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Jun 30, 2009

Investigators Implicate Endolysosomal TLRs in Lupus Development

  • A team from The Scripps Research Institute reports that endolysosomal toll-like receptors (TLRs) are responsible for triggering lupus. The study was done in mice and is reported in the early edition of the Proceedings of the National Academy of Sciences published the week of June 29.

    Humans have 10 different types of TLRs, four of which reside inside immune cells in a compartment known as the endolysosome, where bits of foreign substances usually end up: TLR 3, TLR 7, TLR 8, (which doesn't exist in mice), and TLR 9. These TLRs specifically detect the genetic material of pathogens and stimulate immune cells to produce antibodies against these molecules. The most common types of autoantibodies found in lupus patients are ones to the body's own genetic material, however.

    “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 Dwight Kono, M.D., professor of immunology and microbial science. “So we asked, what happens if you get rid of all the endolysosomal nucleic acid-sensing TLRs at once?”

    To study these TLRs, Dr. Kono and colleagues eliminated TLR 3, TLR 7, and TLR 9 in lupus-prone mice. They achieved this by mutating the Unc93b1 gene, which normally produces UNC-93B, a protein that ferries the TLRs to the endolysosome.

    Compared to lupus-prone mice with a functioning Unc93b1 gene, the mice with the Unc93b1 mutation produced fewer antinuclear antibodies and had fewer and less severe symptoms of lupus.

    The team then treated the mutant mice with a substance that stimulates TLR 4, as TLR 4 stimulation is known to promote the production of autoantibodies. Once again, mice lacking functioning TLR 3, TLR 7, and TLR 9 did not develop lupus.

     



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