Inflammation and immune dysfunction in Parkinson disease

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system and involves a fundamental role of neuroinflammation in its pathophysiology. Neurohistological and neuroimaging studies support the presence of ongoing and end-stage neuroinflammatory processes in PD. Moreover, numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest alterations in markers of inflammation and immune cell populations that could initiate or exacerbate neuroinflammation and perpetuate the neurodegenerative process. A number of disease genes and risk factors have been identified as modulators of immune function in PD and evidence is mounting for a role of viral or bacterial exposure, pesticides and alterations in gut microbiota in disease pathogenesis. This has led to the hypothesis that complex gene-by-environment interactions combine with an ageing immune system to create the 'perfect storm' that enables the development and progression of PD. We discuss the evidence for this hypothesis and opportunities to harness the emerging immunological knowledge from patients with PD to create better preclinical models with the long-term goal of enabling earlier identification of at-risk individuals to prevent, delay and more effectively treat the disease.

Fig. 1. Immune cell ageing interacts with genetic and environmental stressors to accelerate PD pathology.

Although primarily considered a motor-related disorder, Parkinson disease (PD) affects multiple systems, and patients commonly present with accompanying non-motor symptoms, which often start in the prodromal phase. The concept of prodromal PD is supported by the Braak theory (blue box), in which Lewy body pathologies begin in the periphery and olfactory bulb and advance to the brainstem and towards higher brain centres following a predictable caudal-rostral pattern. During the prodromal stage, when neuronal dysfunction begins, a combination of factors, from an ageing immune system, genes and environment, can create the perfect storm to enable the development and progression of PD pathogenesis. Age-associated alterations in the immune system include immunosenescence and inflammageing as well as an impaired adaptive immune system defined by a decline in naive T cells and B cells and memory cell accumulation and a reduction in T cell receptor and B cell receptor diversity and sensitivity to stimuli^–. These deficiencies contribute to an increase in susceptibility to infection and a type of age-acquired autoimmunity where autoantibodies may begin to appear. There are now multiple lines of evidence that suggest a relationship between environmental stressors, including viral and bacterial exposures, pesticides, diet, and alterations in gut microbiota, and the increased risk of developing PD. T_reg cell, regulatory T cell.

Fig. 2. Inflammatory manifestations in PD.

The figure highlights inflammatory manifestations that have been identified in patients with Parkinson disease (PD). Intestinal dysbiosis and inflammation (step 1), increases in levels of circulating pro-inflammatory cytokines (step 2), innate and adaptive immune cell activation and changes in frequency (step 3), blood–brain barrier permeability and peripheral immune cell infiltration of the central nervous system (step 4) and neuroinflammation (step 5) are hallmarks of a pro-inflammatory immune phenotype in PD. ROS, reactive oxygen species.