The immune system is vital - therefore researchers have believed it is not as affected by evolution. Research on cod shows that it is probably more complex.
"Cod is no more sick than other fish", says molecular biologist Synne Arstad Bjørnestad from the Department of Biosciences at the University of Oslo.
She researches the immune system of cod and has recently published an article in which she has looked at one possible explanation for how codfishes manage to compensate for their immunological deficiency.
"We like to say that cod has an immunological deficiency, but it is important to specify that this statement can be made only as we compare different immune systems and use the human immune system as the “best” solution. It is not certain that the human immune system should be the model of what a good immune system is, at least not for all vertebrates", she says.
The cod genus lacks the gene for the part of the immune system called MHC class II and a group of other genes necessary for the function of MHC class II. This means that MHC class II does not work in cod.
The function of MHC class II is in brief to defend the body against bacteria and parasites. Humans with a damaged MHC class II will become seriously ill and die, but the cod survives. That has scientists scratching their heads.
"One explanation of how cod can make up for this deficiency is that it has expanded other parts of the immune system, including the closely related reaction pathway involving MHC class I", explains Bjørnestad.
Thus began the search investigating whether this is true.
What is MHC?
MHC stands for major histocompatibility complex. In Norwegian, this is called the tissue compatibility gene complex, according to Store Norske Leksikon.
We have two classes of MHC – class I and II.
Both MHC classes present protein fragments on the cell surface thus constituting a type of surface molecule that is part of the immune system. During the Covid-19 pandemic, there was a lot of talk about "spike proteins", which are an example of proteins that are fragmented and presented onto MHC to initiate an immune response by activating white blood cells.
MHC class II is part of the immune system used for recognizing intruders circulating the body. It is often called the bacterial defense.
MHC class I is the part of the immune system that reports on what is inside the cells, for example in the case of a viral infection.
What does MHC class II do?
MHC class II is part of the immune system which is called the adaptive system. In human, it is the part that "learns" and therefore adapts, so the body can for example, recognize bacteria that we have been vaccinated against or diseases we have had before. MHC class I is roughly the part that picks up small protein fragments that are inside the cell. These will often be fragments of viruses. MHC class II, on the other hand, picks up protein fragments from invaders that are on the outside of the cell, such as bacteria or parasites. The protein fragments that are picked up by MHC class I and II are transported to the cell surface where the body's immune cells (T cells) can "read" the fragments. If the fragment originates from an intruder, the body will detect the intruder by activating the T cells thus initiating the alarm system. The MHC class II is the part of the immune system that codfishes lack, but apparently do well without.
"We see that the cod has far more gene copies of MHC class I than we see in other species. One theory is that some of these gene variants of MHC class I can carry out what we call cross-presentation to a greater extent. This means that MHC class I takes over some of the role of MHC class II by binding protein fragments originating from outside the cell, thus some of the function of MHC class II can be compensated for", says Bjørnestad.
By analyzing where the different MHC class I variants are located in cod cells, she and other researchers have demonstrated that the hypothesis of increased cross-presentation might be correct. They find MHC class I where they would expected to find MHC class II.
Want to understand more about the immune system
Bjørnestad believes that the research findings in the article is interesting. It is an example of a possible adaptation where, instead of using two very closely related reaction pathways, the cod only uses one reaction pathway with an increased number and more versatile MHC class I molecules.
"MHC I and II are highly conserved gene regions in most vertebrates, but the cod genus lost MHC class II around 100 million years ago", she says.
However, it is not the case that MHC class II loss is unique to codfish. Loss of MHC II or parts of its reaction pathway has also been documented in other groups of fish species, including pipefish, seahorses and Lophiformes (which includes monkfish). These losses in the three groups mentioned (codfish, pipefish and seahorse, as well as Lophiformes) are independent events - with no direct connection. Furthermore, there are also examples of species with intact MHC class II, but with expanded MHC class I, such as, for example, Percomorpha (Perciformes), which is the most species-rich group of bony fish. There are far more species of Percomorpha than there are mammals.
