The Skin – the body's largest organ and defence system

The skin is the body's largest organ. It acts as a protective barrier and protects us against everything from infections to the sun and the cold. It helps us retain heat and keep cool, and it is able to heal itself. Not least is the skin an important part of our identity and the image we present to the outside world.

The skin is at the centre of a billion-dollar industry of beauty products that promise better, more beautiful and younger-looking skin. Skin diseases, such as acne, psoriasis and eczema, can therefore be highly stigmatising.

There are about 3,000 different diseases of the skin, and skin diseases are among the most common health conditions. Globally, an estimate of 900 million people suffer from a skin disease.

Over the years, skin diseases as a research area has not been prioritized highly.

However, despite its high prevalence, researchers still lack knowledge as to why many of the skin diseases occur. The LEO Foundation Skin Immunology Research Center (SIC) at the University of Copenhagen is one of the places where this is being researched. Here, the researchers have particular focus on the immune system, as it plays a major role in about half of all existing skin diseases.

“Over the years, skin diseases as a research area has not been prioritized highly. Diseases of the skin can be incredibly disabling and stigmatising. It is therefore very important to conduct research and reach a better understanding of the diseases so that we can find effective treatments. Understanding how the immune system and the skin work together is crucial in this respect,” says Professor Charlotte Menné Bonefeld, Acting Executive Director of SIC.

30,000 cell divisions per minute

The skin acts as the body's barrier against the outside world and protects the body's interior. At a rate of 30,000 cell divisions per minute, it constantly renews itself. This means that the outer skin layer, the epidermis, completely replaces itself in about a month.

In addition to acting as a protective barrier, the skin has many other important functions. It is a sensory organ that can feel touch, pain, heat and cold. The skin helps to regulate the body's temperature and produces vitamin D and pigment.

Just like the intestines, the skin has its very own microbiome made up of millions of viruses, bacteria and fungi. However, most are commensal microorganisms that interact with the immune system and help protect the skin.

The skin is part of the immune system as an innate anatomical barrier. The same applies to, for example, the cilia that line the mucous membrane in the lungs and the saliva in the mouth, which can inhibit or kill foreign organisms.

But the skin is also one of the parts of the body that has the most immune cells. They protect against infections, viruses and abnormal cells that can be a sign of disease.

The immune system builds a memory. Throughout life it learns to recognise pathogens – microorganisms that are pathogenic – and it typically grows stronger throughout childhood and early adulthood as people develop more and more immunity. This is called acquired immunity.

This means that there are some diseases that people can become immune to and contract only once in life, such as measles and other childhood diseases.

An immune system that attacks itself

In order to fully understand the role of the skin and skin diseases, you have to understand the immune system and how it works.

The immune system consists of millions of different types of cells. Some of the most important ones are the so-called T and B cells, and one of the most important tasks of the B cells is to produce antibodies that attack antigens by binding to them.

An antigen can trigger a reaction from the immune system. Antigens are molecules that are part of foreign cells, bacteria, fungi and viruses, but also the body's own cells. A healthy, well-functioning immune system, however, only responds to the antigens in dangerous organisms.

The antibodies produced by the B cells are an important part of the immune system's memory. They can remember and recognise the invading antigen from for example a virus.

The immune system is like a symphony orchestra, where it all has to come together in order to function..

That means that if you are exposed to the same virus infection again, the antibody can recognise the virus the second time around and quickly activate the immune system and defeat the disease. In this way, you become immune.

The T cells have many different tasks and are divided into several types. Some T cells help activate and control the immune system, while the so-called killer T cells can kill infected cells and invading microorganisms.

Professor Anders Woetmann, the LEO Foundation Skin Immunology Research Center, compares the immune system to an orchestra where the T cells are the conductor who orchestrates it all.

