By Derek Lowe
For many complex diseases, you’ll find that there are a couple of hypotheses floating around them that are hard to prove and hard to disprove: one is that they’re actually caused by some (as yet unrecognized) infectious agent, and the other is that that they’re actually an autoimmune/inflammatory disorder. You can also recognize that these two can have features in common, as seen in something like Guillian-Barré syndrome, where a (usually innocuous and often hardly noticed) viral infection or other stimulus can lead to a sudden autoimmune crisis. A whole list of conditions have had such explanations attached to them, more or less persuasively: Alzheimer’s, obesity, various forms of arthritis (with little doubt on the autoimmune side), diabetes (Type I, certainly, but even Type II), multiple sclerosis, Parkinson’s, and more. Those links lead mainly to autoimmune explanations, but infectious-agent hypotheses are found quite easily as well, and going back many years.
A new paper adds what might be strong evidence to the Parkinson’s explanation. It’s been known for some time that there’s an association between the disease and MHC (major histocompatibility complex) alleles although (at the same time) having another autoimmune disease doesn’t seem to raise the risk for Parkinson’s itself. That’s interesting, in that the brain has mostly been thought of as an “immunoprivileged” compartment, but it’s also been increasingly clear that this doctrine is not as solid as it might be. Many CNS conditions have an undeniable inflammatory component, and it’s also quite possible that they lead to less-restrictive blood-brain barriers (or perhaps it’s the latter leading to the former?) In 2014, a paper came out (from some of the same authors on the current one) on MHC expression in postmortem neuronal tissue from Parkinson’s patients suggesting that catecholinergic neurons might be particularly vulnerable to autoimmune attack in this population.
The latest work extends this line of evidence by looking at specific peptide sequences from alpha-synuclein, which is a protein famously noted to be aggregated in the neurons of Parkinson’s patients. It turns out that T-cells from such patients (and not from controls) recognize these peptides, and this process appears to drive a cytotoxic immune response. This would tie in very well with the MHC genetic connections, and may well be putting us towards a better, more comprehensive explanation of the whole disease.
In general, for diseases that seem to have both a genetic susceptibility component and an environmental exposure/history one, you’d have to think that there could well be an immune system mechanism involved. That’s the part of our bodies that most clearly responds to our own environmental exposures (thus the possibility of vaccination), and is (at the same time) genetically unique to each individual. Add in the way that immune system is capable of inflicting major continuing damage to whatever cell population it targets, and you have the scope to explain almost anything. But without hard data, that explanation isn’t worth much – just saying “Must be some autoimmune thing” doesn’t advance the field. Now, with Parkinson’s the hard data may well be coming in.
http://blogs.sciencemag.org/pipeline/archives/2017/06/28/parkinsons-as-an-autoimmune-disease-more-evidence
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