Isotype (immunology)

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Some antibodies form complexes that bind to multiple antigen molecules. Mono-und-Polymere.svg
Some antibodies form complexes that bind to multiple antigen molecules.
Fab region Fc region Heavy chain (blue) with one variable (VH) domain followed by a constant domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains Light chain (green) with one variable (VL) and one constant (CL) domain Antigen binding site (paratope) Hinge regions Immunoglobulin basic unit.svg
  1. Fab region
  2. Fc region
  3. Heavy chain (blue) with one variable (VH) domain followed by a constant domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains
  4. Light chain (green) with one variable (VL) and one constant (CL) domain
  5. Antigen binding site (paratope)
  6. Hinge regions

In immunology, antibodies (immunoglobulins (Ig)) 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 (or more exactly, an epitope). 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 (triggering different elements of the innate immune system). They appear at different stages of an immune response, differ in structural features, and in their location around the body. [1]

Contents

Isotype expression reflects the maturation stage of a B cell. Naive B cells express IgM and IgD isotypes with unmutated variable genes, which are produced from the same initial transcript following alternative splicing. Expression of other antibody isotypes (in humans: IgG, IgA, and IgE) occurs via a process of class switching after antigen exposure. [2] Class switching is mediated by the enzyme AID (activation-induced cytidine deaminase) and occurs after the B cell binds an antigen through its B cell receptor. Class-switching usually requires interaction with a T helper cell. [3] [4]

In humans, there are five heavy chain isotypes α,δ,γ,ε,μ, corresponding to five antibody isotypes:

There are also two light chain isotypes κ and λ; however, there is no significant difference in function between the two. Thus an antibody isotype is determined by the constant regions of the heavy chains only. [1]

IgM is first expressed as a monomer on the surface of immature B cells. Upon antigenic stimulation, IgM+ B cells secrete pentameric IgM antibody formed by five Ig monomers which are linked via disulfide bonds. The pentamer also contains a polypeptide J-chain, which links two of the monomers and facilitates secretion at mucosal surfaces. The pentameric structure of IgM antibodies makes them efficient at binding antigens with repetitive epitopes (e.g. bacterial capsule, viral capsid) and activation of complement cascade. As IgM antibodies are expressed early in a B cell response, they are rarely highly mutated and have broad antigen reactivity thus providing an early response to a wide range of antigens without the need for T cell help. [5]

IgD isotypes are expressed on naive B cells as they leave bone marrow and populate secondary lymphoid organs. The levels of surface expression of IgD isotype has been associated with differences in B cell activation status but their role in serum is poorly understood. [6]

The IgG, IgE and IgA antibody isotypes are generated following class-switching during germinal centre reaction and provide different effector functions in response to specific antigens. IgG is the most abundant antibody class in the serum and it is divided into 4 subclasses based on differences in the structure of the constant region genes and the ability to trigger different effector functions. Despite the high sequence similarity (90% identical on the amino acid level), each subclass has a different half-life, a unique profile of antigen binding and distinct capacity for complement activation. IgG1 antibodies are the most abundant IgG class and dominate the responses to protein antigens. Impaired production of IgG1 is observed in some cases of immunodeficiency and is associated with recurrent infections. [7] The IgG responses to bacterial capsular polysaccharide antigens are mediated primarily via IgG2 subclass, and deficiencies in this subclass result in susceptibility to certain bacterial species. [8] IgG2 represents the major antibody subclass reacting to glycan antigens but IgG1 and IgG3 subclasses have also been observed in such responses, particularly in the case of protein-glycan conjugates. [9]

IgG3 is an efficient activator of pro-inflammatory responses by triggering the classical complement pathway. [10] It has the shortest half-life compared to the other IgG subclasses [11] and is frequently present together with IgG1 in response to protein antigens after viral infections. [12] IgG4 is the least abundant IgG subclass in the serum and is often generated following repeated exposure to the same antigen or during persistent infections.

