ARTICLE IN BRIEF
Researchers discovered T cells in the blood of patients with Parkinson's disease (PD) that recognize alpha-synuclein peptides, providing evidence that PD may be, in part, an autoimmune disease, and an autoimmune-targeted treatment could potentially slow or stop the disease process.
It may be a radical idea that a neurodegenerative disease may have its root in the immune system run amok, but a team of scientists led by neurobiologist David Sulzer, PhD, of Columbia University Medical Center, and immunologist Alessandro Sette, DrBiolSci, of the La Jolla Institute for Allergy and Immunology, say there is evidence to suggest the association exists.
Reporting their findings in the June 21 online edition of Nature, the researchers said they have discovered a population of T cells in the blood of patients with Parkinson's disease (PD) that recognize alpha-synuclein peptides. It is still not clear whether this autoimmune response triggers the disease process or contributes to the neuronal degeneration, but the study authors contend that it raises the possibility that an autoimmune-targeted treatment could slow or stop the disease process.
The initial foundation for the idea was set in motion in by a 2014 paper in Nature Communications by Dr. Sulzer, professor of psychiatry, neurology and pharmacology at Columbia University. The study showed antigen presentation by neurons in the substantia nigra and the locus coeruleus that are targeted for involvement in PD. That study, which was done on human post-mortem tissue from PD patients, met with stinging criticism, according to Dr. Sulzer. How could neurons generate an autoimmune response? Impossible, the critics said.
But enough scientists began working in their own labs to replicate the findings. The collaboration between Dr. Sulzer and the immunologist Dr. Sette, a professor in the Center for Infectious Disease at the La Jolla Institute, helped fit even more pieces together to strengthen the link between autoimmunity and PD.
Dr. Sulzer and his colleagues wanted to understand why the immune system generates an attack on neurons when it is normally designed to identify and hopefully destroy foreign viruses and bacteria. The T cells from the PD patients' blood samples had a strong response to the alpha-synclein protein fragments. Dr. Sulzer and Dr. Sette said that they suspect that the immune system mistakenly sees the abnormally-misfolded alpha-synuclein as foreign and launches an immune attack.
“Until now, no one has been able to connect the dots,” said Dr. Sulzer. “No one has thought about a T-cell response to neurons because it was just accepted that adult neurons are not antigenic cells.”
He added: “We still don't know whether the immune response to alpha-synuclein is an initial cause of PD or a secondary response that contributes to neuronal death and a worsening of symptoms.”
He suspects that “alpha-synuclein is mishandled by the cell, and that is when you get the epitopes that the body has never seen. Once the body sees the epitopes it has to decide what is self and non-self.”
This isn't the first time that scientists made a connection between the immune system and PD. Dr. Sulzer found a 100-year-old scientific paper showing activated microglia involvement in PD, the most common movement disorder wherein alpha-synuclein aggregates in Lewy bodies are the diagnostic neuronal inclusions.
Others have confirmed the finding. More recently, there have been other clues for an autoimmune component to PD. A genome-wide association study, published in the American Journal of Human Genetics in 2013, identified two specific variants of the HLA-major histocompatibility complex (MHC) that are twice as common in PD patients (30 percent) than in the general population (15 percent). MHC genes make proteins that are part of the acquired immune system and stand on guard for foreign epitopes and then signal T cells to wage an attack. MHC proteins are also involved in autoimmune diseases.
The scientists collected blood from 67 PD patients and 36 age-matched healthy controls, and looked for T cells that recognize peptides derived from alpha-synuclein, the sticky protein that accumulates and forms Lewy bodies in specific regions of the brain. They found significantly more T cells that recognize alpha-synuclein in patients than in controls. Two of the pathological hallmarks of PD are the death of dopaminergic neurons in the substantia nigra and Lewy bodies.
They culled peripheral blood mononuclear cells from the patients' blood samples and stimulated them for two weeks. Some of these cells evolved to protect the body's own proteins from foreign ones (like viruses and bacteria). They presented the cells with about 80 peptides and identified two fragments of alpha-synuclein that activate T cells and drive an autoimmune response.
About 40 percent of the PD patients had reactivity against alpha-synuclein compared to two of the age-matched controls. The researchers believe that the neurons that most express MHC class 1 antigens are in the dopamine neurons of the substantia nigra and in epinephrine neurons in the locus coeruleus.
The investigators are now trying to replicate their findings in other patient blood samples. The team is also working on a T-cell biomarker test for PD that could help identify people at risk for the movement disorder. They will also be testing autoimmune therapies. “If immune system steps are links in the chain you may be able to stop T cells from attacking these forms of alpha-synuclein,” Dr. Sulzer said.
They are also thinking about applying what they've learned to other neurodegenerative diseases.
EXPERTS WEIGH IN
“This is an exciting study,” said Malú G. Tansey, PhD, professor of physiology at Emory University School of Medicine. “It advances our understanding of innate and adaptive immunity in neurodegenerative diseases. T cells are likely to be very important for normal brain health. The accumulation of alpha-synuclein aggregates may trigger an immune response, and T cells may mistake modified aggregated proteins in the brain as foreign. If that happens, we could end up with an autoimmune response that does harm in vulnerable brain regions.”
“As we get older we know that brain cells don't function as well but the immune system is aging right along, and we need to understand how immune responses change and become impaired in the ability to recognize self. It is a perfect storm of aging neurons and the aging immune system.”
Dr. Tansey, an expert on cell regulation and neuroinflammation, added that the work “opens up the possibility that a therapeutic approach could try to boost more protective T cells while keeping cytotoxic T cells out of the brain, approaches being used to manage multiple sclerosis.
“This is an elegant study that will generate a lot more science, and this is an important road to follow,” said John Trojanowski, MD, PhD, professor of geriatric medicine and gerontology in the Center for Neurodegenerative Disease Research at the University of Pennsylvania School of Medicine. “We haven't yet solved the problem of whether activated immune cells in the blood or brains of PD patients are good or bad. They think it is deleterious but it could be beneficial.”
“There are many other questions to answer,” he said. “There are other proteins in Lewy bodies and two other members of the synuclein protein family that are not involved in PD — beta-synuclein and gamma-synuclein. Do they also elicit an immune response? And what about other neurodegenerative diseases?”
“There have been hints in Parkinson's disease that there is an autoimmune component,” said Scott S. Zamvil, MD, PhD, FAAN, the Donnie Smith Chair in Multiple Sclerosis Research and professor of neurology and faculty in the program in immunology at the University of California, San Francisco. “This group is leading the way. They have shown in earlier work that MHC class 1 cells can be expressed in neurons and can activate cytotoxic CD8+ T lymphocytes. Now, they are validating and extending their findings. This is very important work. The question now is whether the aggregation of alpha-synuclein in Parkinson's makes the protein immunogenic or whether the immune system is driving neuronal damage in PD.”
“It is hard to know whether this could lead to a therapy,” he said. “It could be a neurodegenerative disease that sets in motion an autoimmune response. The findings are sparking substantial interest in the field. It opens the door for evaluating T-cell immune responses in other neurodegenerative diseases.”
EXPERTS: ON PARKINSON'S DISEASE AS AN AUTOIMMUNE DISORDER