Clinical example of Fogo-Selvagem erythroderma. Photo courtesy the Autoimmune Blistering Clinic, Department of Dermatology, University of Sao Paulo, Brazil
Fogo Selvagem (FS)—Portuguese for ‘wild fire’—is a superficial blistering form of pemphigus foliaceus endemic in the Mato Grosso do Sul region of Brazil, and a presentation at the 2015 World Congress of Dermatology in Vancouver examined the latest findings relating to its etiology.
The presentation by Dr. Valeria Aoki covered insights gleaned over decades that have led to the current understanding of FS. She is associate professor and vice chair of the Department of Dermatology, Faculty of Medicine, at the University of São Paulo, Brazil, and a co-investigator in the Cooperative Group on Fogo Selvagem research, University of North Carolina at Chapel Hill.
Localized vulnerable population The indigenous Terena people on the Limao Verde reservation in Brazil are at 14 times the risk of developing FS than the general population, said Dr. Aoki. This genetic and geographic localization has led to ongoing research since the 1980s to investigate both potential genetic predispositions and environmental causative factors.
At the time of her talk the most recent findings from the Cooperative Group, published in The Journal of Investigative Dermatology (Mar. 2015; 135(3):913–915) suggest that the etiology of FS may begin with proteins in sand fly saliva. Prior research has shown that many individuals in this tribe have a genetic vulnerability that can cause the immune system—primed to respond to certain foreign antigens—to become confused and sensitive to some of the body’s own antigens, leading to a pathogenic reaction.
“When you have inhabitants from rural areas, they are exposed to hematophagous insect bites. They may suffer a molecular mimicry, and start producing IgN and IgE auto-antibodies, but they are still normal controls, normal population,” said Dr. Aoki.
“That’s why we find these auto-antibodies present in healthy populations,” she said. “They only recognize the extracellular domain 5 of desmoglein-1. They start producing, then IgG-1 that recognizes this portion of the protein. However, if you are not so lucky, you are born with a certain sequence allele of the HLA-DRB-1 in the position of 61 to 74, you may develop [FS]. You have a relative risk of 14. Then you start making a shift, you start producing IgG-4 auto-antibodies that are pathogenic, and will lead to disease onset.”
Tracking down this potential insect trigger for the disease has been a long effort, requiring significant medical detective work.
“In this region, we detected many familial cases,” said Dr. Aoki, noting that in the village being researched up to three consecutive generations of some families developed FS. “In terms of genetics, we know that there is a relative risk of 14 among those individuals who live in these endemic areas with the HLA sequence seen in the indigenous tribe would have 14 times more risk for having their immune system recognize different parts of the antigen—intramolecular epitope spreading.
“You start recognizing different parts of the [desmoglein-1] protein, which are EC1 and EC2.Then you may also shift in terms of IgG isotypes,” she said. The immune system begins producing IgG4, then developing FS.
“It is a very nice model, and it is important,because it serves other autoimmune blistering diseases,and possibly other diseases that are non-dermatological, such as lupus for instance,” she said.
Searching for a trigger “Finally, is there any environmental trigger for this disease? That’s the question that has been haunting us for years: How could we start studying environmental triggers in FS?” Dr. Aoki said.
One case-control study was conducted in the indigenous tribe in the endemic area, she said. Risk factors examined included type of housing and infectious diseases that geographically overlapped with the region of endemic pemphigus. Most of the residents in the area—poor farmers—lived in adobe homes with thatched roofs that would increase exposure to hematophagous insects,she said.
Two infectious diseases that overlapped the endemic area were Chagas disease and cutaneous leishmaniasis, said Dr. Aoki. Investigators did find individuals in the endemic region with Chagas disease whose immune system reacted to the pemphigus autoantigen, but active Chagas and pemphigus seemed to be mutually exclusive, she said. One patient who developed endemic pemphigus in 1990 developed cutaneous leishmaniasis six years later.
The team looked outside the endemic area to individuals in the rest of Brazil, and found up to 50% of patients with either Chagas disease or cutaneous leishmaniasis reacted to the desmoglein-1antigen.
Finding the sand fly
With the help of U.S. National Institutes of Health investigators Dr. Jesus Valenzuela and Dr. José M.C.Ribeiro, experts on insects and salivary glands, Dr. Aoki and colleagues extracted three proteins from the salivary gland of the sand flies that are vectors for leishmaniasis, she said. These proteins were LJM-11, -17, and -143.
“The next step was to test if our patients would recognize this salivary gland protein from the sand flies. And our results were that patients with fogo selvagem recognize strongly one of our proteins: LJM-11,” said Dr. Aoki.
As well, mice inoculated with desmoglein-1 reacted to the sand fly protein LJM-11, and mice inoculated with LJM-11 reacted to desmoglein-1, she said.
“So this is a proof that this protein from the sandfly cross-reacts with desmoglein-1.”