IgA antibodies are secreted in the respiratory or the intestinal tract and act as the main mediators of mucosal immunity. [13] They are monomeric in the serum, but appear as a dimer termed secretory IgA (sIgA) at mucosal surfaces. The secretory IgA is associated with a J-chain and another polypeptide chain called the secretory component. [14] IgA antibodies are divided into two subclasses that differ in the size of their hinge region. [15] IgA1 has a longer hinge region which increases its sensitivity to bacterial proteases. [16] Therefore, this subclass dominates the serum IgA, while IgA2 is predominantly found in mucosal secretions. Complement fixation by IgA is not a major effector mechanism at the mucosal surface but IgA receptor is expressed on neutrophils which may be activated to mediate antibody-dependent cellular cytotoxicity. [17] sIgA has also been shown to potentiate the immune response in intestinal tissue by uptake of antigen together with the bound antibody by dendritic cells. [18]

IgE antibodies are present at lowest concentrations in peripheral blood but constitute the main antibody class in allergic responses through the engagement of mast cells, eosinophils and Langerhans cells. [19] Responses to specific helminths are also characterised with elevated levels of IgE antibodies. [20]

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.

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<span class="mw-page-title-main">Immunoglobulin G</span> Antibody isotype

Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

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.

<span class="mw-page-title-main">Immunoglobulin D</span> Antibody isotype

Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum, representing 0.25% of immunoglobulins in serum. The relative molecular mass and half-life of secreted IgD is 185 kDa and 2.8 days, respectively. Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.

<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.

<span class="mw-page-title-main">Immunoglobulin heavy chain</span> Large polypeptide subunit of an antibody

The immunoglobulin heavy chain (IgH) is the large polypeptide subunit of an antibody (immunoglobulin). In human genome, the IgH gene loci are on chromosome 14.

<span class="mw-page-title-main">Antibody opsonization</span> Immune system process

Antibody opsonization is a process by which a pathogen is marked for phagocytosis through coating of a target cell with antibodies. Immunoglobulins participate in molecular tagging of pathogens which display antigens recognised by their specific paratope. The binding of antibodies enhances pathogen identification and recruitment of immune effector cells, ultimately accelerating microbial clearance through phagocytic destruction or antibody-dependent cellular cytotoxicity.

<span class="mw-page-title-main">Protein A</span> Surface protein in bacteria cell walls

Protein A is a 42 kDa surface protein originally found in the cell wall of the bacteria Staphylococcus aureus. It is encoded by the spa gene and its regulation is controlled by DNA topology, cellular osmolarity, and a two-component system called ArlS-ArlR. It has found use in biochemical research because of its ability to bind immunoglobulins. It is composed of five homologous Ig-binding domains that fold into a three-helix bundle. Each domain is able to bind proteins from many mammalian species, most notably IgGs. It binds the heavy chain within the Fc region of most immunoglobulins and also within the Fab region in the case of the human VH3 family. Through these interactions in serum, where IgG molecules are bound in the wrong orientation, the bacteria disrupts opsonization and phagocytosis.

<span class="mw-page-title-main">Fragment crystallizable region</span> Tail region of an antibody

The fragment crystallizable region is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This region allows antibodies to activate the immune system, for example, through binding to Fc receptors. In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains; IgM and IgE Fc regions contain three heavy chain constant domains in each polypeptide chain. The Fc regions of IgGs bear a highly conserved N-glycosylation site. Glycosylation of the Fc fragment is essential for Fc receptor-mediated activity. The N-glycans attached to this site are predominantly core-fucosylated diantennary structures of the complex type. In addition, small amounts of these N-glycans also bear bisecting GlcNAc and α-2,6 linked sialic acid residues.

<span class="mw-page-title-main">Complement component 1q</span> Protein complex

The complement component 1q is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex.

<span class="mw-page-title-main">Immunoglobulin class switching</span> Biological mechanism

Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG. During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same. Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.

<span class="mw-page-title-main">Immunoglobulin light chain</span> Small antibody polypeptide subunit (immunoglobin)

The immunoglobulin light chain is the small polypeptide subunit of an antibody (immunoglobulin).

