July 30, 2001 LA JOLLA, CALIF. -- 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 tapers 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.
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