Some of you may be surprised to see a blog with this title. ‘Of course alopecia areata is an autoimmune disease, I’ve been told this from day one!’ will be the cry from many, we are sure.

Recently we attended a seminar with the European Hair Research Society (EHRS).  We were surprised to hear it mentioned that alopecia areata was not necessarily an autoimmune disease.  For years, Alopecia UK was cautious around definitively stating this and we used to say ‘Alopecia areata is thought to be an autoimmune disease’. A few years ago, because other alopecia organisations and researchers were saying alopecia areata is an autoimmune disease, we changed our stance. 

But now we are back to questioning whether we should have done that. To explore this further, we have chatted with Professor Ralf Paus (the researcher who made the comment in the EHRS meeting which has prompted this blog post!), Professor Andrew Messenger and Professor Des Tobin (both Alopecia UK Research Committee members) and our Research and Liaison Manager, Julie Clayton.

First up, a summary of thoughts from Professor Ralf Paus…

When Ralf began his research on alopecia areata in the early 1990s, he suspected that AA may be what is called a ‘classical autoimmune disease’ but he found that many scientists were not convinced.

Ralf was referring to the prevailing ideas of a classical autoimmune disease being when the immune system’s white blood cells, which normally do the job of fighting off potentially harmful bacteria, viruses and fungal infections, have for some reason started attacking the body’s own tissues. We know that our immune system has its own checks and balances that normally prevent this attack on ‘self’ tissues. But in some conditions, this protection has broken down, causing white blood cells to release lots of chemicals that draw others into the area. This ‘inflammation’ – which can cause skin to become reddened and sore or itchy - is what normally helps to fight off infections, but it can be damaging when it occurs at the wrong time and place.

Similar unwanted inflammation was known to occur in other autoimmune conditions, for example in rheumatoid arthritis and type 1 diabetes.

Ralf knew that by the time patients are diagnosed with alopecia areata, this kind of inflammation is already underway – when doctors look at small skin biopsies under the microscope, they can see lots of different immune cells around the hair follicle – what Ralf calls a ‘swarm of bees’. The question is, however, what brought the swarm to the hair follicle? And herein lies the conundrum.

Setting out his ideas to the research community, Ralf proposed a mechanism for how alopecia areata could occur, if this inflammation seen in alopecia areata were due to a very targeted attack on hair follicles by T cells of the immune system. This was biological precision at its best – like a guided missile, T cells can normally pick out one protein amongst the rest (and just one part of one protein – for example on a virus, or in a vaccine). Ralf and other researchers then found lots of evidence to support this hypothesis.

However, the deeper they dug, the more Ralf and other researchers have also come up with other possibilities for how inflammation around hair follicles can be triggered. And not always involving the missile-like T cells. Other players may be driving the damage, including cells called natural killer cells and gamma-delta cells. And then there is now evidence that yet another type of cell – the ‘regulatory T cells’ which normally put the breaks on unwanted inflammation - have stopped doing their job, causing hair follicles to ‘lose’ their normal ‘immune privilege’ as Ralf describes it. And this is what Ralf was reporting at the recent EHRS symposium.

But why should this matter? Isn’t it all just semantics if what we end up with is inflammation by some route or other, and the hair loss of alopecia areata?

According to Ralf, “Whenever you come up with a persuasive theory, it is both important and good scientific fun to keep questioning yourself whether it truly depicts reality comprehensively and convincingly enough; especially when that theory relates to a serious disease which causes much human suffering and for which we still do not have any causal, but only imperfect symptomatic therapy.”

Ralf says: “Where does this leave us? Well, the logical conclusion is that different disease pathways can lead to the same clinical outcome that physicians uniformly diagnose as "alopecia areata", on the basis of the very characteristic hair loss pattern and microscopic features we see - even though the disease pathway can have been initiated by rather distinct mechanisms… In other words, my old alopecia areata pathogenesis theory is still very much alive and kicking - it just got more differentiated.”

The detail then, is very important. Whether some people’s alopecia areata involves the ‘classical autoimmune disease’, while for others it’s a different trigger, our hopes of one day designing more individualised therapies depend on understanding what causes the inflammation. And Ralf hopes that one day researchers will identify ‘biomarkers’ – chemical signs - that distinguish between the different causes.