Cod can be important for medical research
The genes for the immune system are believed to be "conserved" across species. This means that there are few evolutionary changes over a long period of time. Now it seems that this is not true, and Bjørnestad finds it interesting to understand how the immune system of other species works.
This means that the immune system is more dynamic than we have thought.
"It then becomes dangerous to use humans, or mice, as a model organism to understand how it works in other species", she says.
The notion held by many immunologists and cell biologists that the mouse and human immune system is the best model for all vertebrates is wrong. It may apply to mammals, but not to fish, where many different variants of the immune system have recently been discovered.
Although this is basic research, Bjørnestad believes the knowledge is important. The deficiency in cod can indeed make it an interesting model organism for understanding how disease in humans with defective MHC class II can possibly be overcome in the future.
Moreover, attempts have been made to farm cod, however it has worked poorly as cod does not respond to vaccination like other farmed fish, due to their distinct immune system. When scientists understand the cod's immune system better, we will possibly be able to develop new strategies for vaccination, and who knows, maybe it will also be useful if there is another pandemic?
"The cod is completely healthy. It is not sicker than other fish, but it lacks an important part of the adaptive immune system which is central to the production of antibodies with increased specificity and ability to fight pathogens. Without MHC class II, the cod is unable to produce specific antibodies against pathogens or when vaccinated. Nevertheless, cod are healthy in their natural environment, and they develop immunity to pathogens, but this immunity is not based on antibodies. Cod has an innate immune system and here we also see big differences compared to other species. Most likely, cod uses the interplay between the innate and adaptive immune systems to a greater extent. Understanding more about this interplay is exciting. There is a lot we still don't know, thus more knowledge about this is important", she says.
It may have been a "cod pandemic" that led to the change
Bjørnestad says it is possible that it was a disease that led to the change in the immune system.
"The reason why the cod genus may have lost MHC class II may be the result of a disease that used a receptor on the white blood cells to infect the cell, somewhat the same as with HIV in humans", says Bjørnestad.
MHC class II cooperates with a type of white blood cell that has a receptor on its surface called CD4. If this cod virus used CD4 as a gateway to enter the cell, fish without the receptor would not be infected and would survive to a greater extent. The result would be more cod without CD4 and thus the task of MHC class II would be lost. The gene for MHC class II would thus disappear over time via genetic drift. This hypothesis is supported by the fact that cod also lacks the gene for CD4.
It is possible that the codfish were exposed to such a disease, and those who survived did so precisely because they were missing that part. Since this event, about 100 million years have passed and the conclusion seems to be that the cod has managed very well without it.
"Maintaining and running an immune system requires energy for an organism, so in a way the cod can benefit from this by using less energy", says Bjørnestad. What we know is that the development of the MHC class I complex in cod fish coincides with increases speciation.
But what happens to the cod when it is sick?
When we get sick, during the course of the illness, we will react more and more specific to the virus or bacteria that has made us sick by producing more specific antibodies - but this is what cod lacks.
"But what happens to the cod when it gets sick?"
"We don't really know, but it survives. MHC class I also fights disease, but in a different way than MHC class II. Traditionally, MHC class I cooperates with a type of T‑cell that eliminates pathogens in a slightly more brutal way than MHC class II does", says Bjørnestad.
She emphasizes that there are still many missing pieces in the immune puzzle. Although she now has contributed to the discovery of how MHC class I possibly takes over for parts of MHC class II, there are still many unanswered questions. But one thing is certain: The cod does not necessarily have a poor immune system, even if it is different from ours.
"It is important to have a more open mind about what constitutes a good immune system", she concludes.
Read the research article here:
Synne Arstad Bjørnestad, Monica Hongrø Solbakken, Kjetill S. Jakobsen, Sissel Jentoft, Oddmund Bakke and Cinzia Progida, Atlantic cod (Gadus morhua) MHC I localizes to endolysosomal compartments independently of cytosolic sorting signals, Frontiers in Cell and Developmental Biology, January 2023
Translated from Norwegian to English by Åslaug Brynildsen.