“When an infection occurs, the immune system is activated. It remains activated for as long as the infection lasts. As soon as the infection goes away, you recover and the immune system is, so to say, deactivated. But if that process goes awry, the immune system may potentially be really dangerous. Here, skin diseases are just one example,” Anders Woetmann says, adding:

“The immune system is like a symphony orchestra, where it all has to come together in order to function. At times, some function of the immune system goes awry, and then the orchestra plays false or out of time. At the centre of it all you find the conductor, the T cells. T cells play a key role in an incredible number of skin diseases which is why it is so important to understand and research their role.”

When things go wrong for the immune system, it can attack innocuous foreign antigens. This is for example the case with allergies to nickel and substances in perfume.

Other times, an error occurs when the immune system has to differentiate between the body's own cells and foreign organisms. This may cause the immune system to attack the body’s own harmless, cells. When the cells react to the body itself, they become autoreactive.

This is what happens in autoimmune diseases such as the skin disease psoriasis. About 165,000 Danes suffer from psoriasis, which is a hereditary and chronic disease. There are various treatments that can relieve and diminish the symptoms, but there is no cure.

It is not yet known why the disease occurs. But it is known that T cells play a big role. In psoriasis, the T cells are overactive and do not function properly. Instead of attacking, for example, an infection, the T cells attack healthy skin cells.

“In connection with psoriasis, all sorts of other immune cells are summoned, but the T cells are key in orchestrating what goes wrong. Somehow, they become chronically activated. They become overactive and they remain active even if there is no infection.”

“Right now, there is only a symptom treatment for psoriasis. We can remove the symptoms, but not the cause of the disease. We would really like to know why the disease occurs and not just how it happens. If we can get to that point, then we can start to actually cure,” Anders Woetmann says.

Another disease in which the T cells play a key role is in a particular type of lymphoma of the skin called cutaneous T cell lymphoma. Here, the disease begins in the T cells, which become dysfunctional and begin to divide uncontrollably. As a result, the skin barrier becomes, so to speak, defective and the patients suffer severe infections. Why the disease occurs and why the T cells become overactive is unknown.

There are more than twice as many T cells in the skin as in the blood. A great deal of research in skin diseases centres on precisely the T cells, their function and how they interact with one another and the rest of the immune system.

Another disease that is being researched extensively and in which T cells also play a key role is atopic dermatitis.

Eczema during childhood paves the way for allergies

About 20 percent of all children develop atopic dermatitis at varying levels of severity. The disorder appears as a red rash with dry, itchy skin that may sometimes ooze fluid. Most children outgrow the disease. For two out of three, the eczema disappears before they reach puberty.

We know a lot of factors that increase the risk of eczema, but basically we do not know why people get it.

Clinical Professor Jacob P. Thyssen explains that you have a barrier defect in the skin and an overactive, dysfunctional immune system when you have eczema.

The disease cannot be cured, and it is still unknown why some people develop eczema and others go free. But the researchers know that factors such as geography, birth month and exposure to so-called hard water when bathing play a role.

“We know a lot of factors that increase the risk of eczema, but basically we do not know why people get it. We can see that atopic dermatitis is much more frequent in the Nordic countries. Those who grow up in an area with a high concentration of calcium in the water, as in the eastern part of Denmark, also have more eczema due to exposure through bathing.”

“The seasons also play a role. People born during autumn and winter in Denmark have more eczema. The cold is bad for your skin barrier, so it is probably because of the cold weather,” says Jacob P. Thyssen, who works at Herlev Gentofte Hospital and the LEO Foundation Skin Immunology Research Center.

The researchers have also found a connection between having atopic dermatitis and later developing food allergies, asthma and hay fever. The connection depends on the severity of the disease.

People with mild atopic dermatitis do not necessarily develop other allergies. On the other hand, about half of all the people with severe atopic dermatitis will develop asthma later in life.

“It often begins with atopic dermatitis. Later comes food allergy, then asthma and eventually hay fever. It is as if the allergies come along like beads on a string, as the child grows older. There is a clear connection between suffering from all these diseases and having severe atopic dermatitis.”

“Not everyone with atopic dermatitis develops these allergies. Conversely, if you look at, for example, 100 children with food allergies, then almost everyone will also have atopic dermatitis. Atopic dermatitis is the starting point or gateway to quite a lot of allergies. But not everyone goes through the gateway,” says Jacob P. Thyssen.

