New evidence on the links between immune activation and neuroinflammation and Parkinson's disease

Reviewed by Emily Henderson, B.Sc.Dec 1 2022

In this special supplement to the Journal of Parkinson's Disease, "The Immune System in Parkinson's Disease," experts highlight the latest research breakthroughs on the links between immune activation and neuroinflammation and Parkinson's disease (PD) and discuss the challenges and novel therapeutic strategies targeting the immune system with the hope of reducing or reversing neurodegeneration.

Although multiple independent studies have provided evidence of the involvement of central and peripheral immune and inflammatory processes in PD, the cause-and-effect relationship between neuroinflammation and neurodegeneration in PD is difficult to determine as the initiating event(s) likely occur many years before neuronal loss and clinical manifestations arise. There is growing evidence, however, that inflammation might play a causative role in PD rather than being a consequence or an epiphenomenon of the neurodegenerative process.

"PD risk is influenced by many factors including a mix of immunogenetics and the environment, such as infection history," commented Guest Editors Bastiaan R. Bloem, MD, PhD, Patrik Brundin, MD, PhD, Ashley Harms, PhD, Cecilia Lindestam Arlehamn, PhD, Eng King Tan, MD, and Caroline Williams-Gray, PhD. "In recent years, increasing evidence suggests an association with autoimmune conditions and involvement of the immune system or its aberrant responses in patients with PD and various experimental models."

Topics included in this supplement cover:

• Immunogenetic determinants of PD
• Epidemiological evidence for an immune component of PD
• Influence of infections and the microbiome
• Links between the GBA1 gene and immune changes in PD
• The role of T lymphocytes
• The role of B lymphocytes
• Natural killer cells in PD
• Age-related immune changes in PD
• Microglial activation in the brains of patients with neurodegenerative disorders including PD
• Current evidence and knowledge gaps around inflammasome activation in PD
• The role of central and peripheral inflammation
• Neuroinflammation and immune changes in prodromal PD
• Inflammatory animal models of PD
• Biomarkers of inflammation in PD
• Therapeutic strategies targeting the immune system in PD

Patients with PD and other synucleinopathies often exhibit autoimmune features, including immune cells (CD4+ and CD8+ T lymphocytes) that recognize forms of alpha-synuclein. A review article by Benjamin D. Hobson, MD/PhD student, and David Sulzer, PhD, both of Columbia University Irving Medical Center, focuses on how peripheral T lymphocytes can enter into brain areas that are primarily affected in PD. Neurons in these brain regions can present antigens bound to MHC class 1 molecules on the cell surface and signal the cell's physiological state to immune cells (such as T cells). Certain subtypes of T cells (CD8+) have been shown to bind to the antigen: MHC class 1 complex on the cell surface promoting further immune responses leading to cell damage and finally death of the neurons.

"Recent animal models suggest the possibility of T cell autoreactivity to mitochondrial antigens in PD," noted Dr. Sulzer. "However, it remains unclear if neuronal antigen presentation plays a role in PD or other neurodegenerative disorders, and efforts are underway to better understand the potential impact of autoimmune responses on neurodegeneration."

"In summary, multiple independent studies in clinical and preclinical models have provided corroborative evidence of the involvement of central and peripheral immune and inflammatory processes in PD," noted the Guest Editors. "Our knowledge of how the immune system contributes to PD pathogenesis is constantly evolving, with increasing evidence for a role of several genes and susceptibility loci."

A major challenge is to use these data and knowledge to identify specific targets within the immune system or target major pathogenic proteins involved in aberrant immune responses; and potentially to identify subsets of patients who are more likely to respond to immune modulatory therapies.

"Clinical trials targeting alpha-synuclein have already commenced and both clinical and experimental trials focusing on different immune components are ongoing," commented co-Guest Editor and JPD's co-Editor-in-Chief Bastiaan R. Bloem, MD, PhD, Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Centre, Nijmegen.

The Guest Editors emphasize that considerable research is still needed to determine the individual and collective roles of the individual immune cells (and their subsets), and how they interact with each other within the neurovascular units and with alpha-synuclein and other key proteins.

Longitudinal studies using molecular imaging that measures microglial activation in the brain, and detailed blood and CSF immune function tests and phenotyping in at-risk subjects or prodromic PD may identify crucial clues on the temporal cause-effect relationship between neuroinflammation and PD."

Professor Bastiaan R. Bloem, MD, PhD

Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. It is the second most common age-related neurodegenerative disorder affecting about 3% of the population by the age of 65 and up to 5% of individuals over 85 years of age.