With lisence to kill

The next movie about James Bond, the hero with lisence to kill, will be the 27th film in the series. Immunologists don’t need to wait several years between each time we get to see and hear new stories about secret agents with lisence to kill. We’ve got the killer T-cells.

One of the major challenges to the immune system is to detect whether one of the body’s cells are infected with a virus. Virus is a chemical information package that can penetrate cells and take over the cell’s machinery to replicate itself. These new virus particles will eventually slip out of the host cell and can then infect new cells. What initially was a small problem (namely a few viruses and a few virus infected cells) may quickly become an insurmountable problem because of the need to handle large quantities of new virus particles and new virus infected cells. This is where T cells with a lisence to kill enters the narrative.

T cell recognizes virus infected cell and kills it

Peptides from a virus bind to HLA molecules. The HLA-peptide complex is  brought to the cell surface, allowing T cells to recognize the virus infected cell and kill it.

A virus infected cell will always contain some virus proteins. Some of these viral proteins will be cut into shorter pieces or peptides. The peptides are then pumped into the cell compartment where HLA molecules are made. HLA molecules actually need peptides in order to be fully made. Without a peptide bound to the groove, an HLA molecule is unstable and may fall apart like a house of cards. When an HLA molecule has been produced and the groove contains a peptide, it is transported out to the cell surface. All cells in the body except for red blood cells have HLA molecules on their surface. This is the cell’s way of reporting on the latest hours events inside the cell.

Killer T-cells constantly patrol the body. They check all body cells they pass. Each of these secret agent cells are in particular looking for a specific virus. If a T cell finds a body cell that displays a peptide from this particular virus, it gets turned on. The killer T-cell establishes physical contact with the body cell. It then produces holes in the virus-infected cell so it dies. This method of killing is effective. When the job is done, the T cell go on searching for more virus-infected cells to kill.

The first time we become infected by a virus, there are not very many T cells with the lisence to kill cells that are infected with this particular virus. It will therefore take some time before all the virus infected cells are tracked down and killed. Meanwhile, the virus has had plenty of time to multiply and damage body cells.

Thus, the first time you are infected with a given virus, it is therefore likely that you will become ill. Next time, however, your killer T-cells are better prepared. They are more numerous and they attack faster. Most often you do not know that you have become infected by the same virus again. The immune system clears away the danger before you notice anything.

Blog written by Anne Spurkland, first published in Norwegian October 13 2012
English version publishsed November 19 2016

Cream cake or cream cake?

Recipes for cream cakes often go down through Norwegian families. The exact combination of filling and decoration can vary substantially from family to family. But no one is ever in doubt that the result is cream cake, nor that the cake looks yummy.

Likewise there are some genes that exist in countless variations in the population. But every one of us has only inherited two varieties of each such gene, one from our father and one from our mother. The variants of any such diverse (polymorphic) gene all give the recipe for a given protein in the body, although the resulting molecules may vary widely.

By far the most polymorphic genes we have are the HLA genes. HLA molecules are crucial for the immune system to react to unknown threats such as microbes and cancer cells.

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Different HLA molecules bind different sets of peptides

There are over 3,000 different varieties of the HLA-B gene, and also for the other five HLA genes (A, C, DR, DQ and DP) there are very many variants known so far. Almost all the differences between the variants of each HLA molecule are localized to the groove. The groove is the part of the molecule that can bind and show off foreign substances to the immune cells. The groove has room to accommodate a peptide, that is a short piece of a protein. The shape and structure of the groove determines which peptides that can bind to it. Each particular groove can bind a great number of different but similar peptides. However, for each groove there will be many peptides that can not bind.

This means that since each of us is equipped with a limited number of HLA molecules, we also have a limited ability to bind and present peptides from microbes and cancer cells to our immune cells. This may have consequences for our chances of survival in an epidemy, if the bacterium or the virus have peptides that only binds well to some but not all HLA molecules. But generally the set of HLA molecules that each of us are equipped with, is adequate for surviving most of the infections we may experience.

Thus in the same way as the Norwegian cream cake serves as party food or dessert almost irrespective of any choice of decoration and filling, so do our HLA molecules serve well as defense against almost any virus or bacteria that we are exposed to.

It is not possible to foresee whether an HLA molecule is especially “good” or “bad”, it depends on the microbes we are exposed to through our lifetime. Neither is it easy to know which cream cake will prevail in the weekly magazine’s cake competition. Which variant will have the strongest appeal at any given time? A layered cream sponge decorated with wafer biscuits for example?

