Could the immune system be causing the progression of Parkinson’s?
In the news this week, scientists say they have found the first direct evidence that the immune system attacks the brain in Parkinson’s disease. We look at the science behind the headlines to see if the immune system can drive the progression of Parkinson’s.
The body’s immune system is designed to protect us against infection e.g. infected skin graze etc. and promote tissue repair. The blood cells which mediate this response against invading infection causing bacteria or virus, do so by recognising proteins on their surface as not human. Once an infective bacteria or virus is detected by the immune system they then attack and destroy them. Normally our immune system is very good at differentiating which proteins are found in our bodies and those found on infective bacteria and viruses.
However, sometimes this can go wrong and the immune system starts to recognise a human protein as foreign. In these rare instances the immune system is then directed to seek out and kill human cells that contain that protein. This is referred to as an autoimmune response and occurs in clinical conditions like multiple sclerosis. alpha-synuclein is a protein that has been linked to the development of Parkinson’s. Abnormal processing of alpha-synuclein, may reveal parts of the protein structure which are not normally exposed, causing the immune system to recognise this as a foreign protein.
There are a numbers of ways in which alpha-synuclein can cause the unwanted activation of immune cells. Firstly, an extensive number of previous studies have shown that abnormally processed alpha-synuclein can directly activate the brains resident immune cells, microglia. Activated microglia then release chemical messengers, which can then damage nerve cells in their vicinity.
Nerve cells which produce dopamine as their chemical messenger are particularly affected in Parkinson’s, loss of which causes the major symptoms e.g. slowness of movement etc. A second study by Cebrian and colleagues (2104) demonstrated that these nerves cells display an important series of proteins on their surface, called antigen presenting proteins, called MHC class 1. These sophisticated proteins can deliberately expose the part of the abnormally processed alpha-synuclein protein structure on surface of the nerve. This causes the immune cells in the brain to think the cell is foreign, stimulating them to attack and kill the nerve cells.
Genetic studies have identified a number of genes, which stimulate the formation of different proteins that increase the risk of a person developing Parkinson’s. 2 of these genes stimulate the formation of unusual forms of the antigen presenting proteins, called MHC class II DRB5 and DRB1. These MHC class II proteins are expressed on immune cells which are usually found outside the brain. About 15% of the general population carry the genes but it was not known how these genes could be linked to the development of Parkinson’s.
In a third very recent study by Sulzer and Colleagues (2017), has examined the ability of different portions of the abnormally processed alpha-synuclein protein structure to activate an unwanted immune response. They looked in blood cells taken from 67 individuals affected by Parkinson’s compared to 36 healthy volunteers. This study demonstrated that 2 portions of the abnormally processed alpha-synuclein protein, one of which is commonly found in Lewy bodies (structures containing sticky clumps of alpha-synuclein in the Parkinson’s brain), caused marked activation of immune cells (principally T cells). To add validity to this important finding, they replicated this finding in an additional group of Parkinson’s and healthy subjects.
Sulzer’s research team then examined the ability the 2 portions of alpha-synuclein to attach to the different types of MHC class II proteins. Interestingly, they found that the 2 alpha-synuclein portions attached much stronger to the rarer forms of MCH class II which have been associated with Parkinson’s, i.e. DRB5 and DRB1, than any other type of MHC class II protein. Furthermore, they demonstrated that people carrying the genes for DRB5 and DBR1 MHC Class II proteins were not only more likely to react against alpha-synuclein but also the size of the unwanted immune response was bigger. Hence, for the first time there is direct evidence that abnormally processed portions of the alpha-synuclein protein are capable of activating immune cells. This also occurs much more frequently, and to a higher degree, in those individuals carrying the Parkinson’s risk genes encoding for the MHC class II DRB5 and DRB1 proteins.
In conclusion, Sulzer and colleagues raised the concept that the driving force behind the progression of Parkinson’s may be due to an auto-immune response to abnormally processed alpha-synuclein. This aberrant activation of the immune cells in the blood could then facilitate their entry into the brain. Once in the brain the immune cells can not only directly attack neurons containing abnormally processed alpha-synuclein but also drive the activation of brain microglia, which will amplify damaging potential of the immune activation.
So what is the potential impact of all this research? Clearly, firstly further studies are required to prove that this mechanism plays a critical role in Parkinson’s. However, if the immune system is proven to drive the pathological process in Parkinson’s, there are a number of immune modulatory therapies which have already been successfully developed for other autoimmune disorders e.g. multiple sclerosis etc. which could be rapidly utilised in clinical trials to see whether they can slow down Parkinson’s.
References used in this blog post:
Nat Commun. 2014 Apr 16;5:3633. doi: 10.1038/ncomms4633. Research Support, N.I.H., Extramural; Research Support, Non-U…www.ncbi.nlm.nih.gov