http://unisci.com/stories/20013/0713012.htm
13-Jul-2001
Salk scientists have created an animal
model for autoimmune diseases that closely mirrors the perplexing patterns
of symptoms observed in human autoimmunity, including an increased susceptibility
of females over males.
The model suggests a new mechanism
for the origin of autoimmunity and offers a potential new approach for
treating this class of diseases.
"These mice display a broad spectrum
of autoimmune disease symptoms, including rheumatoid arthritis and lupus,"
said Salk Professor Greg Lemke, senior author of the study, which appears
in the current Science.
The autoimmune mice were created
by deleting or "knocking out" three genes: Tyro3, Mer and Axl, which encode
a class of molecules known as receptor tyrosine kinases.
"An important next step is to examine
these genes in people with autoimmune diseases and see if variations can
be found that associate with arthritis, lupus or diabetes," said Lemke.
"The products of these genes would then be candidates for drug targets
to treat autoimmune conditions by boosting the functions of their encoded
proteins back up to normal levels."
Receptor tyrosine kinases normally
receive messages from a cell's external environment and, upon activation,
add a phosphorus molecule to intracellular proteins. The addition of phosphorus,
called phosphorylation, has been commonly documented as a regulatory signal
in many systems, including the loss of growth control that triggers cancer.
"In this case, there are excess lymphocytes
that appear normal, not cancerous," said Lemke. "But they are 'hyper-activated,'
in a constant state of 'alert.'"
Lemke's group found that the model
animals produce enormous numbers of lymphocytes; their spleens can be up
to ten times larger than normal. Lymphocytes include B cells, which produce
antibodies, and T cells, specialized for functions such as killing viral-infected
cells and encouraging the proliferation of B cells.
Normally, lymphocytes are stimulated
to divide during the course of an infection when they encounter a class
of cells called APCs (for antigen presenting cells). The APCs essentially
turn on lymphocytes, stimulating them to make antibodies or perform other
infection-fighting functions. When an infection is over, the APCs go off
duty and lymphocyte numbers and activity taper off.
"The genes we removed from these
mice are normally active in the antigen-presenting cells," said Lemke.
"What appears to be happening is that when these receptors are absent,
the APCs never shut down after activation -- they don't 'self-extinguish'
but remain in a red-alert state and keep the lymphocytes in this state
as well. Indeed, the entire immune system remains chronically activated."
"As a result, we think the APCs overwhelm
the regulatory mechanisms that normally distinguish 'self' from 'non-self.'"
Other mouse models of autoimmunity
have focused on mutations in B and T cells themselves, which render mice
susceptible to arthritis and other diseases but do not always display the
sexual dimorphism seen in the Salk mice.
"In our mouse strains, the autoimmune
problems are more severe in the females, which have average life spans
12 weeks shorter than those of males. This is similar to the situation
in many human autoimmune diseases," said Lemke. "Lupus, for example, is
diagnosed almost ten times more frequently in women than in men."
The study showed that removing any
one or two of the receptor kinase genes also led to autoimmunity, and the
severity correlates with the number of missing genes in an approximately
linear fashion.
"It's extremely unlikely that there
are many people missing all three of these genes," Lemke said. "It's more
probable that one of them is slightly defective or dysfunctional, leading
to chronic inflammation over time."
The study, called "Homeostatic regulation
of the immune system by receptor tyrosine kinases of the Tyro3 family"
was funded by the National Institutes of Health. Qingxian Lu, a senior
research associate in Lemke's laboratory, is first author.
The Salk Institute for Biological
Studies, located in La Jolla, Calif., is an independent nonprofit institution
dedicated to fundamental discoveries in the life sciences, the improvement
of human health and conditions, and the training of future generations
of researchers. The Institute was founded in 1960 by Jonas Salk, M.D.,
with a gift of land from the City of San Diego and the financial support
of the March of Dimes Birth Defects Foundation.
Related website:
The
Salk Institute for Biological Studies
[Contact: Warren R. Froelich, Suzanne
Clancy]