A group of men living amid the gold mines and disappearing jungles of northeastern Colombia, is giving a Medical College of Georgia scientist unprecedented access to study how the wrong combination of genetics and environment cause the body to turn on itself.
Type 1 diabetes, rheumatoid arthritis and lupus are familiar autoimmune diseases; but it's the rare endemic pemphigus foliaceus – which plagues nearly 5 percent of men age 30 to 70 and a smaller percentage of postmenopausal women living on the outskirts of the tiny municipality of El Bagre, Colombia – providing a rare opportunity to dissect the factors that prompt the immune system to harm instead of protect.
"The cells of the patients, they will tell us," says Dr. Ana Maria Abreu-Velez, dermatologist, immunologist and a native of the country where the disease surfaced in the mid-1980s as a mining boon changed the landscape. "These people were dying. They had huge blisters, their skin was coming apart," she says of the disease in which the immune system attacks multiple proteins that hold skin cells together. The disease can be limited to patches on the skin but its more deadly systemic version can spread across the skin and, preliminary data indicates, to other organs such as the heart and brain.
In 1990, Dr. Abreu-Velez was living less than an hour's flying time from El Bagre when she first made the trip through 33 creeks and the jungle to get to the town. The disease was emerging as those jungles were cleared to get to the gold in the rivers and rocks. That journey changed her life and the lives of patients with the disease, who were shunned by townspeople and even family members concerned about black magic and contagion. Victims congregated on the outskirts of town, untreated and dying. Dr. Abreu-Velez helped local medical doctors called shaman and townspeople understand that the disease was not contagious and establish programs and laws to make food and health care available.
Today she follows about 150 patients with the disease as well as those at risk, men and postmenopausal women living in the most rural areas outside the town. Last year she published six articles in journals including the Journal of the American Academy of Dermatology and the Journal of Dermatologic Science detailing unique aspects of the disease. Her latest finding, detailed in the February issue of Archives of Dermatology Research, is an inexpensive blood test that can be used in the field clinically not only to identify those with the antibodies to immune system triggers called antigens, but also the 30 percent of those with antibodies that might subsequently develop the disease. The test enables intervention to halt disease progression, with treatments such as antioxidants that destroy damaging free radicals and tightly controlled doses of immunosuppressive drugs that lessen the immune response without significantly increasing susceptibility to infectious diseases, such as tuberculosis and herpes, which are pervasive in the rural environment. The test, like the disease itself, will also help scientists dissect disease development and better understand autoimmunity.
"When you are doing epidemiological studies, you need to find the source of the disease," she says. "With this test, we can look for antibodies and the immune response and can follow the whole process. We can detect cases before they appear clinically, " she says. One of her many goals is to identify that lucky subset of people who develop antibodies but not the disease and see if she can find why they don't. "What is the pivotal trigger. What molecule can you block and there is no disease?"
Dr. Abreu-Velez actually identified the two primary antigens, or points of attack by the immune system, in the pemphigus variant found in her native land. Desmosomes and the plectins linked to them are glycoproteins, protein-carbohydrate compounds that work like glue to help hold skins cells together and give skin its shape. "It's like a bridge," she says, and most tissues have this bridge, including cardiac and brain tissue, which is why these areas can be affected in the worst cases of pemphigus.
In work published in the October 2003 Journal of the American Academy of Dermatology, she reports characteristics of the El Bagre variant that distinguish it from similar diseases, including Senear-Usher, a combination of lupus and pemphigus found sporadically across the United States. The El Bagre disease has much in common with another form of endemic pemphigus foliaceus found in some similarly rural and mined regions of Brazil, but that disease affects primarily children, including boys and girls, and although the two diseases share antigens, they do not share all of them.
She believes that something the El Bagre disease has in common with all types of autoimmune disease is environmental triggers. Her work published in 2003 in the American Journal of Dermatopathology showed that people with and without the disease living in El Bagre have mercury in their skin, nails, hair and urine. The acidic soil of El Bagre is naturally rich in minerals, metalloids and trace elements. However mercury, which has been shown in the laboratory to trigger an autoimmune response in animals with the right genetics, is present because it's used in gold mining. Mercury was found in highest levels in those with the disease and closely associated with the antigen desmosomes in those patients.
Ultraviolet radiation exposure, which has increased dramatically because of jungle destruction, also is a major factor, she says. Exposure to herpes virus seems to be an aggravating factor while female hormones seem to protect against this particular variant of the disease since only postmenopausal women get it, she says.
"We must understand how all these environmental factors combined with genetics result in disease," Dr. Abreu-Velez says. The unfortunate synergy is evident in the fact that the disease perpetuates in an area where many blood relatives live in close association. Every time she travels to El Bagre, there are five to nine new patients and just about that many have died. "If it were an epidemic, like the flu, the levels would change over time," she says.
Funding sources for Dr. Abreu-Velez's work include the Embassy of Japan in Colombia, Colombia's State Tax Stamp Program, the University of Antioquia and MCG's Institute of Molecule Medicine and Genetics. She recently submitted a grant to the National Institutes of Health to further explore immunological differences and causative factors in the Brazilian and Colombia variants.
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