Professor Kevin McElwee, from the University of Bradford Centre for Skin Sciences, takes a look at what we know about the causes of Alopecia Areata.

What causes Alopecia Areata?

What causes Alopecia Areata (AA) is one of the most common questions that doctors and scientists studying AA receive, but it is one of the hardest questions to answer. We have some ideas about what causes AA, and some limited research evidence, but the short answer is we don’t know – at least not with complete confidence. It’s worth noting that not all the causes of AA will be relevant for each individual. Different causes of AA may be active in different people – there are likely several different biological pathways that can trigger onset of hair loss, but all the pathways eventually reach the same destination of AA. Deciding which causes are relevant to which individuals is mostly still just guesswork. While there is much argument and debate, here is a summary of the possible causes for AA.

Genetics:

For some people there is a very clear genetic link. AA can run in some families and there may be several people in an extended family that can have AA. Not everyone in the family will be affected. Often AA can skip generations. Someone with AA may find that a grandparent, or an aunt/uncle had the condition. Sometimes, identical twins can develop AA, and may even have similar patterns of hair loss. In recent years there has been a lot of research to look for genes that might be involved in AA using a method called “genome wide association studies” (GWAS). These studies involve collecting blood from a large number of patients, and also people who don’t have AA (very often other family members), and then examining their genome to see what specific gene sequences are more commonly present in AA patients. So far there are 15 candidate gene sequences (called gene “alleles”) that probably have an influence on AA.

New studies are being published all the time, so this number will probably increase in the future. Not all 15 genes need to be present in each person with AA, but the more of these genes a person has, the more likely they are to develop AA at some point in their lives. In addition, the more gene sequences present in the same person, the more likely their AA will be more extensive and also more persistent. It’s still not clear what all of these gene sequences do, but several are involved with controlling immune cell responses and some are involved with controlling hair growth. A few of the gene sequences that have been found are the same as gene sequences found in other autoimmune conditions such as rheumatoid arthritis, for example. This may be why some people with AA also develop other autoimmune conditions. 

Environment:

For some people genetics may play quite a strong role in deciding whether they develop AA. However, just having the gene sequences that make AA more likely does not mean someone will actually develop AA. Most dermatologists and scientists agree that some kind of trigger is needed to actually induce the onset of hair loss. In addition, there are many people who do not have a family history of AA. While there may still be some genetic influence, factors in the environment may play a much bigger role in promoting onset of their AA. The environmental causes are potentially many and varied. For some people, just one big environmental trigger may be enough to cause AA, for others, perhaps several environmental triggers combine at the same time and together their effect is strong enough to induce onset of AA.

There has been very little research to identify environmental triggers that cause AA, partly because it is hard to identify specific triggers when people live their lives each with somewhat different environmental exposures unique to them. So far there have been some very small studies that hint that environmental triggers could involve; infections (Epstein-Barr virus has been found in a few people with AA), diet (a study with an animal model of AA suggested dietary soy oil might have an influence), chemicals (a very few studies have suggested exposure to certain toxic chemicals may cause AA), and microbes in the gut and on the skin.

From research on other autoimmune diseases, it seems that what kind of microbes we have in our guts can affect the kind of immune responses we have. Certain microbes in the gut (and maybe also on the skin) might increase the level of immune cell activity and so make it more likely someone will develop an autoimmune disease. There is research on gut and skin microbes in AA patients underway right now, so we should be seeing some publications on this in the near future. It might be that a transfer of “good” gut and/or skin microbes might help to prevent or reverse AA.

Stress:

Stress is part of our environment, but it’s added here as something separate because there is lot of research published on the role of stress in AA. For some people there is a very clear link between stress and AA. People with AA can sometimes point to a severe shock or a very stressful event that occurred in the weeks before AA developed. Others report experiencing chronic stress over a long period of time before their AA developed. When we experience stress, our brains (and specifically the pituitary gland at the base of the brain) start secreting stress hormones and these can have a big impact on other tissues and cells elsewhere in the body. The chemical signals from the pituitary also stimulate the adrenal glands that sit on top of our kidneys to increase the production of another hormone called cortisol.

Cortisol is a signal our body uses to prepare for a “fight or flight” response in times of stress. Cortisol can have a big impact on immune cells and also on hair follicles, as well as other tissues. In addition, there is research to show that the skin and hair follicles themselves can produce several stress hormones. So there is a local production of chemical signals in the skin that can also affect hair growth and the immune cells in the skin. While some stress hormones suppress the immune system, other stress hormones stimulate the immune cells.

While it is not clear what stress does in AA, the suspicion is that stress can throw the immune system cells out of balance and immune cells that are normally dormant, become active and target the hair follicles. Stress might also alter the hair follicle cells so that they become more “irritating” to the immune cells. There may also be a feedback loop between immune cells and stress hormones. In chronic inflammation, the chemical signals that immune cells use to communicate with each other (called cytokines) also affect the brain and pituitary gland. As a result, chronic inflammation may increase the production of stress hormones.

