Immunoglobulin M is one of the most common antibodies in our blood. Recent research has now shown that this molecule is composed differently than previously thought: it contains an extra protein called CD5L.
The antibody Immunoglobulin M (IgM) has been studied in laboratories around the world for decades. In the 1990s it was thought that they already had a detailed understanding of how the antibody was put together. But now, several decades later, the antibody appears to still have surprises in store for us: it contains an extra protein. “When you discover something like this first, you think: how is that possible?” According to researcher Albert Heck. “IgM has already been studied by thousands of people. Why are we the first to see this?”
Immunoglobuline M
Let’s start at the beginning. When a pathogen, such as a virus or bacteria, enters our body, our immune system responds by producing IgM. This molecule plays a crucial role in preventing infections by attaching to the pathogen. The pathogen can then no longer bind to a cell and therefore no longer enter the cell.
Structure
For decades, scientists thought they had a good idea of how this essential antibody works. It is a huge molecule that has the shape of a pentamer, or a five-armed shape that resembles a ‘starfish’. This specific structure is described in detail in all common textbooks.
Something isn’t right…
However, Utrecht researchers and colleagues from Amsterdam’s Sanquin simultaneously discovered that something was wrong with the structure described in the textbooks. The two research groups decided to work together to find out exactly what was going on. Using various techniques, the researchers managed to accurately determine the mass of IgM. In this way they discovered that a small protein was missing from the described structure of the antibody.
CD5L
It means that IgM contains an extra protein. And it is the protein CD5L, as can be read in the scientific journal PNAS. Although it was already known that CD5L can bind to IgM, the researchers have now shown for the first time that CD5L is bound to all the IgM present in our blood. In addition, they discovered that the concentrations of both IgM and CD5L in the blood always increase and decrease simultaneously.
The five-armed IgM with the CD5L protein attached (red). Image: Utrecht University
To ask
According to Heck, this discovery raises many new questions. For example, although IgM is produced by B cells – specialized immune cells – it is still unknown where CD5L is produced and where exactly it is linked to IgM. The function of the CD5L protein as part of IgM also remains unclear.
Saliva and milk
What is also remarkable is the fact that IgM in saliva and milk shows no binding at all with CD5L. Heck does have some possible explanations for this. “It’s still speculation, but it could be a form of fine-tuning,” he suggests. “Antibodies are locally adapted to the pathogens they most frequently encounter. And there are different bacteria in your blood than in your mouth or on your skin.” It could also be that CD5L may function as a kind of transport passport. “Perhaps IgM needs CD5L to enter the blood, or CD5L must be surrendered in order to pass from the blood into milk or saliva,” Heck thinks.
Therapeutic applications
All in all, the well-known and essential antibody IgM appears to surprise us quite a bit, even after years of research. Not only does the new insight mean that textbooks on biochemistry and immunology must be revised, the discovery also has consequences for therapeutic applications. “These results put a lot of previous research on so-called free CD5L in a different light, so that it may have to be interpreted differently,” Heck explains. “In addition, companies that now produce IgMs as therapeutic antibodies will have to look carefully at whether they are making the right molecule. And depending on what the precise role of CD5L is, it may be possible to make IgMs that go specifically to the blood or specifically to the saliva.”
The researchers involved plan to continue their study of the formation and function of CD5L together. Because as mentioned, the unexpected discovery raises many new questions, which they hope to answer in further research. Moreover, Heck does not actually find it surprising that something established decades ago turns out not to be entirely accurate. “Thanks to the greatly improved techniques we now use, you can always encounter new things,” he says. “But if you look back at publications from recent years with current knowledge, you see that this really could have been discovered earlier. It clearly shows that if you blindly rely on what is in the textbooks, you can overlook things.”
2023-12-08 16:03:09
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