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

The word allotype comes from two Greek roots, allo meaning 'other or differing from the norm' and typos meaning 'mark'. In immunology, allotype is an immunoglobulin variation that can be found among antibody classes and is manifested by heterogeneity of immunoglobulins present in a single vertebrate species. The structure of immunoglobulin polypeptide chain is dictated and controlled by number of genes encoded in the germ line. However, these genes, as it was discovered by serologic and chemical methods, could be highly polymorphic. This polymorphism is subsequently projected to the overall amino acid structure of antibody chains. Polymorphic epitopes can be present on immunoglobulin constant regions on both heavy and light chains, differing between individuals or ethnic groups and in some cases may pose as immunogenic determinants. Exposure of individuals to a non-self allotype might elicit an anti- allotype response and became cause of problems for example in a patient after transfusion of blood or in a pregnant woman. However, it is important to mention that not all variations in immunoglobulin amino acid sequence pose as a determinant responsible for immune response. Some of these allotypic determinants may be present at places that are not well exposed and therefore can be hardly serologically discriminated. In other cases, variation in one isotype can be compensated by the presence of this determinant on another antibody isotype in one individual. This means that divergent allotype of heavy chain of IgG antibody may be balanced by presence of this allotype on heavy chain of for example IgA antibody and therefore is called isoallotypic variant. Especially large number of polymorphisms were discovered in IgG antibody subclasses. Which were practically used in forensic medicine and in paternity testing, before replaced by modern day DNA fingerprinting.

<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">IgG deficiency</span> Form of immune disorder

IgG deficiency is a form of dysgammaglobulinemia where the proportional levels of the IgG isotype are reduced relative to other immunoglobulin isotypes.

<span class="mw-page-title-main">Lactobacillus vaccine</span> Vaccine using an inactivated strain of Lactobacillus

Lactobacillus vaccines are used in the therapy and prophylaxis of non-specific bacterial vaginitis and trichomoniasis. The vaccines consist of specific inactivated strains of Lactobacilli, called "aberrant" strains in the relevant literature dating from the 1980s. These strains were isolated from the vaginal secretions of patients with acute colpitis. The lactobacilli in question are polymorphic, often shortened or coccoid in shape and do not produce an acidic, anti-pathogenic vaginal environment. A colonization with aberrant lactobacilli has been associated with an increased susceptibility to vaginal infections and a high rate of relapse following antimicrobial treatment. Intramuscular administration of inactivated aberrant lactobacilli provokes a humoral immune response. The production of specific antibodies both in serum and in the vaginal secretion has been demonstrated. As a result of the immune stimulation, the abnormal lactobacilli are inhibited, the population of normal, rod-shaped lactobacilli can grow and exert its defense functions against pathogenic microorganisms.

Anti-immunoglobulin antibodies are defined as a protein that detects other antibodies from an organism. Specifically, anti-immunoglobulin antibodies are created by B-cells as antibodies to bind to other immunoglobulins. Immunoglobulins have two regions: the constant region and the variable region. The constant region is involved in effector function, while the variable region is involved in recognizing and binding to antigens. Anti-immunoglobulin antibodies may bind to either the variable or constant region of the immunoglobulin. Anti-immunoglobulin antibodies are a type of secondary antibody. They are able to detect primary antibodies through multiple methods such as a Western blot, immunohistochemistry, immunofluorescence staining, flow cytometry, and ELISA.

