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Scripps research scientists find new genetic mutation that halts the development of lupus
January 18, 2008Findings pinpoint numerous proteins as potential autoimmune disease targets
The new study was published in the January 18 edition (Volume 28, Issue 1) of the journal Immunity.
The lupus-suppressing action is the result of what is known as a nonsense mutation of the Coronin-1A gene (Coro1a) required for the development of the disease. A nonsense mutation causes the gene to produce proteins that no longer function. The Coronin-1A gene is a multifunctional regulator of the cytoskeleton, a network of protein fibers or filaments in the cell that helps maintain cell shape and is the key contributor to cell movement.
"The mutation reduced symptoms of the disease by interfering with the development and activation of T cells and other immune responses," said Dwight Kono, an associate professor at The Scripps Research Institute. "These findings solidify the critical role of Coronin-1A in normal immune responses, and identify it as a potential therapeutic target for lupus."
Two Sides of Lupus Genetics
Systemic lupus erythematosus is a serious autoimmune disease that affects approximately 1.5 million Americans. It is influenced by genetic, environmental, and hormonal factors, although genetic predisposition appears to be the single greatest contributor to its onset.
There has been considerable interest in defining the genetics of systemic lupus erythematosus in recent years, not only for gaining a better understanding of the fundamental causes of the disease but also for the development of potential therapies.
"We were searching for a lupus susceptibility gene," Kono said. "After mapping and cloning the Coronin-1A gene, we discovered this spontaneous mutation in a single strain of mice-those that don't get severe or systemic lupus-like disease. More than likely, the mutation had existed undetected in our mouse colony for years.
"We ended up cloning a disease-resistance gene when we were thinking about doing the opposite," he continued. "Suppressive genes may, in fact, play an important role in lupus susceptibility."
The study suggests genetic-mapping studies need to adequately distinguish between predisposing or suppressive alleles or alternate gene forms, and that other lupus-related loci might also be associated with suppressive alleles. In addition to traditional predisposing genes, disease-suppressing genes and spontaneous mutations, as in the case for CoroLmb3, are likely to be important contributors to an entire repertoire of genetic variations that could help alter the onset and severity of the disease in lupus patients.
"Obviously, these types of variations will further complicate the identification of susceptibility genes," Kono added. "However, as in the case of disease-suppressing genes such as we found in our study, their identification can provide important clues to pathogenesis and possibly therapy."
Pointing to New Possibilities
The Scripps Research scientists found the mutation on a single genetic locus-the position of a gene on a chromosome-called Lmb3 that plays a major role in modulating autoimmunity in transgenic mice. The cloned version of the Lmb3 mutation resulted in developmental and functional alterations in T cells, including reduced migration, survival, and activation. The study also showed that the Lmb3 autoimmune-suppressing phenotype could be transmitted only through Coro1aLmb3 T cells.
"The fact that its action appears to be somewhat specific for T cells is unusual," Kono said. "Because we were able to show that blocking CoroLmb3 has specific effects, this work suggests other cytoskeleton proteins might prove to be good targets. This opens up an area that hasn't really been considered, and gives more impetus to study these genes for autoimmunity."
Because the actin cytoskeleton is essential for many crucial cellular functions and involves complex regulatory mechanisms in specific cell types, these new findings highlight the importance of actin regulation in lupus pathogenesis. They also suggest that alteration of an actin-regulatory protein can have limited but important effects on specific immune system functions.
"There may be quite a few regulatory proteins that can be used as targets," Kono said. "We really don't know right now. What we would like to do is identify all the genes that block autoimmunity one way or another. Finding these suppressing genes may be important in identifying future therapeutic targets."
Scripps Research Institute
"The mutation reduced symptoms of the disease by interfering with the development and activation of T cells and other immune responses," said Dwight Kono, an associate professor at The Scripps Research Institute. "These findings solidify the critical role of Coronin-1A in normal immune responses, and identify it as a potential therapeutic target for lupus."
Two Sides of Lupus Genetics
Systemic lupus erythematosus is a serious autoimmune disease that affects approximately 1.5 million Americans. It is influenced by genetic, environmental, and hormonal factors, although genetic predisposition appears to be the single greatest contributor to its onset.