The fact that each of us has a limited number of HLA molecules is the result of a compromise the immune system has had to do, which I shall come back to in a later blog post. Suffice it to say now that both too few and too many HLA molecules is problematic, just like a festive cake buffet indeed may contain too few or too many different cakes.

Blogpost by Anne Spurkland, first published in Norwegian October 12 2012
English version published August 25 2016

Funnel chanterelle

I love picking mushrooms, especially funnel chanterelles. They are small, brown and easy to recognize on their yellow, slightly angular stem, which is hollow from the hat down to the root. In addition the gills under the cap extends down the stem. Yet, in recent years I have become more careful when I pick and clean the funnel chanterelles. I do not want include a piece of deadly webcap by pure carelessness.

When I worked on my PhD project on HLA molecules, I also examined my own HLA genes. HLA molecules are essential for the immune system’s T cells to detect viruses and bacteria.

That's a 25% chance that a sister or brother has inherited the same HLA haplotypes from parents as yourself.

That’s a 25% chance that a sister or brother has inherited the same HLA haplotypes from parents as yourself.

There are a large number of different HLA gene variants and thus many different HLA molecules. But each of us has inherited only a limited number of HLA gene variants, a mere total of 6 -16 different HLA molecules each. The HLA genes are so closely located on chromosome number 6, that they are usually inherited together as a “package”. Thus we inherit one package of about 6-8 HLA genes from our father and the same from our mother. These packages (or haplotypes) are quite stable, so many people have actually inherited the same combination of HLA genes although they are not otherwise related.

It turned out that I had inherited an unprecedented combination of HLA genes. Simply a new haplotype! The entire family was investigated and we discovered that the new haplotype originated from the Norwegian west coast. As a byproduct of this effort, I learned that I have inherited exactly the same HLA genes as my sister.

It is here that the deadly webcap enters the scene. This fungus, which resembles the funnel chanterelle and grows in the same locations, is extremely toxic. Kidney failure is certain 7-10 days after having eaten even a tiny piece. There have been several tragic incidents over the last decade, where families have mistaken funnel chanterelle for deadly webcap and where everyone in the family has got kidney failure after ingestion of the fungus. It is not so many years ago that deadly webcap was first found in Norway. Mushrooms experts believe that this fungus has become increasingly common, and puts this in the context of environmental pollution.

Treatment of kidney failure is kidney transplantation. It is possible to get a new kidney from “anyone”, but it is a great advantage if the donor and the recipient have as many HLA molecules in common as possible. We want to avoid that the immune system consider the new kidney to be a huge collection of bacteria or viruses and sets off to get rid of it as quickly as possible.

If the HLA molecules of the kidney are similar to those of the patient, the T cells will in principle experience the new kidney as similar to the original kidney. In practice, however, kidney transplant patients are always given medication that suppress T cells to avoid that they attack the transplanted kidney.

We all have two kidneys, while one is adequate for good health. Norway is a world leader in the use of kidney transplants from living donors. These donors are usually relatives of the patient, and shares half or all of the HLA molecules with the patient. A sister or brother who have inherited exactly the same HLA genes as the patient, is of course the most ideal organ donor of all.

So every fall, when I wander in the darkest corners of the pine forest around Oslo looking for funnel chanterelles, I think of my HLA-identical sister and that I MUST NOT inadvertly get the deadly webcap in the basket together with the chanterelles. And for safety’s sake, I eat the chanterelles myself, my sister will be served something different when she comes for dinner.

Blogpost by Anne Spurkland, originally posted in Norwegian October 1, 2012
English version posted August 23, 2016

Granma’s cream puff

I was 13 when my grandma taught me how to bake cream puffs. Puffs are these round, hollow and slightly crispy pastries that can be filled with cream. I was an eager teenager housewife and she was an experienced baker. Nevertheless, the first round of puffs turned out a failure. The puffs did not rise, the dough had been too hot. That day I learned that some recipes must be followed to the letter, else it will not work.

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The groove

When my boyfriend finally returned from Africa in 1989, two years of intense letter writing came to an end. I had written about my life as a budding researcher, he about his life as a volunteer in the bush. Still I became a bit puzzled the morning of our reunion in Paris, when he after a night in a cheap hotel bed announced that he had dreamt that we were competing peptides in the HLA groove!

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Dulce de leche “Hapå”

Although I am an omnivore, I must have dairy butter on my morning sandwich, otherwise I lose my appetite. Similarly, the Norwegian dulce de leche type spread “Hapå” is according the Nestlé advertisment an effective means to get the kids to eat their sandwiches.

The macrophages behave a bit in the same way. They eat everything, but it helps a lot if a bacterium is covered with “Hapå”. It then goes down a lot faster.

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