Immunoglobulin heavy chain

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Schematic diagram of a typical antibody showing two Ig heavy chains (purple) joined by disulfide bonds to two Ig light chains (green). The constant (C) and variable (V) domains are shown. AntibodyChains.svg
Schematic diagram of a typical antibody showing two Ig heavy chains (purple) joined by disulfide bonds to two Ig light chains (green). The constant (C) and variable (V) domains are shown.
An antibody molecule. The two heavy chains are colored red and blue and the two light chains green and yellow. Antibody IgG2.png
An antibody molecule. The two heavy chains are colored red and blue and the two light chains green and yellow.

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.

Contents

A typical antibody is composed of two immunoglobulin (Ig) heavy chains and two Ig light chains. Several different types of heavy chain exist that define the class or isotype of an antibody. These heavy chain types vary between different animals. All heavy chains contain a series of immunoglobulin domains, usually with one variable domain (VH) that is important for binding antigen and several constant domains (CH1, CH2, etc.). Production of a viable heavy chain is a key step in B cell maturation. If the heavy chain is able to bind to a surrogate light chain and move to the plasma membrane, then the developing B cell can begin producing its light chain. [2]

The heavy chain does not always have to bind to a light chain. Pre-B lymphocytes can synthesize heavy chain in the absence of light chain, which then can allow the heavy chain to bind to a heavy-chain binding protein. [3]

In mammals

Classes

There are five types of mammalian immunoglobulin heavy chain: γ, δ, α, μ and ε. [4] They define classes of immunoglobulins: IgG, IgD, IgA, IgM and IgE, respectively.

Regions

Each heavy chain has two regions:

Cows

Cows, specifically Bos taurus , show a variation on the general mammalian theme in which the heavy chain CDR H3 region has adapted to produce a divergent repertoire of antibodies which present a "stalk and knob" antigen interaction surface instead of the more familiar bivalent tip surface. [7] The bovine CDR is unusually long and contains unique sequence attributes which support the production of paired cysteine residues during somatic hypermutation. [7] Thus, where in humans the somatic hypermutation step targets the V(D)J recombination process, the target in cows is on the creation of diverse disulfide bonds and the generation of unique sets of loops which interact with antigen. [7] A speculated evolutionary driver for this variation is the presence of a vastly more diverse microbial environment in the digestive system of the cow as a consequence of their being ruminants. [7]

In fish

Jawed fish appear to be the most primitive animals that are able to make antibodies like those described for mammals. [8] However, fish do not have the same repertoire of antibodies that mammals possess. [9] Three distinct Ig heavy chains have so far been identified in bony fish.

Similar to the situation observed for bony fish, three distinct Ig heavy chain isotypes have been identified in cartilaginous fish. With the exception of μ, these Ig heavy chain isotypes appear to be unique to cartilaginous fish. The resulting antibodies are designated IgW (also called IgX or IgNARC) and IgNAR (immunoglobulin new antigen receptor). [13] [14] The latter type is a heavy-chain antibody, an antibody lacking light chains, and can be used to produce single-domain antibodies, which are essentially the variable domain (VNAR) of an IgNAR. [15] [16] [17] Shark single domain antibodies (VNARs) to tumor or viral antigens can be isolated from a large naïve nurse shark VNAR library using phage display technology. [16] [18]

IgW has now also been found in the group of lobe finned fishes including the coelacanth and lungfish. The IgW1 and IgW2 in coelacanth has a usual (VD)n-Jn-C structure as well as having a large number of constant domains. [19] [20]

In amphibians

Frogs can synthesize IgX and IgY. [21]

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) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are 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">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">Single-domain antibody</span> Antibody fragment

A single-domain antibody (sdAb), also known as a Nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight of only 12–15 kDa, single-domain antibodies are much smaller than common antibodies which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments and single-chain variable fragments.

V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively. The process is a defining feature of the adaptive immune system.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

<span class="mw-page-title-main">Complementarity-determining region</span> Part of the variable chains in immunoglobulins and T cell receptors

Complementarity-determining regions (CDRs) are polypeptide segments of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively. CDRs are where these molecules bind to their specific antigen and their structure/sequence determines the binding activity of the respective antibody. A set of CDRs constitutes a paratope, or the antigen-binding site. As the most variable parts of the molecules, CDRs are crucial to the diversity of antigen specificities generated by lymphocytes.

<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">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">IGHE</span>

Ig epsilon chain C region is a protein that in humans is encoded by the IGHE gene.

<span class="mw-page-title-main">CD79A</span> Mammalian protein found in Homo sapiens

Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.

