Objective: To characterise the infiltration of peripheral innate immune cells (NK cells, monocytes and neutrophils) into the brain in Parkinson’s disease (PD) and to investigate their relationship with neuroinflammation and alpha-synuclein pathology.

Background: Evidence has suggested that peripheral and central inflammation are involved in the pathogenesis and progression of PD. Immunohistochemistry of post-mortem brain tissue in PD has shown increased numbers of activated resident microglia and CD4+ and CD8+ T lymphocyte infiltration (1,2). However, despite evidence that monocytes and NK cells are activated peripherally in PD, it has not been established whether these innate immune cells infiltrate into the brain (3,4).

Method: Formalin-fixed paraffin-embedded post-mortem brain sections from 23 people with PD and 10 age and sex matched controls without neurological disease were obtained from the Cambridge Brain Bank. Immunohistochemistry has been performed on sections of the putamen, frontal lobe, amygdala and substantia nigra for CD163 (a scavenger receptor whose expression is limited to monocytes and macrophages of peripheral origin), as well as markers of resident microglial activation and protein pathology (5). Immunofluorescence staining has been performed using antibodies for NKp46, present on the surface of all NK cells, CD68, a marker of activated microglia, and α-synuclein. Immunofluorescence staining for infiltrating neutrophils is planned. We are investigating the proximity of infiltrating NK cells, monocytes and neutrophils to areas of microglial activation and Lewy bodies.

Results: Positive CD163 staining was present in both PD and control brains, but at significantly higher levels in PD versus controls in the substantia nigra. Positive NKp46 staining was present in the substantia nigra in 80% of PD brains but only 20% of control brains. NKp46 staining was identified in close proximity to positive α-synuclein staining in PD.

Conclusion: Our results suggest that peripheral monocytes and NK cells infiltrate into pathologically relevant regions in PD and may contribute to neuroinflammation. Further analyses will explore the relationship between innate immune cell infiltrates, neurodegenerative pathology and clinical outcomes.

References: 1. McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988 Aug 1;38(8):1285–91.

2. Kouli A, Camacho M, Allinson K, Williams-Gray CH. Neuroinflammation and protein pathology in Parkinson’s disease dementia. Acta Neuropathol Commun. 2020 Dec 3;8:211.

3. Holbrook J, Patel B, Camacho M, Kahanawita L, Greenland J, Williams-Gray CH. Natural killer cells have an activated profile in early Parkinson’s disease. J Neuroimmunol. 2023 Sep 15;382:578154.

4. Wijeyekoon RS, Kronenberg-Versteeg D, Scott KM, Hayat S, Kuan WL, Evans JR, et al. Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson’s disease. Brain Behav Immun. 2020 Jul;87:473–88.

5. Rezaie P, Male D. Microglia in Fetal and Adult Human Brain Can Be Distinguished from Other Mononuclear Phagocytes through Their Lack of CD163 Expression. Neuroembryology. 2004 Nov 17;2(3):130–3.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterising-peripheral-innate-immune-cell-infiltration-into-the-brain-in-parkinsons-disease/