2005 General Immune System Function
With funding from the LRI, Dr. Lemke pursued a novel idea: that a curious family of “TAM” receptors might function as a core ‘control switch’ over the immune system’s inflammatory response.
He was on target, and reported finding this entirely new and powerful molecular switch in the journal Cell in December 2007.
Now that this switch has been identified, new methods can be pursued to shut down uncontrolled inflammation, restore immune system regulation, and treat chronic autoimmune disorders such as lupus.
In autoimmunity, the immune system designed to fend off outside invaders mistakenly mounts an out-of-control destructive inflammatory attack against the body’s own tissues and organs.
In his study, Dr. Lemke builds upon findings that he and his team previously reported, when he noticed that mice genetically engineered to be born without a tiny family of three receptors—TAM receptor tyrosine kinases—developed an autoimmune illness similar to lupus in humans.
In the Cell article, Dr. Lemke illustrates how these “TAM” receptors, under normal circumstances, are so critical in stopping the immune system from mounting an out-of-control inflammatory response against invading viruses and bacteria. When chemical messengers (cytokines) prompt immune cells to attack, he explains, they also activate TAM receptors, which then alert the cells to no longer react to the cytokines. This keeps the immune system orderly as well as relatively tranquil.
But in people with lupus and certain other autoimmune illnesses, the TAM signalling network may be seriously compromised. The switch to inhibit inflammation on this network may be absent—thereby resulting in immune system pandemonium.
People with lupus tend to have low levels of a blood factor (proteins S) that TAM receptors require to carry out their job. Giving modified versions of protein S, or its related TAM activator Gas6, to people with lupus may represent a means of halting the immune system destruction of precious organs and tissues. “This is definitely something we intend to investigate,” Dr. Lemke said.
Further results published in 2009 showed that protein S keeps the blood flowing in more than one way, contributing to the formation and function of healthy blood vessels.
The researchers found that mice lacking protein S suffered massive blood clots, but also had defective blood vessels that allow blood cells to leak into the surrounding tissue.
"Protein S is a really interesting molecule," says Greg Lemke, Ph.D., a professor in the Salk's Molecular Neurobiology Laboratory, who led the study, which appears in the Sept. 1, 2009, issue of the Journal of Clinical Investigation. "During the course of evolution, it was co-opted from the coagulation cascade for the regulation of inflammation in the immune system."
The moment a blood vessel is breached, the coagulation cascade activates a series of enzymes in domino-like fashion, which allows the rapid formation of a plug at the site of injury. As part of a carefully calibrated system of checks and balances, Protein S aids with the inactivation of clotting factors Va and VIIIa, preventing excessive clotting.
In patients who are born with two abnormal copies of the protein S gene, a severe form of thrombosis called purpura fulminans can result. This life-threatening condition involves severe clotting throughout much of the body, ultimately causing death to the tissues.
But Protein S also binds to and activates a trio of receptors, Tyro3, Axl, and Mer, which are collectively known as TAMs. Apart from being involved in a host of cellular processes, the TAMs most famously act as a molecular "trip switch" that prevents the immune system from spiraling out of control and turning against one's own body.
Though protein S's dual role in coagulation and inflammation is one that scientists have known about for years, its exact function has remained a mystery. Lemke and Burstyn-Cohen, wanting to understand the molecular details, created knockout mice missing the ProS1 gene, which encodes protein S.
"It was the last gene encoding a critical component of the blood coagulation cascade to be inactivated in mice," says Burstyn-Cohen, "and the resulting phenotype is probably the most severe of them all." Mice without functional protein S die in utero with massive consumptive blood clots, which soak up all available clotting factors, causing severe hemorrhaging elsewhere.
In addition to blood clots, these mice also had problems with vascular integrity and the functioning of these blood vessels. "TAM receptors are important for maintaining the physiological integrity of the smooth muscles that line blood vessels," explains Burstyn-Cohen. "Without protein S the muscle layer is disordered, and the vessels become leaky."
Like other components of the clotting cascade, most of the circulating protein S is produced by hepatocytes in the liver, or so it was thought. When Burstyn-Cohen shut down the production of protein S in hepatocytes, however, levels of protein S only dropped by half. A closer look revealed that the endothelial cells lining blood vessels themselves provided most of the remaining protein.
"Blood clotting disorders are a good target for gene therapy since the absence of a single factor can sabotage the body's ability to stanch bleeding or stop the coagulation process," says Lemke. "Our findings suggest that in addition to hepatocytes, endothelial cells, which are easily accessible via the circulatory system, may be a particularly good target for gene therapy to correct genetic or acquired defects in ProS or other regulators of blood coagulation."
Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. Burstyn-Cohen T, Heeb MJ, Lemke G. J Clin Invest. 2009 Oct;119(10):2942-53.
TAM receptors are pleiotropic inhibitors of the innate immune response. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. Cell. 2007 Dec 14;131(6):1124-36.
Dr. Lemke has been awarded $1.4 million from the NIH and others to explore exciting new approaches to mastering this switch—shutting down the uncontrolled inflammation of lupus and other autoimmune illnesses by restoring immune system regulation.