Immunoglobulins play a vital role in our immune system, where their main job is to identify and neutralize foreign substances such as bacteria and viruses. Immunoglobulin M (IgM), one of the five types of antibodies, stands out due to its unique capability of polymerization. IgM is produced by B lymphocytes and is the earliest type of antibody that is expressed on the cell surface in response to antigens. Every IgM antibody molecule is made up of five or six single units, or monomers, that are interconnected via disulfide bonds along with a J-chain peptide. These linkages form larger molecules that are either pentamers or hexamers. The ability to polymerize in such a manner is unique to IgM, and it grants it a high valency. This means that it can bind to multiple mannose residues on pathogens at once, enhancing its effectiveness in neutralizing threats to our bodies. This article aims to explicate the process through which this polymerization takes place.
Polymerization of IgM
The polymerization process of IgM commences in the endoplasmic reticulum (ER) of B cells. Each IgM monomer is made up of two heavy chains and two light chains linked by disulfide bonds. The heavy chains contain an extra domain, named Mu, which is significant for the polymerization process. Cysteine residues in the C-terminal of the Mu domain play a critical role in the polymerization. These residues can form disulfide bonds with residues in other monomeric units, leading to the formation of pentamers or hexamers. Experimental evidence shows that the cysteine residues C414, C575, and C414 in the invariant region play a critical part in this process. After the initial formation of the pentameric or hexameric structure, an additional peptide chain, the J-chain, is incorporated. The J-chain facilitates the formation of disulfide bonds between adjacent monomers, thereby stabilizing the entire polymer. Furthermore, the J-chain also has a critical role in IgM secretion from B cells, helping transport IgM to the cell surface and aiding with the binding to the poly Ig receptor, which enables subsequent transcytosis across epithelial cells.
Fig 1. A model for IgM polymerization.1
Role of ER Chaperone Proteins in IgM Polymerization
The interplay between ER chaperone proteins such as calnexin and BiP, and enzymes involved in disulphide bond formation, like protein disulphide isomerase (PDI), also plays a significant role in IgM polymerization. These proteins assist in proper folding of the Mu domain, and the formation of inter-chain disulphide bonds, therefore ensuring the correct assembly and, consequently, the functionality of the IgM molecule. The polymerization of IgM dramatically amplifies its antigen-binding capabilities, strengthening immunity. However, aberrant polymerization can lead to the formation of poorly functioning IgM or even the induction of the unfolded protein response, leading to cellular stress and potentially B cell death. Hence, understanding the fundamental mechanism of IgM polymerization is vital for elucidating B cell biology and immunity against pathogens.
Despite substantial progress in understanding the mechanism of IgM polymerization, several questions remain unanswered, such as the exact role of different chaperones and co-chaperones, and how exactly ER-based quality control mechanisms ensure the accurate assembly of IgM. Moreover, any dysregulation in the process leading to dysfunctions in B cells or autoimmune responses needs extensive scrutiny. Future research in these areas will provide greater insight into B cell functionality and its mechanisms to ward off pathogens. At Creative Biolabs, our team of professionals provides a wide range of non-IgG antibody development services to clients around the globe. In addition, we can provide a full range of IgM antibodies from different species, such as rat, mouse, and Armenian hamster for different applications. If you have any related needs, please feel free to contact us for more information and a detailed quote.
Reference
- Giannone, Chiara, et al. "Biogenesis of secretory immunoglobulin M requires intermediate non‐native disulfide bonds and engagement of the protein disulfide isomerase ERp44." The EMBO Journal 41.3 (2022): e108518.
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