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 doesn't 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]

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. [18] [19]

In amphibians

Frogs can synthesize IgX and IgY. [20]

See also

Related Research Articles

Antibody Immune system protein

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

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 has two antigen binding sites.

Immunoglobulin A Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A is an antibody that plays a crucial 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.

Immunoglobulin D

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.

Immunoglobulin E 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 4 Ig-like constant domains (Cε1-Cε4). IgE's main function is immunity to parasites such as helminths like Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a last line of defense to protect against venoms.

Immunoglobulin M One of several isotypes of antibody

Immunoglobulin M (IgM) is one of several isotypes of antibody that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antigen. In the case of humans and other mammals that have been studied, the spleen, where plasmablasts responsible for antibody production reside, is the major site of specific IgM production.

Single-domain antibody 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.

B-cell receptor

The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell. B cell receptors are composed of immunoglobulin molecules that form a type 1 transmembrane receptor protein, and are 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.

Complementarity-determining region Part of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively

Complementarity-determining regions (CDRs) are part of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively, where these molecules bind to their specific antigen. A set of CDRs constitutes a paratope. As the most variable parts of the molecules, CDRs are crucial to the diversity of antigen specificities generated by lymphocytes.

Fragment crystallizable region 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 property allows antibodies to activate the immune system. 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.

Immunoglobulin class switching Switching of activated B cells from IgM biosynthesis to biosynthesis of other isotypes of immunoglobulin

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.

Immunoglobulin light chain

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

Allotype (immunology)

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.

Isotype (immunology)

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.

CD79A

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.

Humoral immune deficiency

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.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.
  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.
  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.
  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: 1–9. doi: 10.1093/abt/tbaa001 .
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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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