The innate immune system factors heavily in Parkinson’s disease, but evidence has been thinner for its pickier twin, the adaptive immune system. The latter draws renewed suspicion from a paper in the June 21 Nature. In it, scientists led by David Sulzer of Columbia University, New York, and Alessandro Sette, La Jolla Institute for Allergy and Immunology, California, report that T cells from PD patients readily respond to peptides derived from α-synuclein, a protein that aggregates in Parkinson’s. Specifically, fragments of α-synuclein are displayed on neurons of the substantia nigra by major histocompatibility proteins (also called human leukocyte antigen, or HLA, proteins) whose genes are known to be associated with PD. “We are showing that in PD, there is a response against the patients’ own proteins,” Sulzer told Alzforum. “That opens up the possibility that there’s an autoimmune response in PD.”
“The current study creates a functional link between the genetic associations of the HLA-DRB genes and the pathological changes that are correlated with disease progression,” said Andrew West, University of Alabama, Birmingham. “It’s uncovering interesting biology around α-synuclein.”
Cells chop up proteins into peptides and display them on their surface via MHC proteins. Passing T cells patrolling the brain and body are trained to recognize foreign matter and ignore anything that comes from the “self.” When a T cell comes across a foreign peptide that matches its unique receptor, it binds and proliferates. The resulting cells become helper or cytotoxic T cells that generate an immune response or kill the host cell.
Certain MHC proteins, such as DRB1 and DRB5, had been tied to PD previously, but it was unclear what they have to do with the disease. A clue came with Sulzer and colleagues’ previous report that dopaminergic neurons in the substantia nigra and locus coeruleus of human brains presented antigens on MHC proteins (Cebrián at el., 2014). Most neurons don’t present antigens, but these particular ones do, and they die off in droves in PD. These researchers found that mouse substantia nigra neurons that were made to express foreign antigens died when the corresponding cytotoxic T cells were added. Could this property of antigen presentation play a role in the neurons’ demise in PD?
To find out, the researchers joined forces with the Sette lab to sample blood from 67 patients with PD and 36 age-matched controls. They separated the white blood cells and exposed them to fragments of α-synuclein to see if they would become activated to release either interferon-g (IFNg) or interleukin-5 (IL-5). Two fragments did the job: one at the N terminus known as the Y39 region, and one at the C terminus, known as S129. To react with T cells, the latter required a phosphorylation at S129, a modification found in α-synuclein peptides of Lewy bodies (Fujiwara et al., 2002). Responses were pronounced in T cells from PD patients, but relatively rare in healthy controls.
These specific α-synuclein fragments were posted on two MHC proteins previously tied to PD, i.e. DRB1*15:01 and DRB5*01:01 (Wissemann et al., 2013). Importantly, the alleles for these particular MHC proteins were twice as common in PD patients as in controls. DQB1*03:04 and the MHC class I allele A*11:01 also appeared more frequently in responders, and A*11:01 bound the Y39 α-synuclein fragment. Every participant whose T cells responded to the Y39 α-synuclein peptide carried one of those four HLA variants. The results imply that specific MHC alleles are linked with Parkinson’s because they specialize in displaying α-synuclein fragments.
Patient T cells were also activated in response to protofibrils of α-synuclein, whereas T cells from healthy people had little if any response. The few people whose T cells did respond could be in the early stages of PD, Sulzer said. Overall, his results imply that T cell responsiveness to α-synuclein could be a potential early biomarker of disease, he said.
How might this play out in Parkinson’s? Sulzer hypothesized that as PD takes hold, accumulating α-synuclein proteins are no longer sufficiently degraded via their normal clearance pathways. Neurons instead break it down into peptides that appear on MHC signposts. Alternatively or in addition, α-synuclein may be cut up outside cells and those peptides bind to MHC complexes on neurons; microglia may also digest the protein and themselves display the peptides on MHC molecules, Sulzer said. He noted that he has yet to test whether α-synuclein appears on neuronal MHC complexes.
In all scenarios, since these peptides are not around early in life when the immune system is maturing, T cells are not trained to tolerate them as “self.” Instead, the T cells mistake these MHC-presented α-synuclein peptides for foreign material. T cells then proliferate and may attack neurons, or cause an inflammatory response that causes bystander damage, which may explain why they die, Sulzer speculated. Whether the activated T cells kill neurons in human disease remains to be seen, he cautioned, as his group has only observed that in mouse models.
“This provides further evidence for a causal role of adaptive immunity in the etiology of PD,” wrote Heidi McBride, McGill University, Montreal, to Alzforum. “This opens new possibilities for strategic therapeutic intervention to inhibit the immune system to halt progression of PD.”
West noted that the cohort was small and cross-sectional, and said researchers need to test if the finding generalizes to larger patient samples. He also wondered if the immune state is a lifelong one, or reflects a late-life reaction to disease. Since only 40 percent of all PD patients in this study had T cells reactive to α-synuclein, West suggested there might be disease subgroups that respond differently to anti-inflammatory therapies.
The results align with some previous reports that α-synuclein can cause a T cell response in mice and rats (see Theodore et al., 2008; Benner et al., 2008). T cells were previously found to infiltrate the substantia nigra in mouse models of PD (Brochard et al., 2009). Sulzer and colleagues will try to replicate these data in an independent set of patients and controls. They are also looking for ways to better model this response in the lab.—Gwyneth Dickey Zakaib
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