<span class="mw-page-title-main">Humoral immune deficiency</span> Medical condition

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population. They are associated with increased vulnerability to infection, but can be difficult to detect in the absence of infection.

A heavy-chain antibody is an antibody which consists only of two heavy chains and lacks the two light chains usually found in antibodies.

Antibody structure is made up of two heavy-chains and two light-chains. These chains are held together by disulfide bonds. The arrangement or processes that put together different parts of this antibody molecule play important role in antibody diversity and production of different subclasses or classes of antibodies. The organization and processes take place during the development and differentiation of B cells. That is, the controlled gene expression during transcription and translation coupled with the rearrangements of immunoglobulin gene segments result in the generation of antibody repertoire during development and maturation of B cells.

Recombinant antibodies are antibody fragments produced by using recombinant antibody coding genes. They mostly consist of a heavy and light chain of the variable region of immunoglobulin. Recombinant antibodies have many advantages in both medical and research applications, which make them a popular subject of exploration and new production against specific targets. The most commonly used form is the single chain variable fragment (scFv), which has shown the most promising traits exploitable in human medicine and research. In contrast to monoclonal antibodies produced by hybridoma technology, which may lose the capacity to produce the desired antibody over time or the antibody may undergo unwanted changes, which affect its functionality, recombinant antibodies produced in phage display maintain high standard of specificity and low immunogenicity.

