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In a rare but serious complication of cancer, the body鈥檚 own immune system can start attacking the brain, causing rapid-onset memory loss and cognitive deficits. What triggers this sudden biological civil war was largely unknown.
Now, researchers at 麻豆学生精品版 have found that some tumors can release a protein that looks like a virus, kickstarting an out-of-control immune reaction that may damage brain cells.
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A Rapid Immune Attack
associate professor of neurobiology at 麻豆学生精品版 and last author on the study, explains that the swift escalation of symptoms鈥攚hich can include memory and behavioral changes, loss of coordination, and even seizures鈥攊s a hallmark of the disease, called anti-Ma2 paraneoplastic neurological syndrome. The disease is one of a group of cancer-related neurological syndromes that occur in less than one in 10,000 people with cancer. The precise symptoms of these diseases vary, but all involve rapid immune reactions against the nervous system. 鈥淭he symptoms come in quickly and can be quite debilitating,鈥 Shepherd says.
鈥淭his fascinating research illustrates how tumor cells can manipulate their environment,鈥 says ., executive director of the Comprehensive Cancer Center at Huntsman Cancer Institute at the University of Utah and a Jon M. and Karen Huntsman Presidential Professor in Cancer Research at the U. 鈥淲e hope that this innovative transdisciplinary research will positively impact both the lives of cancer patients and of those who experience neurological symptoms.鈥
Stacey L. Clardy, M.D., Ph.D., a neurologist at U of U Health and a coauthor on the study, adds, 鈥淢ost patients begin to experience these unusual neurologic symptoms before they even know they have a cancer.鈥
These rapid-onset symptoms are the result of the immune system suddenly starting to target specific proteins that are found in the brain. Scientists knew that this flare of immunity often targets a protein called PNMA2. But nobody knew why PNMA2 provokes such a strong immune response, which left researchers at a loss for ways to prevent it. 鈥淲e do not understand what is happening at the cellular or molecular level to actually cause the syndrome,鈥 Clardy says, 鈥渁nd understanding the mechanism of disease is crucial to developing better treatments.鈥
A Virus Lookalike
To figure out how PNMA2 kickstarts an immune reaction, a graduate researcher in neurobiology at U of U Health and the lead author on the study, examined the protein鈥檚 structure using advanced microscopy. When he saw the first clear image of the protein, he was 鈥渟o, so excited,鈥 Xu says. Multiple PNMA2 proteins had spontaneously self-organized into 12-sided complexes that bore a striking resemblance to the geometric protein shells of some viruses.
One of the immune system鈥檚 healthy functions is to attack viruses, and PNMA2鈥檚 virus-like structure makes it particularly prone to being targeted as well, the researchers found.
Wrong Place, Wrong Time
The location of PNMA2 in the body is also a crucial piece of the puzzle, the scientists found. 鈥淭his protein normally is only expressed in the brain, in neurons,鈥 Xu says, 鈥渂ut some cancer cells can express it, which can trigger an immune response.鈥
As long as PNMA2 stays in the brain, the immune system won鈥檛 react to it. But rarely, a tumor elsewhere in the body will start producing PNMA2 protein. And when the immune system detects PNMA2 protein outside the brain, it reacts like it would to any foreign invader. The immune system makes antibodies that bind to the unfamiliar substance, and those antibodies direct immune cells to attack.
But, once activated, the immune system doesn鈥檛 just attack the PNMA2 produced by the cancer. It also targets the parts of the brain that produce PNMA2 normally, including regions involved in memory, learning, and movement. The brain normally has a degree of protection from the immune system, leaving the brain especially vulnerable to this immune onslaught.
In future work, the researchers aim to figure out which aspect of the immune response leads to patients鈥 rapid cognitive decline鈥攖he antibodies themselves, immune cells making their way into the brain, or some combination of the two.
Understanding how the immune system causes neurological symptoms may help scientists design targeted treatments, Shepherd says. 鈥淚f we show that PNMA2 antibodies are the culprit that really drives the neurological symptoms, you could devise a way to block those antibodies from getting into the brain or mop them up with something as a treatment鈥 If you can alleviate some of those neurological symptoms, it really would be huge.鈥
