The immune system is crucial for our survival, but we can appreciate that when it becomes dysregulated the immune system can be a potent driver of disease through inappropriate cytolytic targeting of non-infected host cells and the production of cytotoxic levels of inflammatory mediators. We can clearly perceive these phenomena in conditions such as autoimmune disorders, allergy, and septic shock; however, over the past few decades, we have come to understand that dysregulated immune responses are contributing to far more diseases than we had previously thought, including neurodegenerative diseases such as Parkinson’s disease. Although once viewed as simply a motor disorder of the central nervous system, Parkinson’s disease is now considered a multi-system disorder with notable immune dysfunction throughout the body and the brain. Clinical data have revealed alterations in cytokine production in individuals with Parkinson’s disease compared to age-matched healthy controls, with an overall reduction in circulating anti-inflammatory cytokines such as IL-4 and IL-1RA, and a reciprocal increase in circulating pro-inflammatory cytokines such as TNF, IL-1b, and IL-6. Moreover, studies have identified increases in pro-inflammatory immune cell subsets such as activated T cells and monocyte populations, in both the circulation and cerebral spinal fluid of individuals with Parkinson’s disease.

Interestingly, the brain was long thought to be immune privileged, and thus the pathophysiology of neurological diseases was considered independent of the influence of the immune system. This notion has since been proven incorrect in Parkinson’s disease with the discovery of activated microglia, the brain resident immune cell, as well as infiltrating peripheral T cells in the substantia nigra, where dopamine-producing neurons reside, in postmortem tissue of individuals with Parkinson’s disease. Moreover, blood-brain barrier dysfunction has been described in Parkinson’s disease which allows for both inflammatory mediators and peripheral immune cells to infiltrate the brain and influence neuroinflammation. This has been further supported by the subsequent findings that dopaminergic neurons, the loss of which gives rise to the motor symptoms of Parkinson’s disease, are especially vulnerable to inflammatory mediators and immune cell-derived reactive oxygen species (ROS). Importantly, activated microglia have been identified in Parkinson’s disease in vivo with the use of positron emission tomography (PET) imaging and this enhanced microglial activation and cytokine expression in the cerebral spinal fluid can be detected very early in disease in newly diagnosed and untreated individuals, indicating that inflammation is a prominent aspect of early disease stages and not just a consequence of neuronal death in advanced stages of disease.

Additionally, mouse models have demonstrated that peripheral induction of systemic inflammation is sufficient to induce neuroinflammation and enhance synuclein pathology and neurodegeneration. Interestingly, immune dysfunction resulting from low-grade chronic systemic inflammation, which is associated with inflammaging, has been identified as a risk factor for the development of Parkinson’s disease. Correspondingly, a multitude of significant genetic risk variants for Parkinson’s disease such as HLA, GBA, SNCA LRRK2, Parkin, and Pink1 have been implicated in immune function. Furthermore, it is believed that the gene-by-environment interplay is necessary for the development and progression of Parkinson’s disease. Such risk factors include aging, exposure to industrial toxicants, poor diet, gut dysbiosis, physical inactivity, stress, disturbed sleep, and pre-existing chronic inflammatory diseases (CIDs) such as inflammatory bowel disease (IBD), all of which have been identified as common sources for chronic systemic inflammation. Lastly, epidemiological studies based on millions of medical records from individuals who already suffer from a chronic inflammatory disease suggest that controlling inflammation in mid-life can reduce the risk or even prevent the onset of neurodegenerative diseases like Parkinson’s and Alzheimer’s disease. Together, these findings support the idea that the interplay between genetic predisposition and environmental risk factors may converge on immune and inflammatory processes to modify an individual’s lifetime risk for Parkinson’s disease development and suggest that mitigating chronic systemic inflammation may be an effective intervention to delay, arrest, or prevent the development and progression of Parkinson’s disease.

A few outstanding questions remain on the role of inflammation in Parkinson’s disease. Critically, longitudinal studies in humans are necessary to determine exactly when and how the inflammatory processes begin and change with aging leading to the development of the disease. It would be important to establish how early dysfunctional peripheral immune responses manifest before the onset of multi-organ pathology and the development of motor phenotypes. Second, it is critical that we understand how to modulate the immune response to inhibit disease pathophysiology without putting individuals at greater risk with immunosuppressive therapies. In sum, timely and selective targeting of critical immunoregulatory cascades altered in Parkinson’s disease may prove to be an effective risk mitigation strategy for the management of Parkinson’s disease.

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Janna Jernigan, PhD, Graduate Assistant - Lab of Malu Tansey, Department of Neuroscience, University of Florida - College of Medicine.

Ideas and opinions expressed in this post reflect that of the author solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®