Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease.

Autor: Wijeyekoon RS; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK. Electronic address: rsw27@cam.ac.uk., Kronenberg-Versteeg D; Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Scott KM; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK., Hayat S; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK., Kuan WL; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK., Evans JR; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; Nottingham University Hospital NHS Trust, Nottingham, UK., Breen DP; Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49, Little France Crescent, Edinburgh EH16 4SB, UK; Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Chancellor's Building, 49, Little France Crescent, Edinburgh EH16 4SB, UK; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, 9, Little France Road, Edinburgh BioQuarter, Edinburgh EH16 4UX, UK., Cummins G; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK., Jones JL; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Clatworthy MR; Department of Medicine, University of Cambridge, Cambridge, UK., Floto RA; Department of Medicine, University of Cambridge, Cambridge, UK., Barker RA; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Williams-Gray CH; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2020 Jul; Vol. 87, pp. 473-488. Date of Electronic Publication: 2020 Jan 30.
DOI: 10.1016/j.bbi.2020.01.018
Abstrakt: The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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