Identifying Lupus's Key Culprits
Professor Dwight Kono (right) with co-author Professor Argyrios Theofilopoulos, chair of Immunology and Microbial Science. Photo by Kevin Fung.
It isn't only when something we rely on stops working that problems arise. Sometimes the worst outcomes result from something working well, but incorrectly.
That's the case for the 1.5 million Americans with lupus. Their immune systems work, but they have turned upon themselves, destroying the very cells and tissues they're meant to protect.
Now, Scripps Research Professor of Immunology and Microbial Science Dwight Kono has proved that three proteins, called Toll-like receptors (TLRs), are necessary for this autodestruction to occur. They could prove effective targets for new treatments for lupus and other autoimmune diseases.
Lupus causes a variety of symptoms that flare and subside, often including painful or swollen joints, extreme fatigue, skin rashes, fever, and kidney problems.
In response to infection, a healthy immune system produces antibodies to fight and destroy invading pathogens such as viruses and bacteria. But with lupus, something goes awry with the chain of events leading to antibody production, and the immune system produces "autoantibodies" that target some of the body's own molecules, cells, and tissues.
TLRs are proteins found in immune cells that normally help stimulate the immune system's initial response to foreign pathogens. Humans have 10 different types of TLRs. Some of them sit on the surface of immune cells and seek out molecules that appear on the coating of bacteria and viruses. Other TLRs reside inside immune cells in a compartment known as the endolysosome, where bits of foreign substances usually end up.
When bacteria or viruses enter the body, some are engulfed by immune cells and degraded in the endolysosome. Inside this compartment, resident TLRs detect the genetic material of the pathogens – viral DNA, viral RNA, and bacterial DNA – and stimulate immune cells to produce antibodies against these molecules.
But in lupus patients, the production of antibodies against foreign DNA and RNA seems to be particularly prone to error. Instead of producing antibodies to fight off the invading substances, the immune systems of lupus patients create autoantibodies that fight the body's own DNA and RNA. In fact, doctors often test for the presence of these "antinuclear" antibodies to diagnose lupus.
"That's the Achilles heel," says Kono. "These endolysosomal TLRs are needed for viral and bacterial immunity, but they open the possibility of self reactivity."
Scientists don't know quite how antinuclear antibodies develop, but have suspected for some time that TLRs might be involved. By engineering mice that lack three specific TLRs, Kono's team gathered evidence that they may play a role in the disease.
"Earlier studies had strongly suggested that endolysosomal TLRs were important, but if you eliminate one or the other you do not get a huge effect," says Kono. "So we asked, 'What happens if you get rid of all the endolysosomal nucleic acid-sensing TLRs at once?'"
Using mice genetically pre-disposed to lupus, the team engineered some mice to lack a gene that produces a protein that facilitates TLR transport. And what the scientists found was that those without that gene had fewer and less severe symptoms of lupus.
"It seems like these three TLRs are absolutely required for optimal autoantibody production," says Kono. The results "suggest that the three endolysosomal TLRs, or [the protein-producing gene] itself might be good targets for therapy," says Kono.
"We are definitely getting closer to understanding the etiology of this immune disease," Kono says, but more tests will be needed before these findings can be translated into treatments for patients.