"Speaking of Vitiligo..."

Do we truly know what causes vitiligo? Is it really an autoimmune disease? Isn’t the cause “unknown”, and aren’t there many alternative theories that are equally likely? These questions drive me nuts, but people keep asking them, so I thought I should probably take the time to answer. I recently attended the first international symposium on vitiligo in Rome, Italy, where many vitiligo experts came together to discuss our research in vitiligo, as well as what we should focus on next. Dr. Richard Spritz, who has done wonderful work on the genetics of vitiligo, said that he was frustrated that papers published on vitiligo still start with, “The cause of vitiligo is unknown. There are many hypotheses as to the true cause. . .”. He finds this frustrating because we know SO MUCH about what causes vitiligo. I then got up to the podium and agreed, saying that whoever writes those sentences must have missed all of the papers that have been published in the past 30 years.

In fact, we know more about what causes vitiligo than any other autoimmune disease, including diabetes, thyroiditis, lupus, and others. It’s true that there have been many different ideas in the past about what causes vitiligo, from autoimmunity to cellular stress, chemicals, nerves, and genetics. And many scientists have spent a long time arguing about which one was correct. It turns out that most of them are correct, and work together to cause the clinical disease we call vitiligo. Have you ever heard the story about the blind men and the elephant? It describes a situation in which 3 blind men stumble upon an elephant and attempt to determine what it is, simply by touching it. One at the trunk believes it is a snake, another at the tusk claims it is a piece of rock, and the third at the leg argues that it is a pillar. At first they argue vehemently, but once they discuss and move around to examine it from the others’ perspectives, they collaborate to realize that each of them was correct in describing part of the whole, and that together they could discover the bigger truth.

Early clinicians noticed that vitiligo frequently occurred in patients and their family members with other autoimmune diseases, particularly thyroid disease and juvenile diabetes, suggesting that it was also autoimmune. Antibodies to melanocytes were discovered in the blood of patients, which seemed to support this idea. Then, others found that melanocytes from vitiligo patients were abnormal and sick, and then argued that it was primarily a degenerative disease of melanocytes, and any observed immune responses were only secondary to this degeneration. Then examination of affected skin under the microscope revealed that T cells were right next to dying melanocytes, again suggesting that immune cells were key players in the disease.

Then an experiment found that immune T cells could be isolated from white skin, put together with unaffected, pigmented skin from the same patient, and the T cells crawled into this skin and killed melanocytes, proving that T cells were necessary and sufficient to cause vitiligo in the patient. The “Convergence Theory of vitiligo” was developed, essentially representing the communication among the 3 blind men when they figured it all out. This theory suggested that the abnormal melanocytes induced inflammation in the skin, which resulted in T cell-mediated killing of the melanocytes. This tied together both the cellular stress and autoimmune theories. Then additional studies found that certain chemicals could induce cellular stress in otherwise healthy melanocytes, which served as an environmental exposure that could also help to start the autoimmune disease.

That left another “competing” theory, the genetic theory. Well, stating this as an alternative theory is just silly, because genetics influences all of these pathways. The abnormal melanocytes are likely that way because of their genetic makeup. The hyperactive T cells that decide to target and kill melanocytes are likely that way because of their genetic makeup. The sensitivity to chemicals can also be affected by the patient’s genetic makeup. Thus, rather than being an alternative theory, studying the genetics of vitiligo patients could help us to understand a lot about what causes the disease, and that turns out to be true. Most of the genes that have been connected with vitiligo are key components of the immune response, confirming the importance of autoimmunity in vitiligo. A few others appear to be involved in melanocyte function and cellular stress, although there are much fewer of these. So this clearly connects genetics in vitiligo to the other theories. You can read more about this in my discussion with the geneticist Dr. Richard Spritz here.

That leaves just the “neural theory” of vitiligo, which is simply unsupported and probably not true at all. It was initially suggested because a subtype of vitiligo, segmental vitiligo, occurs only on one side of the body, and rarely crosses the center of the body. This is a similar pattern to shingles, which is a viral infection in the nerves of the skin and doesn’t cross the midline. So some thought that segmental vitiligo involved the nerves. But when examined closely, segmental vitiligo does not follow nerve patterns at all, and often crosses them in exactly the wrong direction. So this doesn’t support the involvement of nerves. Others thought nerves might be involved because emotional stress can affect the severity of vitiligo, but this occurs in other autoimmune diseases as well, and there’s no evidence that this is from nerves, but instead it’s probably related to hormonal changes that occur during emotional stress. Others thought nerves were involved because catecholamine chemicals, secreted by nerves, are elevated in the urine of vitiligo patients. But these are secreted by melanocytes as well, which makes a lot more sense as their source. Others implicated nerves because fish control their coloring by their nerves, but there’s no evidence this happens in mammals. Finally, some physicians reported that vitiligo improved on the same side as nerve injuries, but over time others reported the opposite. So in the end that leaves no evidence that nerves are involved in vitiligo, at least for now.

In summary, these observations make it pretty clear that vitiligo is an autoimmune disease that is initiated by melanocyte stress, which can be worsened by exposure to chemicals. Genes, inherited from your parents, influence all of these pieces. The Convergence Theory appears to be correct, and you can read more about the details here. Now when scientists, lay bloggers, or other people start to question the evidence for these accepted theories of vitiligo or question the “true cause” of vitiligo, it’s usually because they’re pushing their own interests, trying to sell something, or both. When scientists make discoveries that new proteins appear to be involved, they have an opportunity to connect this new data to existing data to strengthen it, or to question the mountains of existing data in order to make theirs look more important. This makes me suspicious. So be careful what you read, and always keep these caveats in mind as you think about your vitiligo!