References

  1. 1 2 Janeway, CA; Travers, P; Walport, M; et al. (2001). "Immunobiology: The Immune System in Health and Disease. 5th edition". NCBI. NCBI. Retrieved 2016-01-19.
  2. ↑ Stavnezer, Janet (1996). "Immunoglobulin Class Switching". Current Opinion in Immunology. 8 (2): 199–205. doi:10.1016/s0952-7915(96)80058-6. PMID   8725943.
  3. ↑ Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2002-01-01). "Helper T Cells and Lymphocyte Activation".
  4. ↑ Chandra, Vivek; Bortnick, Alexandra; Murre, Cornelis (2015-09-01). "AID targeting: old mysteries and new challenges". Trends in Immunology. 36 (9): 527–535. doi:10.1016/j.it.2015.07.003. PMC   4567449 . PMID   26254147.
  5. ↑ Chen, J, Boes, M (1998). "A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection". J Exp Med. 188 (12): 2381–6. doi:10.1084/jem.188.12.2381. PMC   2212438 . PMID   9858525.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  7. ↑ Acton, R. T., Barton, J. C. (2016). "Selective Subnormal IgG1 in 54 Adult Index Patients with Frequent or Severe Bacterial Respiratory Tract Infections". J Immunol Res. 2016: 1405950. doi: 10.1155/2016/1405950 . PMC   4830719 . PMID   27123464.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Out, T. A., Kuijpers, T. W. (1992). "IgG subclass deficiencies and recurrent pyogenic infections, unresponsiveness against bacterial polysaccharide antigens". Allergol Immunopathol (Madr). 20 (1): 28–34. PMID   1509985.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Jonsdottir, I., Vidarsson, G. (1998). "Isotypes and opsonophagocytosis of pneumococcus type 6B antibodies elicited in infants and adults by an experimental pneumococcus type 6B-tetanus toxoid vaccine". Infect Immun. 66 (6): 2866–70. doi:10.1128/IAI.66.6.2866-2870.1998. PMC   108283 . PMID   9596761.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Barandun, S., Morell, A. (1972). "IgG subclasses: development of the serum concentrations in "normal" infants and children". J Pediatr. 80 (6): 960–4. doi:10.1016/s0022-3476(72)80007-6. PMID   4623683.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ↑ Smith, C. I., Hassan, M. S. (1991). "Biological half-life of normal and truncated human IgG3 in scid mice". Eur J Immunol. 21 (5): 1319–22. doi:10.1002/eji.1830210534. PMID   2037016. S2CID   45417913.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ Wahren, B., Linde, G. A. (1983). "Virus-specific antibody activity of different subclasses of immunoglobulins G and A in cytomegalovirus infections". Infect Immun. 42 (1): 237–44. doi:10.1128/iai.42.1.237-244.1983. PMC   264549 . PMID   6311746.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ↑ Honjo, T.; Făgărășan, Sidonia (2001). "In situ class switching and differentiation to IgA-producing cells in the gut lamina propria". Nature. 413 (6856): 639–43. Bibcode:2001Natur.413..639F. doi:10.1038/35098100. PMID   11675788. S2CID   4393498.
  14. ↑ Hilschmann, N., Bastian, A. (1992). "Intra- and interchain disulfide bridges of the human J chain in secretory immunoglobulin A". Biol Chem Hoppe-Seyler. 373 (2): 1255–63. doi:10.1515/bchm3.1992.373.2.1255. PMID   1292512.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ↑ Perkins, S. J., Furtado, P. B. (2004). "Solution structure determination of monomeric human IgA2 by X-ray and neutron scattering, analytical ultracentrifugation and constrained modelling: a comparison with monomeric human IgA1". J Mol Biol. 338 (5): 921–41. doi:10.1016/j.jmb.2004.03.007. PMID   15111057.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  17. ↑ Palese, P., Mullarkey, C. E. (2016). "Broadly Neutralizing Hemagglutinin Stalk-Specific Antibodies Induce Potent Phagocytosis of Immune Complexes by Neutrophils in an Fc-Dependent Manner". mBio. 7 (5): e01624-16. doi:10.1128/mBio.01624-16. PMC   5050345 . PMID   27703076.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ↑ van Kooten, C., Heystek, H. C. (2002). "Human immature dendritic cells efficiently bind and take up secretory IgA without the induction of maturation". J Immunol. 168 (1): 102–7. doi: 10.4049/jimmunol.168.1.102 . PMID   11751952.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ↑ Walport M, Janeway CA Jr (2001). Immunobiology: The Immune System in Health and Disease.
  20. ↑ Groenen, P. J, Appenzeller, S. (2015). "Immunoglobulin rearrangement analysis from multiple lesions in the same patient using next-generation sequencing". Histopathology. 67 (6): 843–58. doi:10.1111/his.12714. PMID   25891511. S2CID   36669923.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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