The New England Journal of Medicine
Richard Spritz, M.D. March 22, 2007

In a study appearing in the March 22, 2007 edition of The New England Journal of Medicine, researchers at the University of Colorado at Denver and Health Sciences Center and St. Georges, the University of London, have discovered a specific human gene involved in the chronic skin condition generalized vitiligo and also in an array of other autoimmune diseases. A group of approximately 80 different disorders that can involve almost any tissue, organ or system, autoimmune diseases affect 15 million to 25 million people in the United States. In women, they rank among the top ten causes of death.

In generalized vitiligo, melanocytes, the cells that make skin pigment, are destroyed. As a result, white patches appear on the skin, mucous membranes (tissues that line the inside of the mouth and nose) and perhaps the retina (inner layer of the eyeball). The hair that grows on skin areas affected by vitiligo sometimes turns white.

The researchers, led by Richard Spritz, MD, Director of the Human Medical Genetics Program at the University of Colorado at Denver and Health Sciences Center, began a search for the genes involved in vitiligo almost a decade ago with the help of the Vitiligo Society in the United Kingdom. The researchers sent a questionnaire to all members of the Society, and subsequently to the membership of the National Vitiligo Foundation based in the United States, asking them about their own vitiligo and whether other family members were affected. As part of the questionnaire, they also asked about other autoimmune diseases. What they learned was that about one-third of patients with vitiligo reported at least one affected relative and that vitiligo was very highly associated with other autoimmune diseases, especially thyroid disease, but also others such as pernicious anemia, rheumatoid arthritis, psoriasis, lupus, Addison’s disease and adult-onset autoimmune diabetes. In addition, the researchers found that close relatives of persons with vitiligo also have elevated risk of these same autoimmune diseases, even those relatives without vitiligo. These results suggested that families inherit specific genes that predispose to this entire group of autoimmune diseases.

The researchers then set out to find those genes. “In the beginning we studied families with multiple relatives affected with vitiligo,” said Dr. Spritz. The study monitored two series of vitiligo families from 1996 through 2005. In total, samples were obtained from 656 Caucasian individuals from 114 extended families with vitiligo and other autoimmune diseases from the United States and the United Kingdom.

“We searched for areas of the genome that affected relatives seemed to share disproportionately,” said Dr. Spritz. By searching the entire genome, the researchers found indications of shared regions of several chromosomes, but particularly on part of chromosome number 17, termed “17p.” This chromosomal region had previously turned up in searches for genes involved in causing another important autoimmune disease, systemic lupus erythematosus, particularly in families that also had members with vitiligo and other autoimmune diseases. However, that gene had never been specifically identified.

Through detailed analysis of chromosome 17p in the 114 families with vitiligo and other autoimmune diseases, Dr. Spritz and his colleagues were able to show that a specific gene in this region, NALP1, was key to predisposing family members to vitiligo and these other autoimmune diseases. Said Dr. Spritz: “About 25 percent of people with vitiligo get at least one additional autoimmune disease and NALP1 appears to be an important gene involved in this.”

Dr. Spritz believes the implications of this finding are pretty exciting. NALP1 controls part of what is called the innate immune system, which mediates our body’s first response to infection. “When we are attacked by viruses or bacteria, the innate immune system revs up what’s called the inflammatory pathways and then stimulates the rest of the immune system to action.” NALP1 appears to be particularly important in the skin, where it seems to function as part of the surveillance system for infection by bacteria. Certain infectious agentsThese bacteria thus may be triggers for autoimmune diseases, including vitiligo.

“What’s really exciting is that NALP1 hasn’t been specifically implicated in autoimmune diseases before,” said Dr. Spritz. “But NALP1 has been under intense study by basic scientists for some time because it was suspected of playing some important role. So, we are not starting from ground zero in terms of what we know about it.”

Learning about genes involved in causing disease helps researchers better understand the biological pathways involved, and that is essential for developing new treatments and, ultimately, ways to prevent disease altogether. “This discovery may open up new approaches to treatment, possibly for many different autoimmune diseases, and eventually may even lead to disease prevention, particularly in people with high genetic susceptibility,” said Dr. Spritz.

In fact, the most immediate applications might be for the disease that began the research – vitiligo. Doctors most commonly treat vitiligo with ultraviolet light to stimulate regeneration of skin melanocytes, a treatment whose efficacy is somewhat limited, perhaps because it does not simultaneously block autoimmune attack against melanocytes. However, if NALP1-mediated autoimmunity is due to elevated function of the inflammatory pathways, then drugs that specifically block these pathways might be of benefit, particularly if used in combination with ultraviolet light treatment to stimulate melanocyte regeneration.

Dr. Spritz and his team hope to soon begin organizing a clinical trial for vitiligo, based on their NALP1 discovery. “What we would like to do is a clinical trial in patients with vitiligo who are selected on the basis of having high risk due to this gene,” said Dr. Spritz. “We can actually choose the right patients as being most likely to respond. Unfortunately, it is very difficult to obtain research funding for clinical trials.”

Dr. Spritz foresees other labs using the information from this study to replicate or test their results in other families or groups of patients, both with vitiligo and with other autoimmune diseases, to determine how broad potential applications might be. His hope is that NALP1 is found to be involved in many other autoimmune and autoinflammatory diseases such as type 1 diabetes, Addison’s disease, thyroid disease, and lupus, among others. “All autoimmune diseases are complex, involving multiple different genes interacting with environmental triggers in concert. You are born with your genes, but you are not born with these diseases. If NALP1 turns out to be one of the major genes involved in many different autoimmune diseases, and if we can interrupt its effects, we may have the chance to treat numerous chronic autoimmune disorders like vitiligo, lupus, psoriasis, diabetes, and others, and eventually perhaps eliminate them altogether.”

Funding for this study was provided by the National Institutes of Health, the Vitiligo Society and the National Vitiligo Foundation.

SOURCE: Jin Y, Mailloux C, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA. NAPL1 In Vitiligo-Associated Multiple Autoimmune Disease. NEJM. 2007; 356,1216-25.