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The Way To a New Discover

Disclaimer: I collect in this section a series of thoughts that only intend to explain my scientific and clinical path that led me to the hypothesis which I then demonstrated. This section contains data and personal opinions which have no academic or educational value, but are only for narrative purposes. M. Bordignon, MD, PhD.

 

Since I started my residency in Dermatology at University of Padua (Italy), I immediately dedicated my time to the clinical and research activities, realizing immediately that a physician dedicated to science must also have a clear conception of the clinical expression of the disease, and that only in a second time he could target its studies on the molecular components.

 

It so happened that during my second year of residency I started taking care of patients suffering from vitiligo. With the availability of many treatments (phototherapy, microphototherapy and more) I thought  "for sure now I will feel better all my patients!".

 

And so I dedicated myself to accurately visit men, women and children suffering from vitiligo ... in the those years, I met many people and many different stories, often connected to the suffering in the soul that this disease (considered by many as just "cosmetic"!) causes in those who are affected. And with the people, I observed their hypopigmented patches, spread almost everywhere but very frequently in some characteristic anatomic sites (face, hands, feet) and often variously treated ... but still there, as if this spots would like to take joke of the medical science and its practitioners, as if they would like to challenge us Dermatologists and our theories.

 

And patient after patient, spot after spot, ineffective therapy after ineffective therapy, I began to realize that I was faced with a great dermatological mystery ... in front of me there was a skin absolutely perfect in every detail ... no redness , no burning, no itching sensation, no change in the consistency or in the annexes, no scale or papule or wheal or otherwise. A skin like everyone else, but anyway so different for the total lack of pigmentation. Only a well-defined margin to try stopping the incumbent of the "white".

 

Pigmentation ... melanocytes ... but where these melanocytes ended up ? How did they to leave the skin without giving any other sign or symptom ... to my pathophysiological knowledge of the skin, this was really impossible! A cell that is destroyed or disappears without leaving any trace, very often always in the same areas ..... this phenomenon had no equal in the cutaneous diseases.

 

It's immune system's fault! This is the explanation that I heard in almost all the congresses! ... The immune system, this severe sentinel that too often turns against those who must protect ... but it's always really its fault? In medicine, over the years, a lot of guilty factors have passed such as viruses, genetics, immune system ... when you do not know whose fault it is, you must always consider the immune system (a bit like the butler, isn't it ?).

 

But if it is really the fault of the immune system, I was wondering, why our conventional weapons to defeat it (ie corticosteroids or immunosuppressants) are so ineffective against vitiligo? Was it really a so smart and clever  disease, able to give no sign of itself apart from hypopigmentation, to rise where it wanted and to render ineffective the immunosuppressive drugs although it was theoretically claimed to have an autoimmune pathogenesis?

 

It began to slowly make its way into my mind that it was not so clever itself ... the diseases, all of them, are stupid ... they act in their way because they can not do otherwise ... really, WE who do not understand them ! ... and perhaps, I think we had not really understood so much of vitiligo during these years!....

 

 

 

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So, I decided to try to understand something more.

 

I spent a lot of time for reading almost all the existing literature concerning vitiligo ... I wondered why an author claimed a determined autoimmune cause (ie autoantibodies..) , and a few months after another author promptly stated that cause failed the test of reproducibility. When in scientific discoveries the confirmations are folloewd by denials, there is always something going wrong!

 

I kept still asking myself also why everyone insisted on autoimmune pathogenesis of vitiligo, when all clinical and therapeutic and scientific also signs said the opposite! Yes, even the scientific evidence ... a lot of papers by various authors pointed out that there was nothing to be immunosuppressed ... but for some reason, some authors are always poorly taken into consideration. 

 

So I came to be convinced that maybe we dermatologists had not understand so much of this disease. And at that point, I behaved as always: if the path marked out does not convince me, I go for my way ... I should also go for first!

 

I started thinking about which elements should I consider first ... if it was not the fault of the immune system, what could cause this loss of melanocytes?

 

Watching and visiting my patients, I noticed something very simple: the sites where most commonly vitiligo developed are locations of trauma. Face, hands, feet, eyes are subjected to friction daily (even in very small amount, such as the use of shoes or wipe the mouth after eating, or washing the hands and so on) .... and this could not be a coincidence! other diseases have an already stated role for traumatism (such as psoriasis) .. why this feature could not be referred also to vitiligo? .... yes, the trauma seemed to me a good starting point ... just remained to understand why trauma provocated vitiligo in some people but not in all the rest ! very simple, isn't it ???

 

The day I realized this thought I was happy: I had taken the first step ! And maybe this time, the road would take me very far away! (...)

 

 

 

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The traumatism seemed like to be a good starting point ... but how it was linked to the formation of hypopigmented patches?

 

As often happens in life, the solution was under my nose. From a quick search on Pubmed (the database of scientific publications in the medical field) I found an article really fantastic !

 

An English author had discovered that if we consider the pigmented skin of a patient suffering from vitiligo (close to a white spot already present) and we cause an artificial traumatism with an electric toothbrush for a few minutes and then if we go to pick up a piece of that skin and we analyze it, we will find the melanocytes detached from the basement membrane and in the middle of the epidermis.

 

When I read this article, I couldn't believe....

 

Short note: the normal structure of the skin is divided into two layers (epidermis and dermis) separated by a structure which is called dermal-epidermal junction (or basament membrane). Upon this structure the melanocytes are posed, and through their dendrites, they transfer the produced melanin to keratinocytes.  It is therefore impossible that melanocytes could be found normally in the middle of the epidermal layer. Or so I even knew before reading this article ...

 

I had an excellent starting data, but at the same time it opened up another question ... it has been scientifically proven that the trauma does remove the melanocytes from their place and this fact makes them disperse through the epidermal layer. But why this event happens only to those who are affected by vitiligo? ... obviously, there had to be something else, a so called "priming factor" that could allow this detachment. 

 

Another step was made: the detachment of melanocytes favoured by trauma (and probably also by other factors, such as oxidative stress and autoantibodies) was the true mechanism that causes vitiligo and that explained everything! This detachment achieved the result that the immune system was not alerted ... and that's why the patches were not red or itchy or inflamed ... and that's why the various immunosuppressants do not work at all or very poorly!

 

The melanocytes left the scene in silence, without any noise.

 

(to be continued...)

 

 

 

 

 

 

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