This section includes a series of thoughts aimed at explaining the scientific and clinical path that led me to formulate the hypothesis which I then went on to demonstrate.

After starting my specialist training, I immediately focused on clinical activity and research, realising that a professional dedicated to science should also have a clear idea of the clinical expression of the disease, only then to direct the studies to the molecular component.

During my second year, I found myself attending a clinic for the treatment of vitiligo. As there were many machines available (phototherapy, micro-phototherapy, etc.), I felt sure that I could make my patients feel better. With passion, I devoted myself to seeing men, women and children suffering from vitiligo… In three years of attending the clinic, countless people passed before my eyes, all having different stories, often linked to the personal suffering caused by this disease (defined by many as just “cosmetic”!). As I saw these people, I observed their colour patches, spread everywhere but very often in some characteristic points (face, hands, feet) and often treated in different ways… but nevertheless still there, almost making a mockery of medical science and those who practise it, challenging us dermatologists and our theories.

So, patient after patient, skin patch after skin patch, ineffective treatment after ineffective treatment, I started to realise that I was faced with a real mystery… skin that was absolutely perfect in all its details… no reddening, no burning, no itchy sensation, no change in texture or adnexa, no scales or papules or wheals or anything of that nature. Skin just like everyone else’s but different – due to the complete lack of pigmentation, only a very sharp margin, almost cut with a knife blade, defining a boundary with very little there to stop the advancement of the “white”.

So where did the melanocytes go? How did they leave, without giving any other sign or symptom…? Due to my pathophysiological knowledge of the skin, this really was a mystery! A cell that disappears or is destroyed without leaving a trace, very often always in the same areas… This phenomenon had no equal in skin diseases.

The immune system is to blame! This was the explanation I heard at all the conferences! The immune system, this watchman who so often turns against the person it should be keeping an eye on… but is it really always the immune system’s fault? In medicine, over the years, we have gone from viruses, to genetics, to the immune system… when we don’t know who is at fault we drag the immune system into it. But if it really was to blame, why weren’t our traditional weapons for making it see who is really in charge (corticosteroids or immunosuppressants) effective against vitiligo? Was this disease so clever, so capable of giving no sign of itself other than hypo pigmentation, of manifesting itself wherever it wanted and making immunosuppressant treatments ineffective, despite theoretically having an autoimmune pathogenesis?

It was slowly starting to dawn on me that it was not the disease that was clever: all diseases are stupid. They behave that way because they can’t do anything else… we are the ones who don’t understand them! In hindsight, therefore, I can definitely say that until then we had understood very little about this disease.

At this point, I decided to try and understand more about it.

I spent a long time reading a large part of the literature that already existed in the field… I was amazed that as soon as a possible cause was found (for many years the trend was for autoantibodies against everything and everyone), that particular cause promptly failed the reproducibility test. In essence, one author found very high levels of autoantibodies, while a few months later another wrote that he hadn’t found any… and so on. When discoveries follow one another rapidly in the scientific field and are promptly denied, there is always something that doesn’t add up!

I also still kept wondering why everyone continued to insist on the autoimmune pathogenesis of vitiligo, when all the clinical and therapeutic – and even scientific – signs were saying the opposite! Yes, even the scientific elements… many articles by various authors reported that, in fact, there was absolutely nothing to immunosuppress… but, goodness knows why, certain voices always go unheard.

This is how I came to develop the belief that perhaps not much had been understood about this disease. At that point I did what I always do: if the road that is marked out doesn’t convince me, I go my own way… even if I have to be the first!

So I found myself thinking about the elements I should start with… if the immune system was not to blame, what could be causing this loss of melanocytes?

When examining my patients, I noticed a very simple thing: the sites where vitiligo most commonly arose were traumatism sites. The face, hands, feet, and eyes are rubbed on a daily basis (even minimally, such as when wearing shoes or cleaning your mouth after eating)… and this couldn’t be a coincidence! Other pathologies already have a codified role of traumatism (such as psoriasis)… why couldn’t vitiligo have one, too? Yes, traumatism seemed like a good starting point… I still had to figure out why traumatism brought about vitiligo in some people and not in others. The day I realised this, I was very happy: I had taken the first step. And perhaps this time, the road would take me far.

Traumatism seemed an excellent starting point… but how was it linked to the formation of hypochromic patches? As is often the case in life, the solution was right under my nose. After a quick search on PubMed (the database of scientific publications in the medical field) I immediately found an article that was enlightening, to say the least: an English author had discovered that if we take the pigmented skin of a patient suffering from vitiligo (close to a patch that is already present) and traumatise it with an electric toothbrush placed on it for a few minutes and if we then take a piece of skin and analyse it, we will find melanocytes detached from the basal membrane and in the middle of the epidermis.

