunity 58 (9): 2733–7. PMC 313560. PMID 2117567.
- ^ St Geme, JW 3rd; de la Morena, ML; Falkow, S (Oct 1994). "A Haemophilus influenzae IgA protease-like protein promotes intimate interaction with human epithelial cells". Molecular microbiology 14 (2): 217–33. doi:10.1111/j.1365-2958.1994.tb01283.x. PMID 7830568.
- ^ IgA Nephropathy on eMedicine
- ^ Prince, HE; Norman, GL; Binder, WL (Mar 2000). "Immunoglobulin A (IgA) deficiency and alternative celiac disease-associated antibodies in sera submitted to a reference laboratory for endomysial IgA testing". Clinical and diagnostic laboratory immunology 7 (2): 192–6. doi:10.1128/cdli.7.2.192-196.2000. PMC 95847. PMID 10702491.
- ^ Cunningham-Rundles C (Sep 2001). "Physiology of IgA and IgA deficiency". J. Clin. Immunol. 21 (5): 303–9. doi:10.1023/A:1012241117984. PMID 11720003.
- ^ Rai, A; Nast, C; Adler, S (Dec 1999). "Henoch-Schönlein purpura nephritis". J Am Soc Nephrol. 10 (12): 2637–44. PMID 10589705.
- ^ He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, Grando SA, Zone JJ, Maverakis E (2015). "Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab". JAMA Dermatol 151 (6): 646–50. doi:10.1001/jamadermatol.2015.59. PMID 25901938.
External links
- Immunoglobulin A at the US National Library of Medicine Medical Subject Headings (MeSH)
|
Immunology: lymphocytic adaptive immune system and complement
|
|
| Lymphoid |
| Antigens |
- Antigen presentation/Professional APCs: Dendritic cell
- Macrophage
- B cell
- Immunogen
|
|
| Antibodies |
- Antibody
- Monoclonal antibodies
- Polyclonal antibodies
- Autoantibody
- Microantibody
- Polyclonal B cell response
- Allotype
- Isotype
- Idiotype
|
|
Immunity vs.
tolerance |
- action: Immunity
- Autoimmunity
- Alloimmunity
- Allergy
- Hypersensitivity
- Inflammation
- Cross-reactivity
- inaction: Tolerance
- Central
- Peripheral
- Clonal anergy
- Clonal deletion
- Tolerance in pregnancy
- Immunodeficiency
|
|
| Immunogenetics |
- Affinity maturation (Somatic hypermutation
- Clonal selection)
- V(D)J recombination
- Junctional diversity
- Immunoglobulin class switching
- MHC/HLA
|
|
|
| Lymphocytes |
- Cellular (T cell)
- Humoral (B cell)
- NK cell
|
|
| Substances |
- Cytokines
- Opsonin
- Cytolysin
|
|
|
Index of the immune system
|
|
| Description |
- Physiology
- cells
- autoantigens
- autoantibodies
- complement
- surface antigens
- IG receptors
|
|
| Disease |
- Allergies
- Immunodeficiency
- Immunoproliferative immunoglobulin disorders
- Hypersensitivity and autoimmune disorders
- Neoplasms and cancer
|
|
| Treatment |
- Procedures
- Drugs
- antihistamines
- immunostimulants
- immunosuppressants
- monoclonal antibodies
|
|
Index of the lymphatic system
|
|
| Description |
- Anatomy
- Physiology
- Development
|
|
| Disease |
- Vessels
- Organs
- congenital
- neoplasms and cancer
|
|
| Treatment |
|
|
|
|
Antibodies
|
|
| Antibodies |
- Heavy chain
- IgA
- IgD
- IgE
- IgG
- IgM
- IgY
- Heavy-chain antibody/IgNAR
|
|
- see also disorders of globin and globulin proteins
|
Index of proteins
|
|
| Description |
- Proteins
- Membrane
- Globular
- Antibodies
- Fibrous
|
|
Index of the immune system
|
|
| Description |
- Physiology
- cells
- autoantigens
- autoantibodies
- complement
- surface antigens
- IG receptors
|
|
| Disease |
- Allergies
- Immunodeficiency
- Immunoproliferative immunoglobulin disorders
- Hypersensitivity and autoimmune disorders
- Neoplasms and cancer
|
|
| Treatment |
- Procedures
- Drugs
- antihistamines
- immunostimulants
- immunosuppressants
- monoclonal antibodies
|
|
|
