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.
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.
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?
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.