He notes however, that “a lot of additional research work is needed before we shall hold reliable biomarkers in hand that permit physicians in the clinic to distinguish these two main types of alopecia areata – autoimmune and non-autoimmune - from each other so as to select the best, personalised therapy for every patient.”

In the meantime, “the good news” is that new therapies aiming to stop inflammation are intended to benefit all patients with alopecia areata. As Ralf says, “Any therapy that robustly helps the hair follicle to rebuild its protective immunological cocoon predictably will suppress both forms of alopecia areata and promote spontaneous, lasting hair regrowth.”

You can see Ralf’s full explanation on the issue here.

We recognise that Ralf’s information includes a lot of very-scientific information and language that not everyone will be able to follow (including some of the staff team at AUK!). Andrew, Des and Julie’s explanations break it down a bit further. 

Over to Professor Andrew Messenger… 

“There is little doubt that alopecia areata is an inflammatory disease and that the inflammation is caused by an attack on the hair follicle by cells of the immune system and their products. The prevailing idea is that this attack is most likely auto-immune in nature but the evidence for this is largely circumstantial and we should keep an open mind that there could be other explanations.  One way of looking at it is to regard alopecia areata as a ‘reaction pattern’ rather than a single disease. This means that a tissue, in this case the hair follicle, reacts in a similar way to inflammation with different causes. For example, hepatitis – inflammation of the liver – can be autoimmune in nature but it can also be caused by various infections and by toxic substances. Likewise, dermatitis – a distinctive pattern of inflammation of the skin – can be due to allergic reactions, non-specific irritation, infections and causes unknown. 

At the present time we do not have any strong evidence for causes of alopecia areata other than autoimmunity but we need to be alert to the possibility that the pattern of hair loss that we recognise as alopecia areata could be the end result of inflammation due to other causes.”

And Professor Des Tobin…

“I feel that the best evidence so far is that alopecia areata is an immune-mediated disease and that we still await confirmation that alopecia areata is an bona fide autoimmune disease.  I also feel, like Ralf, that all ‘alopecia areata’ may not be the same disease (note all the strikingly different phenotypic presentations), and this may open the door to an immune-mediated versus an autoimmune disease variants.  There has been a drift of late to simply calling alopecia areata ‘autoimmune’, despite that we have not identified a precipitating autoantigen in the human hair follicle. That I feel is a little scientifically lazy.

I continue to search for autoantigens on the hair follicle that can either trigger or perhaps more likely exacerbate or sustaining the condition (including enabling alopecia areata to relapse and remit in cycles). We were very excited when Kevin McElwee’s lab provided in 2016 supporting evidence to our initial report in 2010 that trichohyalin is likely to be a significant antigen. My lab is actively searching for more evidence of the involvement of trichohyalin in alopecia areata, and for other likely candidate ‘auto’antigens on the hair follicle itself.”

And finally, to Dr Julie Clayton...

“Think of a swarm of bees. My understanding of alopecia areata is that it’s still all about the loss of immune privilege that allows the immune system to go flooding in there like a swarm of bees, attacking the hair follicles. However, not all cases seem to involve antigen-specific cells.

So when we are saying some cases of alopecia areata are autoimmune and some are not, we are saying that one way or another something triggers the immune system to release lots of signals that cause inflammation and damage to different parts of the body; in the case of alopecia areata, hair follicles.

If there is such a thing as an autoantigen trigger, it’s a holy grail to see if you could turn off the trigger so that the inflammatory process never starts in the first place.

Maybe one day researchers will adopt a different term to describe them all as ‘inflammatory diseases’ rather than ‘autoimmune diseases’ – especially if there were more effective treatments. But in the meantime, to answer the initial question of ‘Is alopecia areata an autoimmune disease?’ Well, probably yes. It’s still the immune system doing the damage to the hair follicle, just not always in quite the same way as we initially thought”.

Thank you to Ralf, Andrew, Des and Julie for sharing their insight with us. It is clear that there is still much to discover about alopecia areata. We hope alopecia research projects, that Alopecia UK continues to invest in, will lead to increased knowledge and understanding in the future and, hopefully, lead to better treatment options. 

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