Diseases such as diabetes, rheumatoid arthritis, and psoriasis arise from the body’s inability to distinguish self proteins from those derived from pathogens. The ability to separate self proteins from non-self relies on key molecules of the immune system referred to as major histocompatibility complex (MHC) proteins, which are classified as MHC class I and MHC class II. MHC molecules form part of an antigen processing mechanism in which proteins undergo processing in the proteasome, and short peptides are presented on the cell surface to circulating T cells. Under normal circumstances, if self peptides are expressed in the context of MHC molecules then no immune response is initiated. However, when peptides from pathogens are presented to T cells, this serves as a “danger signal” to initiate an immune response to rid the body of other cells expressing these pathogenic peptides. In autoimmune diseases such as diabetes, an immune response is mistakenly initiated against normal cells that present self peptides.
Neurological diseases such as Parkinson’s disease (PD) have not been considered autoimmune diseases because it was thought that the brain was an immune privileged area protected from immune attack. PD is initiated by the abnormal aggregation of the α-synuclein protein in the brain. This leads to the death of nearby neurons resulting in a fall in the levels of the chemical dopamine, which ultimately affects movement and causes tremors.
A recent study provides the first evidence that the development of PD might be linked to an autoimmune reaction (Sulzer et al. 2017). The research team compared blood samples from patients with PD to healthy controls. The blood was exposed to a cross section of proteins found in brain cells. The authors found that α-synuclein reacted strongly with blood from PD patients, while blood from healthy individuals demonstrated no reaction (Sulzer et al. 2017). The immune reaction was determined by the increased expression of key immunological cytokines IFN-gamma and IL-5 in PD patients.
This observation suggested that immune cells in the blood of PD patients were initiating an immune response to the self protein α-synuclein, indicating the autoimmune nature of the disease. The researchers next addressed whether PD was distinctly linked to T cell recognition of α-synuclein peptides presented by specific MHC alleles. Interestingly, compared to only 15% of the healthy controls, 33% of PD patients carried alleles for the HLA/DRB1*15:01 or HLA/DRB5*01:01 MHC class II molecules (Sulzer et al. 2017). These specific MHC class II molecules were responsible for presenting the Y39 region of the α-synuclein protein to T cells.
This finding supports a previous study showing that mutations in these specific MHC class II molecules are associated with PD (Wissemann et al. 2013). This genome wide association study of 2000 PD patients and 1986 healthy controls showed that the risk of developing PD positively correlated with variation in both HLA/DRB1*15:01 and HLA/DRB5*01:01 alleles. This study also confirmed that 33% of PD patients have mutations in these MHC class II alleles (Wissemann et al. 2013).
The overall insight from these studies is that genetic variants of specific MHC class II alleles in individuals with PD results in the presentation of particular fragments of α-synuclein. This causes T cells to mistakenly identify this self protein as a pathogen and ultimately trigger an autoimmune response that removes any cell expressing α-synuclein.
Further research is needed to determine what other immune related mechanisms might be responsible for the death of neurons, which leads to the development of PD. In addition, whether variants of HLA/DRB1*15:01 and HLA/DRB5*01:01 alleles can be considered diagnostic biomarkers of PD or be targeted therapeutically also requires further investigation.
To help researchers understand the subtypes and markers associated with MHC molecules, we have developed a handy MHC reference guide. You can also find antibodies to human, mouse, rat, and veterinary MHC markers.
Sulzer D et al. (2017). T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 656-661.
Wissemann WT et al. (2013). Association of Parkinson’s disease with structural and regulatory variants in the HLA region. Am J Hum Genet 93, 984-993.