J chain

{{Short description|Protein-coding gene in the species Homo sapiens}}

Image:IgM.pngic antibody molecule (consisting of five base units).
1: Base unit.
2: Heavy chains.
3: Light chains.
4: J chain.
5: Intermolecular disulfide bonds.]]

Image:Dimeric IgA schematic 01.svg showing H-chain (blue), L-chain (red), J-chain (magenta) and secretory component (yellow).]]

The Joining (J) chain is a protein component that links monomers of antibodies IgM and IgA to form polymeric antibodies capable of secretion.{{cite book | publisher = McGraw Hill | title = Medical Microbiology and Immunology | author = Levinson | edition = 11 | pages= 405–6}} 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,{{cite book | vauthors = Schroeder H, Wald D, Greenspan N |title=Fundamental Immunology |publisher=Lippincott Williams & Wilkins |year=2008 |isbn=978-0-7817-6519-0 | veditors = Paul W |edition=6th |location=Philadelphia, PA |pages=125–151 |chapter=Chapter 4: Immunoglobulins: Structure and Function |type=Book}} encoded by the IGJ gene.{{cite journal | vauthors = Max EE, McBride OW, Morton CC, Robinson MA | title = Human J chain gene: chromosomal localization and associated restriction fragment length polymorphisms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 15 | pages = 5592–5596 | date = August 1986 | pmid = 3016707 | pmc = 386334 | doi = 10.1073/pnas.83.15.5592 | doi-access = free | bibcode = 1986PNAS...83.5592M }}{{cite journal | vauthors = Max EE, Korsmeyer SJ | title = Human J chain gene. Structure and expression in B lymphoid cells | journal = The Journal of Experimental Medicine | volume = 161 | issue = 4 | pages = 832–849 | date = April 1985 | pmid = 2984306 | pmc = 2189063 | doi = 10.1084/jem.161.4.832 }}{{cite web | title = Entrez Gene: IGJ immunoglobulin J polypeptide, linker protein for immunoglobulin alpha and mu polypeptides| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3512}}

Structure

The J chain is a glycoprotein of molecular weight 15 kDa. Its secondary structure remains undetermined but is believed to adopt either a single β-barrel or two-domain folded structure with standard immunoglobulin domains.{{cite journal | vauthors = Frutiger S, Hughes GJ, Paquet N, Lüthy R, Jaton JC | title = Disulfide bond assignment in human J chain and its covalent pairing with immunoglobulin M | journal = Biochemistry | volume = 31 | issue = 50 | pages = 12643–12647 | date = December 1992 | doi = 10.1021/bi00165a014 | pmid = 1472500 | url = https://pubs.acs.org/doi/pdf/10.1021/bi00165a014 | url-access = subscription }} The J chain's primary structure is unusually acidic having a high content of negatively charged amino acids.{{cite journal | vauthors = Klimovich VB, Samoĭlovich MP, Klimovich BV | title = [Problem of J-chain of immunoglobulins] | journal = Zhurnal Evoliutsionnoi Biokhimii I Fiziologii | volume = 44 | issue = 2 | pages = 131–143 | date = 2008-04-01 | pmid = 18669274 | doi = 10.1134/S0022093008020023 | s2cid = 20628313 }} It has 8 cysteine residues, 6 of which are involved in intramolecular disulfide bonds while the remaining two function to bind the Fc tailpiece regions of IgA or IgM antibodies, the α chain and μ chain respectively. An N-linked carbohydrate resulting from N-glycosylation is also essential in the protein's incorporation to antibody polymers.{{cite journal | vauthors = Sørensen V, Rasmussen IB, Sundvold V, Michaelsen TE, Sandlie I | title = Structural requirements for incorporation of J chain into human IgM and IgA | journal = International Immunology | volume = 12 | issue = 1 | pages = 19–27 | date = January 2000 | doi = 10.1093/intimm/12.1.19 | pmid = 10607746 | url = https://www.academia.edu/22086121 | doi-access = free }} There is no known protein family with significant homology to the J chain.{{cite journal | vauthors = Castro CD, Flajnik MF | title = Putting J chain back on the map: how might its expression define plasma cell development? | journal = Journal of Immunology | volume = 193 | issue = 7 | pages = 3248–3255 | date = October 2014 | pmid = 25240020 | pmc = 4198949 | doi = 10.4049/jimmunol.1400531 }}

Function

= Antibody polymerization =

The J chain regulates the multimerization of IgM and IgA in mammals. When expressed in cells, it favors the formation of a pentameric IgM and an IgA dimer. IgM pentamers are most commonly found with a single J chain, but some studies have seen as many as 4 J chains associated to a single IgM pentamer.