There has been considerable interest in defining the genetics of systemic lupus erythematosus in recent years, not only for gaining a better understanding of the fundamental causes of the disease but also for the development of potential therapies.
"We were searching for a lupus susceptibility gene," Kono said. "After mapping and cloning the Coronin-1A gene, we discovered this spontaneous mutation in a single strain of mice-those that don't get severe or systemic lupus-like disease. More than likely, the mutation had existed undetected in our mouse colony for years.
"We ended up cloning a disease-resistance gene when we were thinking about doing the opposite," he continued. "Suppressive genes may, in fact, play an important role in lupus susceptibility."
The study suggests genetic-mapping studies need to adequately distinguish between predisposing or suppressive alleles or alternate gene forms, and that other lupus-related loci might also be associated with suppressive alleles. In addition to traditional predisposing genes, disease-suppressing genes and spontaneous mutations, as in the case for CoroLmb3, are likely to be important contributors to an entire repertoire of genetic variations that could help alter the onset and severity of the disease in lupus patients.
"Obviously, these types of variations will further complicate the identification of susceptibility genes," Kono added. "However, as in the case of disease-suppressing genes such as we found in our study, their identification can provide important clues to pathogenesis and possibly therapy."
Pointing to New Possibilities
The Scripps Research scientists found the mutation on a single genetic locus-the position of a gene on a chromosome-called Lmb3 that plays a major role in modulating autoimmunity in transgenic mice. The cloned version of the Lmb3 mutation resulted in developmental and functional alterations in T cells, including reduced migration, survival, and activation. The study also showed that the Lmb3 autoimmune-suppressing phenotype could be transmitted only through Coro1aLmb3 T cells.
"The fact that its action appears to be somewhat specific for T cells is unusual," Kono said. "Because we were able to show that blocking CoroLmb3 has specific effects, this work suggests other cytoskeleton proteins might prove to be good targets. This opens up an area that hasn't really been considered, and gives more impetus to study these genes for autoimmunity."
Because the actin cytoskeleton is essential for many crucial cellular functions and involves complex regulatory mechanisms in specific cell types, these new findings highlight the importance of actin regulation in lupus pathogenesis. They also suggest that alteration of an actin-regulatory protein can have limited but important effects on specific immune system functions.
"There may be quite a few regulatory proteins that can be used as targets," Kono said. "We really don't know right now. What we would like to do is identify all the genes that block autoimmunity one way or another. Finding these suppressing genes may be important in identifying future therapeutic targets."
Scripps Research Institute
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Lupus patients perceive benefit from cardiovascular disease prevention counseling program
According to a new study by Hospital for Special Surgery investigators presented at the American College of Rheumatology meeting on October 21 in Philadelphia, most lupus patients are not aware that their condition puts them at a higher risk for cardiovascular disease and a counseling program is a valuable way to promote education and lifestyle change.
Stanford study identifies cellular mechanism that causes lupuslike symptoms in mice
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National report shines light on lupus 50-year treatment drought
Today, The Lewin Group, a national health care consulting firm, issued recommendations on ways to overcome the barriers that have obstructed lupus drug development resulting in no new drug approval for this disease in more than 50 years - since the Eisenhower Administration.
Promising new target emerges for autoimmune diseases
University of Michigan scientists say they have uncovered a fundamentally new mechanism that holds in check aggressive immune cells that can attack the body's own cells.
McGill/JGH researchers successfully reverse multiple sclerosis in animals
A new experimental treatment for multiple sclerosis (MS) completely reverses the devastating autoimmune disorder in mice, and might work exactly the same way in humans, say researchers at the Jewish General Hospital Lady Davis Institute for Medical Research and McGill University in Montreal.
Taking the Needle's Sting Out of Diabetes
Found in 30% of all human cancer tumors, the Ras protein literally "drives cells crazy," says Prof. Yoel Kloog, the dean of the Faculty of Life Sciences at Tel Aviv University. Prof. Kloog was the first in the world to develop an effective anti-Ras drug against pancreatic cancer, currently in clinical trials.
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