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Wayne T. McCormack, Ph.D.
Associate Professor Department of Pathology, Immunology and Laboratory Medicine University of Florida College of Medicine Gainesville, Florida National Vitiligo Foundation |
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Our laboratory is investigating the possible roles of genes in vitiligo
susceptibility, so that we can learn more about the cause of vitiligo. It is
sometimes said that vitiligo "runs in the family", which means that
some people may be born with genes that make them more susceptible to developing
vitiligo, just as other people are born with genes that make them susceptible to
developing diabetes or cancer. We believe that in the case of vitiligo, some of
these genes may be important for the normal function of the pigment-producing
cells in the skin (melanocytes) and others may help regulate cells of the immune
system (B and T lymphocytes). Environmental factors, such as traumatic skin
injury, sunburn, or stress, probably influence whether or not an individual with
these "susceptibility genes" will ever actually develop vitiligo
during their lifetime. Depending on which genes are involved, what their normal
functions are, and what genetic changes are found in vitiligo patients, it might
be possible to design new treatments or to develop genetic testing to identify
individuals who might be predisposed to developing vitiligo so that
environmental risk factors can be avoided. Our genetic studies have so far
provided evidence for association of three different gene regions with vitiligo
susceptibility.
The first genetic region we find associated with vitiligo encodes the catalase gene. The catalase gene was selected as a candidate gene due to the reduced catalase enzyme activity and accompanying build-up of excess hydrogen peroxide observed in the entire skin of vitiligo patients. This excess hydrogen peroxide is toxic to melanocytes, and is the biochemical basis for the use of pseudocatalase to treat vitiligo by breaking down the hydrogen peroxide. We identified a genetic marker for the catalase gene that is significantly associated with vitiligo using two different association methods, and have identified a number of genetic changes in the catalase gene (although none have been linked to vitiligo yet). We are now testing the hypothesis that such variations in the catalase gene might lead to lowered catalase activity in vitiligo patient skin and contribute to the accumulation of excess hydrogen peroxide. The catalase gene may therefore be a susceptibility gene in some vitiligo patients. The second region associated with vitiligo is a tight cluster of four genes involved in a process called antigen processing, which determines how lymphocytes of the immune system detect pathogens that infect our cells and genetic changes that lead to cancer. The LMP7 and LMP2 genes encode parts of a complex enzyme that breaks down proteins inside the cell into small fragments (peptides). The TAP1 and TAP2 genes encode parts of a channel that helps to transport the peptides to the cell surface, where lymphocytes can examine the peptides. Most of these peptides are usually from normal "self" proteins and are ignored by the lymphocytes. But if a cell is infected with a virus or becomes a cancer cell, the lymphocytes can recognize the virus or cancer-related peptides as being foreign, and the cell is then killed by the immune system. During an autoimmune response, as appears to occur in the skin of some vitiligo patients, lymphocytes mistakenly recognize normal self proteins as being foreign, contributing to the killing of normal melanocytes. Although our preliminary results suggested that LMP7 was associated with vitiligo, further studies with more genetic markers in the region now suggest that the genetic association with vitiligo may actually be with the TAP1 gene. Ongoing experiments are focusing on a comparison of the expression of all four genes in vitiligo vs. control cells, and preliminary results suggest that there may be differences in TAP1 gene expression in patient cells. We will then compare the TAP1 gene sequences between vitiligo patients and control subjects, in order to identify mutations that may be affecting TAP1 expression and/or function in vitiligo patients. The third gene region that appears to be associated with vitiligo encodes the genes CTLA4 and CD28, which regulate the activation of T lymphocytes in the immune system. CD28 is a cell surface receptor that helps "turn on" T cells, whereas CTLA-4 is a cell surface receptor that helps to "turn off" T cells. A British group previously reported that CTLA-4 association occurs only in vitiligo patients with other autoimmune diseases, however, we have found weak evidence for association of this genetic region in vitiligo patients regardless of other autoimmune status. We gratefully acknowledge the many vitiligo patients and family members who have made this research possible by providing blood samples, and the support of the National Vitiligo Foundation. |