The J chain is incorporated late in the formation of IgM polymers and thermodynamically favors the formation of pentamers as opposed to hexamers. In J chain-knockout (KO) mice, the hexameric IgM polymer dominates.{{cite journal | vauthors = Davis AC, Roux KH, Shulman MJ | title = On the structure of polymeric IgM | journal = European Journal of Immunology | volume = 18 | issue = 7 | pages = 1001–1008 | date = July 1988 | doi = 10.1002/eji.1830180705 | pmid = 3136022 | s2cid = 34679165 | url = https://onlinelibrary.wiley.com/doi/10.1002/eji.1830180705 | url-access = subscription }} These J chain negative IgM hexamers are 15-20 times more effective at activating complement than J chain positive IgM pentamers.{{cite journal | vauthors = Johansen FE, Braathen R, Brandtzaeg P | title = Role of J chain in secretory immunoglobulin formation | journal = Scandinavian Journal of Immunology | volume = 52 | issue = 3 | pages = 240–248 | date = September 2000 | doi = 10.1046/j.1365-3083.2000.00790.x | pmid = 10972899 | s2cid = 5958810 | doi-access = free }} However, J chain-KO mice have been shown have low concentrations of hexameric IgM and a deficiency in complement activation, suggesting additional in vivo regulatory mechanisms.{{cite journal | vauthors = Erlandsson L, Andersson K, Sigvardsson M, Lycke N, Leanderson T | title = Mice with an inactivated joining chain locus have perturbed IgM secretion | journal = European Journal of Immunology | volume = 28 | issue = 8 | pages = 2355–2365 | date = August 1998 | doi = 10.1002/(SICI)1521-4141(199808)28:08<2355::AID-IMMU2355>3.0.CO;2-L | pmid = 9710213 | s2cid = 21659055 | doi-access = free }} Another consequence of pentameric IgM reduced complement activation is its allowance of J chain positive pIgM to bind antigen without causing excessive damage to epithelial membranes through complement activation.{{cite journal | vauthors = Grubb AO | title = Quantitation of J chain in human biological fluids by a simple immunochemical procedure | journal = Acta Medica Scandinavica | volume = 204 | issue = 6 | pages = 453–465 | date = 2009-04-24 | pmid = 104551 | doi = 10.1111/j.0954-6820.1978.tb08473.x }}

The J chain facilitates IgA dimerization by linking two monomer secretory tails. Structurally, the J chain joins two antibody monomers asymmetrically by forming intermolecular disulfide bonds and bringing hydrophobic β-sandwiches on each molecule together.{{cite journal | vauthors = Kumar N, Arthur CP, Ciferri C, Matsumoto ML | title = Structure of the secretory immunoglobulin A core | journal = Science | volume = 367 | issue = 6481 | pages = 1008–1014 | date = February 2020 | pmid = 32029686 | doi = 10.1126/science.aaz5807 | bibcode = 2020Sci...367.1008K | s2cid = 211050348 | doi-access = free }} This multimerization mechanism involves chaperone proteins including binding immunoglobulin protein (BiP) and MZB1 each sequentially recruiting distinct factors of the polymerized antibody.{{cite journal | vauthors = Wei H, Wang JY | title = Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis | journal = International Journal of Molecular Sciences | volume = 22 | issue = 5 | pages = 2284 | date = February 2021 | doi = 10.3390/ijms22052284 | pmid = 33668983 | pmc = 7956327 | doi-access = free }}

= Antibody secretion =

Mucosal membrane antibody secretion from the basal membrane to apical epithelial cells is facilitated by the polymeric Ig receptor (pIgR). A basal protein of the pIgR known as secretory component (SC) recognizes Ig ready for secretion.{{cite journal | vauthors = Stadtmueller BM, Huey-Tubman KE, López CJ, Yang Z, Hubbell WL, Bjorkman PJ | title = The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins | journal = eLife | volume = 5 | pages = e10640 | date = March 2016 | pmid = 26943617 | pmc = 4786434 | doi = 10.7554/eLife.10640 | veditors = Kuriyan J | doi-access = free }} The binding between the secretory component and secretory Ig is facilitated by the antibody's J chain which makes physical contact with the secretory component in order to change the transporter's conformation to an open state.{{cite journal | vauthors = Braathen R, Hohman VS, Brandtzaeg P, Johansen FE | title = Secretory antibody formation: conserved binding interactions between J chain and polymeric Ig receptor from humans and amphibians | journal = Journal of Immunology | volume = 178 | issue = 3 | pages = 1589–1597 | date = February 2007 | doi = 10.4049/jimmunol.178.3.1589 | pmid = 17237408 | s2cid = 27721152 | url = https://journals.aai.org/jimmunol/article/178/3/1589/74149 | doi-access = free }} The complex is then transcytosed and the secretory component proteolytically cleaved from the receptor releasing the antibody to the apical side of the epithelial cell and to the lumen at large. This mechanism is thought to be largely conserved between the secretion of IgM and IgA.