While losing hair can be emotionally very stressful in itself, the inflammation in AA could also be increasing stress activity in the body. This feedback loop between the immune system and the stress system in the body can be hard to break and this might be one of the reasons why treatments for AA are not always effective. Again, it is important to remember, stress may be a trigger for some people, but may not play a role in others.

Hormones:

Since the early 1900s dermatologists have been aware of a link between hormones and AA. In women, onset of menopause can be an event that links to AA onset. In addition, women with AA who are pregnant may see temporary hair regrowth, often in the third trimester. These observations suggest estrogen hormones can influence AA. Research on immune cells shows that the cells can increase their activity when they are exposed to estrogens. As estrogen hormones levels increase and decrease with different life events, so there may be changes in immune activity that then affect AA. For men there may also be a hormone influence. Testosterone tends to suppress immune cell activity. As men age, their production of testosterone gradually reduces.  So it may be that men become more susceptible to AA as they grow older.  

The immune system:

There is a lot of research to show that lymphocyte cells from our immune systems cause AA. Lymphocyte “T” cells collect around AA affected hair follicles and some get inside, essentially they interfere with the ability of hair follicles to make hair fibre. Our immune systems are very complex with many different cell types all with overlapping functions. This is generally to our benefit as the immune system protects us from diseases and also helps to heal wounds. Normally our immune systems are “educated” and know that they should attack bacteria, for example, but that they should not attack our own self tissues.

In autoimmune diseases, this “education” fails in some way, and the immune cells start attacking our own tissues. In AA, the immune system cells attacks hair follicles, and sometimes nails, which are basically just big hair follicles. While most cells of the immune system are focused on protecting us from infection, there are a few cells that actually suppress immune responses - called regulatory T cells. These suppressive cells are very important. Among other roles, they selectively block immune cells from attacking our own self tissues. In AA, there is some research that suggests that these regulatory cells can be defective. Either the regulatory cells are too few in number or they don’t function properly and cannot fully block the autoimmune attack. There could be some genetic fault in these regulatory cells.

There may also be some environmental influence that alters the regulatory cells. At the moment, there is a lot of research into regulatory cells as they are important in many autoimmune diseases, but right now there is limited understanding of how these cells fail and what could be done to repair or boost their activity.

Allergies:

We could say allergies are part of the environment and they also involve a faulty immune system, but they deserve their own paragraph to discuss them. It has been known for many years that people with AA are also more likely to have allergies. Allergies can involve; intolerance of certain foods, sneezing in response to pollen or dust in the air, asthma after exposure to some allergen, and/or dermatitis when something applied to the skin causes redness and itching and scaling. In all of these responses, something from the environment causes the immune cells, particularly a type of immune cell called mast cells, to activate. The chemical signals the mast cells produce (histamine and other chemicals) cause the allergic over-response. In some people the response is so severe that it may be life threatening.

While there is much debate as to why allergies are becoming more common in the general population and how to prevent them, the presence of an allergy might also affect the chances of developing AA. One or two studies recently have suggested that AA patients with high levels of an antibody called IgE in their blood, something that is seen in people with allergies, are also less responsive to AA treatments. The signals that mast cells produce, like histamine, have a very broad effect and stimulate many other cells in the immune system. It might be possible that the mast cells activate “T” lymphocytes that then go on to target hair follicles. Once again, not everyone with AA has an allergy, so this mechanism may not be active in everyone.

What we know now:

Overall, there are many possible causes of AA - genetic, environmental, and even hormonal. Different triggers and modifiers of AA will be active in different people and the environmental triggers/modifiers of AA might change over time for the same person. Unfortunately, research on other conditions shows that removing a trigger for onset of autoimmune disease does not always reverse it. Once autoimmune conditions start they can become self-perpetuating - the inflammation feeds on itself. What is really needed is to throw a “spanner in the works” to block the disease mechanism. By understanding the triggers for AA, we can gain a better understanding of the disease mechanisms involved, and where it would be best to target new treatments. In the next few years we should see some new treatment developments around the causes of AA; perhaps interfering with gene activity, altering our gut microbiome, or using anti-histamine drugs alongside other treatments for AA (something which is already happening in Japan), just as a few examples.

Professor McElwee has recently published a review paper discussing the history of alopecia, available here.

Professor McElwee submitted an application to our 2018 Research Pots Scheme and received the Committee's Choice Funding Pot, allowing him and his team to undertake their reseearch project 'Characterising the role of antigen presenting cells in alopecia areata'.

We would really like to be able to continue with our Research Pots Scheme so we can support further alopecia research.

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