Unmasking the role of autoimmunity

The hypothesis that auto-immunity is a major player in PD is gaining support. Both helper and killer T cells from people with Parkinson’s Disease recognize peptide components of alpha-synuclein. David Sulzer (Columbia University, New York, USA) described how recent finding explain why gene studies link PD to specific major histocompatibility complex (MHC) class II alleles and polymorphisms.

If the acquired immune system is involved in Parkinson’s Disease, what might the antigens be; how are they presented; and which specific T cells are involved? The most obvious place to start the search for antigens was alpha-synuclein since, although a “self” protein in origin, “foreign” epitopes might arise through aggregation process.

David Sulzer and colleagues (Columbia, New York, USA) and collaborating immunologists from La Jolla, California, took peripheral blood mononuclear cells from 67 patients and 36 age-matched controls and looked at how the PBMCs responded to potential antigens derived by splitting alpha-synuclein into around 80 fragments of a size that might in theory be presented by alleles.

Two antigenic regions emerged

Patients’ T cells were more likely than control cells to recognize epitopes in two specific alpha-synuclein regions. One was centered around tyrosine 39 (Tyr-39), which was an interesting observation since the majority of PD-related mutations are in or close to that region.

The second region involved is the phosphorylated Ser129 (phosphor S129). In retrospect, this is again not surprising, since that modification is found in people with PD, especially in the presence of Lewy bodies.

Though most epitopes were recognized by CD4 T cells, there were also epitopes recognized by CD8 killer cells.

Could misfolded alpha-synuclein and tau act as neoantigens?

David Sulzer and colleagues are now seeking to replicate these findings in 70 additional patients from Rush University and 70 controls. They are finding responses to the same two antigenic regions. So far, the overall incidence of response to alpha-synuclein antigens – at around 25% – is similar to the incidence of antigen response seen in classic auto-immune disorders such as type 1 diabetes.

Alpha-synuclein epitopes are found in around 40% of patients, but it is likely there are other antigens, with tau a clear candidate. Autopsy shows high levels of tau in PD patients, especially those with cognitive impairment; and mixed aggregates contain tau as well as alpha-synuclein.

Autoantibodies to both proteins are found in blood. So the Columbia team have divided tau into fragments and assessed T cell responses in patients, age matched controls, and younger people. There are certainly T cells that recognize tau. Phosphorylated tau is more recognized than native tau, and so can be  a possible autoantigen.

Multiple “hits”

Evidence for immune system involvement in PD has been slowly accumulating. (See box). In the substantia nigra and locus coeruleus, around 60% of neurons express MHC-1. This is not the case with non-dopaminergic neurons. For a decade, we have known that high numbers of CD4 helper T cells and CD8 killer cells can be found in the substantia nigra. In 2015, David Standaert and colleagues used an animal model of PD including expression of alpha-synuclein to show that CD4 cells are required for toxicity.

T cell responses probably occur after misfolding, ie the neoantigens are downstream

Multiple “hits” may be needed to induce an auto-immune response. Age in itself could induce changes in protein degradation. Catecholamines may be involved: Carolina Cebrian and colleagues have shown that MHC-1 expression makes catecholaminergic neurons susceptible to degeneration mediated by T cells.

It is possible that an interaction between DA and alpha-synuclein leads to misfolding. We need a longitudinal study to chart T cell changes in individuals with time. High calcium levels could also contribute. But how such disparate factors might link together in a pathogenic chain of events is speculative.

Might we eventually genotype patients to see which HLA alleles are present?

Immune system biomarkers?

Auto-immunity may explain at least in part idiopathic PD, and perhaps the spread of pathology from periphery to the CNS. The hypothesis certainly feeds into speculation about a possible enteric origin of the disease. T cells are present in the gut; and they can move to the brain, where they are capable of replication.

Features of the immune system may also provide a means of screening patients. The presence of a particular MHC allele may not necessarily mean the presence of activated T cells but could suggest the possibility of PD in the future. 

The auto-immune hypothesis may also lead us to consider new approaches to therapy. Is there potential in an approach involving vaccines, for example? Perhaps we should be looking more carefully at other auto-immune diseases, notably MS, for parallels -- though the type of T-cell involved is different.

Milestones in understanding immune involvement


In Paris, Charles Foix et al report that the substantia nigra of PD patients contains activated microglia


In the MPTP mouse model of PD, Vanessa Brochard et al describe infiltration into the brain of CD4+ and CD8+ lymphocytes and suggest the adaptive arm of the immune system may be a target for therapy


William Wissemann, from New York, and colleagues report that PD is associated with structural and regulatory variants in the HLA region encoding major histocompatibility complex (MHC) proteins and hence the immune system


Ashley Harms and colleagues including David Standaert show that the death of substantia nigra cells in a rodent model involving alpha-synuclein requires the presence of MHC II


Carolina Cebrian and colleagues from Columbia University provide evidence that catecholaminergic neurons in the human substantia nigra express MHC I and that this expression makes them susceptible to degeneration mediated by T cells

Country selection
We are registering that you are located in Brazil - if that's correct then please continue to Progress in Mind Brazil
You are leaving Progress in Mind
Please confirm your email
We have just sent you an email, with a confirmation link.
Before you can gain full access - you need to confirm your email.
The information on this site is exclusively intented for health care professionals.
All the information included in the Website is related to products of the local market and, therefore, directed to health professionals legally authorized to prescribe or dispense medications with professional practice. The technical information of the drugs is provided merely informative, being the responsibility of the professionals authorized to prescribe drugs and decide, in each concrete case, the most appropriate treatment to the needs of the patient.
Register for access to Progress in Mind in your country