That is the reason why Jacob P. Thyssen and his colleagues are researching, among other things, how to predict the path a child is taking: Is it a child who will outgrow the disease, like most people? Or is it a child who will end up having other allergies as well? In this way, the researchers hope that they will be able to intervene sooner with treatment and counselling.

Although most children outgrow their atopic dermatitis, the disease may still prove to have significance later in life. Once you have had atopic dermatitis, you have a higher risk of developing other types of eczema, including work-related hand eczema.

Contact allergy costs the society millions

Contact allergy or allergic contact dermatitis has become a common disease. About 20 percent of the entire population is believed to have contact allergy. A wide range of different chemical substances may trigger it, for example substances found in perfumes, detergents and beauty products.

Some working groups are at particular risk of developing contact allergy and eczema. For example, nurses who wash their hands a lot during a workday and are exposed to skin irritants such as soap and water. An additional risk factor is having had atopic dermatitis as a child because this means that you have a delicate skin barrier.

If you wash your hands often during your workday, you will thus have a greater risk of developing hand eczema: A so-called irritant contact dermatitis, where the skin barrier has been broken.

A broken skin barrier can also lead to allergies to, for example, to chemicals in rubber gloves and soap. If this happens, you move towards developing contact allergy.

“Atopic dermatitis is the starting point for two directions: The allergic direction and the work-related direction, which can lead to allergic or irritant contact dermatitis or both. People with atopic dermatitis are therefore a group where it really makes sense to try to help early on and make sure that those people do not develop skin problems.”

“Contact allergy and contact dermatitis is in principle harmless as it does not lead to anaphylaxis as allergy to foods. It is not fatal. But it can be very bothersome, even to such an extent that it can ruin a person’s quality of life. You may lose your job or may not be able to use your education. In this way, it is an allergy that is very expensive for the society,” Jacob P. Thyssen explains.

It is estimated that contact dermatitis annually costs the society more than DKK 800 million. If other forms of eczema and allergies are included, the annual amount ends up in billions.

However, over the past decade, new research techniques have emerged that have the potential to significantly impact not just contact allergy, but the entire research area within skin diseases.

Cell sequencing and a skin atlas

Last year, for the first time, researchers from the LEO Foundation Skin Immunology Research Center and the Novo Nordisk Foundation Center for Protein Research mapped the composition of proteins in the skin, in collaboration with international researchers.

That mapping became the foundation for a kind of atlas of skin proteins called the proteomic skin atlas. In total, the researchers categorised almost 11,000 proteins in the skin. They did this by means of tissue samples taken from excess skin from surgeries.

The researchers used the advanced technology of mass spectrometry to study and categorise the proteins in the skin. The atlas shows what healthy skin looks like, and it means that the researchers will now be able to compare healthy skin with diseased skin.

In doing so, they can map and study the major differences between healthy and diseased skin that may explain why different diseases occur. In this way, the hope is that the atlas may help researchers to find new and better treatments for skin diseases such as psoriasis and eczema.

Another technique that the researchers have high hopes for is single cell sequencing: A technique for sequencing individual cells. Sequencing means to identify the structure of DNA or RNA. However, DNA sequencing is often done on tissue samples or on entire cell populations.

With this method it is not possible to tell the differences between the individual cells, which are all unique. Single cell sequencing, on the other hand, makes it possible to study and sequence at a whole new level and to look at just one cell at a time.

The technique will greatly improve the understanding of many diseases, says Anders Woetmann.

“A single cell can affect quite a few other cells around it. If you have one cell that behaves strangely, and tens of thousands of other cells that do not behave strangely, the individual cell will drown in the large mass of cells. But with single cell sequencing, we will be able to find and identify those types of cells.”

“We will gain an understanding of the interaction between the cells and be able to find small unusual subgroups that we have not known before. We will probably be able to find some cells that can do things we have never known about. It will help to revolutionise our understanding of skin diseases and diseases in general,” says Anders Woetmann.