A little aside: the normal structure of the skin has two layers: epidermis and dermis, separated by a structure that we call the dermal-epidermal junction. Melanocytes rest on this structure, then transferring, through their cellular offshoots (dendrites), the melanin to the keratinocytes, performing their function as skin photoprotectors. It is therefore impossible for melanocytes normally to be found in the middle of the epidermal layer.

I had excellent data to start with but then another problem arose… it has been scientifically proven that traumatism causes melanocytes to detach from their location and this causes them to disperse through the epidermal layer. But why does this only happen to those suffering from vitiligo? Clearly, there had to be something else, a so-called “primer” factor, capable of causing this detachment.

I had taken another step: the detachment of the melanocytes encouraged by traumatism (and probably also by other factors, such as oxidative stress and autoantibodies) was the real mechanism that causes vitiligo. The detachment ensured that the immune system was not alerted… and this is why the patches were not red, itchy or inflamed… and why the various immunosuppressants were not working at all or very poorly! The melanocytes, so to speak, left the scene in silence, without a fuss. I had therefore found the murder weapon… but I still needed to find the culprit! The detachment… the loss of adhesiveness… these words whirled around my head for some time, like a malfunctioning spin dryer. Then, suddenly, as often happens in life, a spark of intuition… a light in the dark… and everything became clear!

When you are trying to understand the mechanism that works in a given pathology, I think it is important to start with all the available data, focusing your energies on a single hypothesis. Looking for all the answers all at once – only to throw away some money (whether public or private) – is, in my opinion, futile. Scientific work begins firstly in the head of the researcher, then it moves to the laboratory! And it is precisely on this basis that I started to process the data available to me.

In the intricate puzzle of vitiligo, I had missed out a piece… It is well-known that malignant melanoma (the form of skin cancer that derives from melanocytes) can be associated with the appearance of a form of extensive vitiligo, particularly in its metastatic form. I wanted to understand the still unexplained link between these two observations and as usual I looked for relevant articles on PubMed. My eyes fell upon a name that I hadn’t heard before… and that I haven’t been able to forget since. One article talked about a certain protein known as MIA, an acronym for the term “Melanoma Inhibitory Activity”. This intrigued me a lot: this protein, firstly, did not inhibit melanoma at all! As often happens in the scientific field, once a molecule is discovered, it is given a name linked to the function that it appears to exercise, even if it is later discovered that it does something very different! This is precisely the case of the MIA protein: it was discovered many years ago and it seemed that, if added to cultured melanoma cells, it made them become smaller in some way, and this is why it was given the name of melanoma inhibitory activity.

The wonderful studies by Prof. Anja Katrin Bosserhoff of the Institute of Pathology at the University of Regensburg in Germany then clarified the role of this protein in the context of melanoma. In actual fact, this protein had the capacity to increase the metastatic spread of the melanoma (rather than inhibit it!) and the blood levels of MIA are actually often greatly increased in patients with metastatic melanoma. But until now, not even a whisper of vitiligo!

So how did MIA work? Having read the mechanism of action, I held my breath. MIA has the capacity to break the bond of adhesion between the malignant melanocyte and the surrounding environment, bonds that are implemented through adhesion molecules known as alpha5beta1 integrins (“integrins” are a very vast family of adhesion molecules, and the alpha5beta1 are a sub-family). Therefore, the malignant melanocyte, at some point, produced the MIA, which turned against it, cutting its bonds, thereby facilitating its detachment from the primary site, allowing the diffusion through lymphatic and blood circulation and thus the formation of distant metastases.

Therefore, I had just realised that there was a molecule capable of cutting the connections of the melanocyte (in this case, malignant) and encouraging its detachment. The clue was good, but it needed to be verified.

With my heart in my mouth due to the excitement, I began to read article after article: are alpha5beta1 integrins also present in normal melanocytes? Yes, they are present, well expressed in the dendrites. Is the MIA protein present in healthy skin? No, no trace. So… take a deep breath and see if I’ve got this right… There is a molecule known as MIA, capable of causing the detachment of neoplastic melanocytes by “cutting” some adhesion molecules known as “alpha5beta1 integrins”. These adhesion molecules are physiologically expressed in normal skin and cause melanocytes to attach through them to the basal membrane. The pathogenetic mechanism that explains all the clinical characteristics of vitiligo is based not on the immune system but on the detachment of the melanocytes from the basal membrane, accentuated by some contributory causes and primed by a currently unknown factor.

One by one, all the pieces of the puzzle were fitting together: everything had its place; every question was being answered. Having completed the puzzle, I looked at it from above. It was there, in writing: MIA is the cause of vitiligo… you just have to prove it!

The rest is contained in a scientific article: Bordignon M. et al. “Role of alpha5beta1 integrin and MIA (melanoma inhibitory activity) in the pathogenesis of vitiligo”. Journal of Dermatological Science, 2013.

A small step for a young dermatologist dedicated to science; perhaps a great leap for scientific research on vitiligo and for all patients suffering from this disease.