Antibodies, protective proteins produced by the immune system, play critical roles in the identification and elimination of abnormal substances or antigens within organisms. While their functions are universal, the structure of antibodies varies across different species. In a recent study, the structure of the IgM antibody in the rainbow trout was analyzed, shedding light on how the IgM evolved. Polymeric forms of IgM contain five IgM monomers and one joining chain or six IgM monomers, allowing for the binding to multiple antigens at once for their rapid elimination. Unique to IgM is its presence in both the blood and mucous membranes, a moist tissue that lines various passages in the body such as the nose, mouth, and intestines.
Differences in Immunoglobulin Between Fish and Mammals
Researchers have been studying fish and mammals due to the great differences in their immune systems' evolution, and how these dissimilar evolutions account for their varying methods of antibody production. For instance, a key difference in antibody function between fish and humans is that fish mucosa includes the skin which is frequently exposed to the environment, hence, their antibodies must be structurally stable enough to withstand being washed away by water. Unlike humans, they may encounter an entirely different set of antigens. Fish lack joining chains that bind the tails of five independent units together, forming a sturdy star-shaped antibody. Fish IgM contains only four repeating units instead of humans' five. These variances lead scientists to explore how stable IgM is achieved in fish, and how it performs its function. To gain a better understanding of the structure of fish IgM, IgM from the rainbow trout was utilized in the study.
Fig 1. Comparison of IgM structures from trout and humans.1
The Structural and Functional Differences of Fish IgM
Most research thus far centred on the antibody-antigen binding or the structure of single-unit antibodies. The study of antibodies with multiple units, or polymer antibodies like IgM, only became viable in recent years with the advent of high-resolution cryo-electron microscopy. In humans, each repeating unit of IgM resembles a Y-shape, where two 'hands' bind to antigens, and a 'stem' forms part of the star shape's central core together with the joining chains. Fish IgM units share a similar structure, but interestingly, the researchers discovered that they fold differently at the tail within the core, allowing them to interact with each other without the need for joining chains. This marked the first identification of the structure of fish antibodies. It revealed the assembly of fish IgM in a completely novel manner, demonstrating a distinct structure, in the absence of joining chains, a requirement in the assembly of the majority of IgM in birds and mammals. From an evolutionary perspective, it enlightens us that fish IgM operates differently from human IgM while performing similar antigen binding functions.
Opportunity in Antibody Heterogeneity for Novel Therapies
It remains unclear why teleost fish lack joining chains, but what is evident is that they have evolved a unique method of producing IgMs without joining chains. This methodology might lead to a more stable structure or provide a functional advantage, especially given the different antigens encountered by fish and the various components of their immune system. The research team is now working on constructing the full length IgM, including the currently missing segments. The heterogeneity of antibodies such as those from birds and fish is seen as an opportunity to create novel therapeutic antibodies using this newfound understanding. The study is a prime example of how structural biology can contribute to exploring antibody function differences and enhance our understanding of antibody evolution.
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Reference
- Lyu, Mengfan, Andrey G. Malyutin, and Beth M. Stadtmueller. "The structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function." Nature communications 14.1 (2023): 7583.
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