Objective: To assess transcriptomics signatures for monocytes and T-cells in different stages of Parkinson’s disease (PD) compared to controls and possible correlations with clinical outcomes.

Background: Emerging evidence suggests that the innate and adaptive immune system plays a large role in disease progression in PD[1]. Alteration in immune gene expression has been observed in RNA sequencing of whole blood and single cells from human brain[2,3].

Method: Samples of peripheral blood from 60 PD patients and 30 sex-matched, age-matched etiological controls were FACS enriched for T cells using fluorophore-tagged antibodies against CD4 and CD8 and for Monocytes using antibodies against CD14H + CD16L, CD14H + CD16H and CD14L + CD16H. Libraries for RNA-sequencing were generated using the Smartseq2 protocol[4]. DESeq2 was used for differential gene expression analysis on counts data for genes[5]. Gene Set Enrichment (GSE) on Gene Ontology (GO) terms was used to visualize molecular and biological pathways. Clinical data was obtained from local cohort Biopark for baseline and 5-year follow up. 34 patients were classified as having mild PD (Hoehn & Yahr 1-2,5) and 26 were classified as severe (H&Y 4-5) at baseline.

Results: Monocytes in both mild and severe PD showed an upregulation in genes and pathways associated with increased immune response compared to controls. The upregulation was most prominent in mild PD with a significant upregulation of CXCL3 and IL1B genes. In CD4+ T cells, a downregulation was seen between PD and controls in pathways associated with neutrophil signaling and MHC protein binding. Combined CD4+ and CD8+ T-cell expression showed significantly upregulated IRS1 and IRS2 gene and several T cell receptor alpha genes were downregulated compared to control. HLA-DRB5 was significantly downregulated in T-cells of mild PD compared to severe PD and controls. Furthermore, the overall dysregulation of gene expression seemed to be more striking in CD4+ PD, compared with CD8+ PD, as evident by the sheer number of dysregulated genes when either population is compared between conditions.

Conclusion: Gene expression of peripheral blood mononuclear cells show an increased inflammatory response and signs of dysregulated function in PD compared to healthy controls.

References: 1. Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol 2022;22(11):657-673.
2. Irmady K, Hale CR, Qadri R, et al. Blood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson’s disease. Nat Commun 2023;14(1):3956.
3. Craig DW, Hutchins E, Violich I, et al. RNA sequencing of whole blood reveals early alterations in immune cells and gene expression in Parkinson’s disease. Nature Aging 2021;1(8):734-747.
4. Picelli S, Björklund Å K, Faridani OR, Sagasser S, Winberg G, Sandberg R. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat Methods 2013;10(11):1096-1098.
5. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15(12):550.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/single-cell-transcriptomics-of-peripheral-blood-mononuclear-cells-and-associations-with-clinical-outcomes-in-parkinsons-disease/