Regulation

J chain was originally believed to only be expressed in antibody-secreting plasma cells, however, the J chain has been seen to be expressed in earlier stages of B cell differentiation prior to Ig expression.{{cite journal | vauthors = Mestecky J, Fultz PN | title = Mucosal immune system of the human genital tract | journal = The Journal of Infectious Diseases | volume = 179 | issue = Suppl 3 | pages = S470–S474 | date = May 1999 | doi = 10.1086/314806 | pmid = 10099122 | jstor = 30114178 | doi-access = free }} J chain expression is believed to occur in the early stages of lymphoid cell differentiation as it is expressed in both B and T cell precursors. As cells develop, it seems that expression of the μ-chain becomes necessary for J chain synthesis.{{cite journal | vauthors = Max EE, Korsmeyer SJ | title = Human J chain gene. Structure and expression in B lymphoid cells | journal = The Journal of Experimental Medicine | volume = 161 | issue = 4 | pages = 832–849 | date = April 1985 | pmid = 2984306 | pmc = 2189063 | doi = 10.1084/jem.161.4.832 }}

The J chain gene is transcriptionally regulated through canonical Pax5 repression.{{cite journal | vauthors = Rao S, Karray S, Gackstetter ER, Koshland ME | title = Myocyte enhancer factor-related B-MEF2 is developmentally expressed in B cells and regulates the immunoglobulin J chain promoter | journal = The Journal of Biological Chemistry | volume = 273 | issue = 40 | pages = 26123–26129 | date = October 1998 | pmid = 9748293 | doi = 10.1074/jbc.273.40.26123 | doi-access = free }} As Pax5 is a common transcriptional regulator, the J chain is still expressed in plasma cells that secrete monomeric antibodies. In such cells it is believed to provide no function and is quickly degraded. In plasma cells that secrete monomeric IgA, a Pax5-independent mechanism is likely to prevent IgA dimerization.{{cite journal | vauthors = Hajdu I, Moldoveanu Z, Cooper MD, Mestecky J | title = Ultrastructural studies of human lymphoid cells. mu and J chain expression as a function of B cell differentiation | journal = The Journal of Experimental Medicine | volume = 158 | issue = 6 | pages = 1993–2006 | date = December 1983 | pmid = 6417260 | pmc = 2187181 | doi = 10.1084/jem.158.6.1993 }}

Phylogeny

The J chain is likely to have evolutionarily arisen in early jaw-boned vertebrates.{{cite journal | vauthors = Marchalonis J, Edelman GM | title = Phylogenetic origins of antibody structure. I. Multichain structure of immunoglobulins in the smooth dogfish (Mustelus canis) | journal = The Journal of Experimental Medicine | volume = 122 | issue = 3 | pages = 601–618 | date = September 1965 | doi = 10.1084/jem.122.3.601 | pmid = 4158437 | pmc = 2138074 }} Groups of bony fish including teleosts have since lost J chain expression. Xenopus are able to polymerize mucosal IgX in the absence of J chain, perhaps due to a loss of the conserved cysteine residues that link the J chain and Ig secretory tail.{{cite journal | vauthors = Robert J, Ohta Y | title = Comparative and developmental study of the immune system in Xenopus | journal = Developmental Dynamics | volume = 238 | issue = 6 | pages = 1249–1270 | date = June 2009 | doi = 10.1002/dvdy.21891 | pmid = 19253402 | pmc = 2892269 }}

Sharks do not express IgA and thus use J chain expression solely for the polymerization of IgM.{{cite journal | vauthors = Clem IW, De Boutaud F, Sigel MM | title = Phylogeny of immunoglobulin structure and function. II. Immunoglobulins of the nurse shark | journal = Journal of Immunology | volume = 99 | issue = 6 | pages = 1226–1235 | date = December 1967 | doi = 10.4049/jimmunol.99.6.1226 | pmid = 4168665 | doi-access = free }} This makes sharks an intriguing model organism in studying J chain regulation and polymerization without the confounding variables of mucosal secretion.{{cite journal | vauthors = Hohman VS, Stewart SE, Rumfelt LL, Greenberg AS, Avila DW, Flajnik MF, Steiner LA | title = J chain in the nurse shark: implications for function in a lower vertebrate | journal = Journal of Immunology | volume = 170 | issue = 12 | pages = 6016–6023 | date = June 2003 | pmid = 12794129 | doi = 10.4049/jimmunol.170.12.6016 | s2cid = 292191 | doi-access = free }}