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.
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.
Heavy chains α and γ have approximately 450 amino acids.
Heavy chains μ and ε have approximately 550 amino acids.[4]
Regions
Each heavy chain has two regions:
a constant region (which is the same for all immunoglobulins of the same class but differs between classes).
Heavy chains γ, α and δ have a constant region composed of three tandem (in a line next to each other) immunoglobulin domains but also have a hinge region for added flexibility.[5]
Heavy chains μ and ε have a constant region composed of four domains.[4]
a variable region that differs between different
B cells, but is the same for all immunoglobulins produced by the same B cell or B cell
clone. The variable domain of any heavy chain is composed of a single immunoglobulin domain. These domains are about 110 amino acids long.[6]
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.
The first identified was the μ (or mu) heavy chain that is present in all jawed fish and is the heavy chain for what is thought to be the primordial immunoglobulin. The resulting antibody, IgM, is secreted as a
tetramer in
teleost fish instead of the typical
pentamer found in mammals and sharks.[citation needed]
The heavy chain (δ) for IgD was identified initially from the
channel catfish and
Atlantic salmon and is now well documented for many teleost fish.[10]
The third teleost Ig heavy chain gene was identified very recently and does not resemble any of the heavy chains so far described for mammals. This heavy chain, identified in both
rainbow trout (τ)[11] and
zebrafish (ζ),[12] could potentially form a distinct antibody
isotype (IgT or IgZ) that may precede IgM in evolutionary terms.
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]
^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.
PMID16153707.
^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.
PMID16084588.
^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.
PMID15685175.
S2CID5543330.
^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.
PMID16146649.
^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.
PMID16962608.