References

  1. ↑ "Archived copy". Archived from the original on April 19, 2007. Retrieved April 20, 2007.{{cite web}}: CS1 maint: archived copy as title (link)[ full citation needed ]
  2. ↑ Mårtensson, I-L; Ceredig, R (2017-01-23). "Role of the surrogate light chain and the pre-B-cell receptor in mouse B-cell development". Immunology. 101 (4): 435–441. doi:10.1046/j.1365-2567.2000.00151.x. ISSN   0019-2805. PMC   2327112 . PMID   11122446.
  3. ↑ Haas, Ingrid G.; Wabl, Matthias (1983). "Immunoglobulin heavy chain binding protein". Nature. 306 (5941): 387–9. Bibcode:1983Natur.306..387H. doi:10.1038/306387a0. PMID   6417546. S2CID   4247626.
  4. 1 2 3 Janeway CA, Jr.; et al. (2001). Immunobiology (5th ed.). Garland Publishing. ISBN   0-8153-3642-X. (electronic full text via NCBI Bookshelf).[ page needed ]
  5. ↑ Woof, Jenny M.; Burton, Dennis R. (2004). "Human antibody–Fc receptor interactions illuminated by crystal structures". Nature Reviews Immunology. 4 (2): 89–99. doi:10.1038/nri1266. PMID   15040582. S2CID   30584218.
  6. ↑ "The Biology Project". Antibody Structure. The University of Arizona. Retrieved May 27, 2020.
  7. 1 2 3 4 Wang, Feng; Ekiert, Damian C.; Ahmad, Insha; Yu, Wenli; Zhang, Yong; Bazirgan, Omar; Torkamani, Ali; Raudsepp, Terje; Mwangi, Waithaka; Criscitiello, Michael F.; Wilson, Ian A.; Schultz, Peter G.; Smider, Vaughn V. (2013). "Reshaping Antibody Diversity". Cell. 153 (6): 1379–93. doi:10.1016/j.cell.2013.04.049. PMC   4007204 . PMID   23746848.
  8. ↑ Fish heavy chain and light chain genes [ full citation needed ] Archived March 23, 2007, at the Wayback Machine
  9. ↑ Bengtén, Eva; Clem, L. William; Miller, Norman W.; Warr, Gregory W.; Wilson, Melanie (2006). "Channel catfish immunoglobulins: Repertoire and expression". Developmental & Comparative Immunology. 30 (1–2): 77–92. doi:10.1016/j.dci.2005.06.016. PMID   16153707.
  10. ↑ Solem, Stein Tore; Stenvik, Jørgen (2006). "Antibody repertoire development in teleosts—a review with emphasis on salmonids and Gadus morhua L". Developmental & Comparative Immunology. 30 (1–2): 57–76. doi:10.1016/j.dci.2005.06.007. PMID   16084588.
  11. ↑ Hansen, J. D.; Landis, E. D.; Phillips, R. B. (2005). "Discovery of a unique Ig heavy-chain isotype (IgT) in rainbow trout: Implications for a distinctive B cell developmental pathway in teleost fish". Proceedings of the National Academy of Sciences. 102 (19): 6919–6924. Bibcode:2005PNAS..102.6919H. doi: 10.1073/pnas.0500027102 . JSTOR   3375456. PMC   1100771 . PMID   15863615.
  12. ↑ Danilova, Nadia; Bussmann, Jeroen; Jekosch, Kerstin; Steiner, Lisa A (2005). "The immunoglobulin heavy-chain locus in zebrafish: Identification and expression of a previously unknown isotype, immunoglobulin Z". Nature Immunology. 6 (3): 295–302. doi:10.1038/ni1166. PMID   15685175. S2CID   5543330.
  13. ↑ Dooley, H.; Flajnik, M.F. (2006). "Antibody repertoire development in cartilaginous fish". Developmental & Comparative Immunology. 30 (1–2): 43–56. doi:10.1016/j.dci.2005.06.022. PMID   16146649.
  14. ↑ Simmons, David P.; Abregu, Fiona A.; Krishnan, Usha V.; Proll, David F.; Streltsov, Victor A.; Doughty, Larissa; Hattarki, Meghan K.; Nuttall, Stewart D. (2006). "Dimerisation strategies for shark IgNAR single domain antibody fragments". Journal of Immunological Methods. 315 (1–2): 171–84. doi:10.1016/j.jim.2006.07.019. PMID   16962608.
  15. ↑ Wesolowski, Janusz; Alzogaray, Vanina; Reyelt, Jan; Unger, Mandy; Juarez, Karla; Urrutia, Mariela; Cauerhff, Ana; Danquah, Welbeck; Rissiek, Björn; Scheuplein, Felix; Schwarz, Nicole; Adriouch, Sahil; Boyer, Olivier; Seman, Michel; Licea, Alexei; Serreze, David V.; Goldbaum, Fernando A.; Haag, Friedrich; Koch-Nolte, Friedrich (2009). "Single domain antibodies: Promising experimental and therapeutic tools in infection and immunity". Medical Microbiology and Immunology. 198 (3): 157–74. doi:10.1007/s00430-009-0116-7. PMC   2714450 . PMID   19529959.
  16. 1 2 Feng, Mingqian; Bian, Hejiao; Wu, Xiaolin; Fu, Tianyun; Fu, Ying; Hong, Jessica; Fleming, Bryan D.; Flajnik, Martin F.; Ho, Mitchell (January 2019). "Construction and next-generation sequencing analysis of a large phage-displayed VNAR single-domain antibody library from six naïve nurse sharks". Antibody Therapeutics. 2 (1): 1–11. doi:10.1093/abt/tby011. ISSN   2516-4236. PMC   6312525 . PMID   30627698.
  17. ↑ English, Hejiao; Hong, Jessica; Ho, Mitchell (2020). "Ancient species offers contemporary therapeutics: an update on shark VNAR single domain antibody sequences, phage libraries and potential clinical applications". Antibody Therapeutics. 3 (1): 1–9. doi: 10.1093/abt/tbaa001 . PMC   7034638 . PMID   32118195.
  18. ↑ Li, Dan; English, Hejiao; Hong, Jessica; Liang, Tianyuzhou; Merlino, Glenn; Day, Chi-Ping; Ho, Mitchell (2021-07-21). "A novel PD-L1-targeted shark VNAR single domain-based CAR-T strategy for treating breast cancer and liver cancer": 2021.07.20.453144. doi:10.1101/2021.07.20.453144. S2CID   236203365.{{cite journal}}: Cite journal requires |journal= (help)
  19. ↑ Zhang, Tianyi; Tacchi, Luca; Wei, Zhiguo; Zhao, Yaofeng; Salinas, Irene (2014). "Intraclass diversification of immunoglobulin heavy chain genes in the African lungfish". Immunogenetics. 66 (5): 335–51. doi:10.1007/s00251-014-0769-2. PMC   4348116 . PMID   24676685.
  20. ↑ Ota, T.; Rast, J. P.; Litman, G. W.; Amemiya, C. T. (2003). "Lineage-restricted retention of a primitive immunoglobulin heavy chain isotype within the Dipnoi reveals an evolutionary paradox". Proceedings of the National Academy of Sciences. 100 (5): 2501–6. Bibcode:2003PNAS..100.2501O. doi: 10.1073/pnas.0538029100 . PMC   151370 . PMID   12606718.
  21. ↑ Du, Christina C.; Mashoof, Sara M.; Criscitiello, Michael F. (2012). "Oral immunization of the African clawed frog (Xenopus laevis) upregulates the mucosal immunoglobulin IgX". Veterinary Immunology and Immunopathology. 145 (1–2): 493–8. doi:10.1016/j.vetimm.2011.10.019. PMC   3273591 . PMID   22100190.
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