Two Proteins Have Unexpected Effects
On Autoimmune Diseases Such As Lupus
Blocking the effect of individual immune system proteins
that normally recognize viruses and bacteria produces
surprisingly different effects on the severity of autoimmune
diseases such as Lupus, researchers at Yale School of
Medicine report in the September issue of Immunity.
Drugs that target these proteins could be important
therapies for autoimmunity.
Led by Mark
Shlomchik, M.D., professor of laboratory medicine
and immunobiology at Yale, the researchers examined
the effect on disease when two similar Toll-like receptors
(TLRs) were removed from mice in the study.
"These data showed that TLRs do indeed modulate
overall autoimmune disease but not always in the expected
way," said Shlomchik. "These are the first
findings to show a definitive effect of TLR9 on anti-chromatin
antibodies and are also the first to show the effect
of TLR7 deficiency on autoantibodies and disease."
"We also found that mice without TLR9 lacked antibodies
to DNA and that mice deficient in TLR7 lacked antibodies
to RNA-associated antigens," said Shlomchik. "When
we examined the effect on disease, we were surprised
to find that the two TLRs had very different effects.
Mice deficient in TLR9 had worse disease, despite lacking
anti-DNA antibodies, while TLR7-deficient mice had a
milder form of disease."
Shlomchik said the study supports the idea that drugs
that block TLR7 in particular could be promising as
therapies, but he cautions against just blocking TLR9,
a strategy he said some biotech/pharmaceutical companies
may have already begun.
The study increases understanding of how the immune
system and B cells in particular are activated by 'self'
antigens, putting direct focus on the TLR family of
receptors. B cells make autoantibodies and may also
stimulate the T lymphocytes that destroy tissues.
Shlomchik and his co-authors plan to explore why TLR7
and TLR9 had different effects on disease. "We
were very surprised because these two receptors are
very similar to each other, generate signals in the
same way and are expressed in the same cell types,"
he said. "We need to make mice deficient in both
receptors to determine if TLR7 and TLR9 interact with
each other and if blocking both inhibits disease even
more effectively than blocking TLR7 alone."
Other authors on the study included Sean R. Christensen,
Jonathan Shupe, Kevin Nickerson, Michael Kashgarian,
and Richard Flavell.
The study was funded by the National Institute of Arthritis
and Musculoskeletal and Skin Diseases and the National
Institute of Allergy and Infectious Diseases.
Citation: Immunity, Vol. 25, 417-428 (September 2006)
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