Humans; Female; CD8-Positive T-Lymphocytes; Cell Differentiation; Immunologic Memory; Parkinson Disease/genetics; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
Abstract :
[en] Neuroinflammation in the brain contributes to the pathogenesis of Parkinson's disease (PD), but the potential dysregulation of peripheral immunity has not been systematically investigated for idiopathic PD (iPD). Here we showed an elevated peripheral cytotoxic immune milieu, with more terminally-differentiated effector memory (TEMRA) CD8 T, CD8+ NKT cells and circulating cytotoxic molecules in fresh blood of patients with early-to-mid iPD, especially females, after analyzing > 700 innate and adaptive immune features. This profile, also reflected by fewer CD8+FOXP3+ T cells, was confirmed in another subcohort. Co-expression between cytotoxic molecules was selectively enhanced in CD8 TEMRA and effector memory (TEM) cells. Single-cell RNA-sequencing analysis demonstrated the accelerated differentiation within CD8 compartments, enhanced cytotoxic pathways in CD8 TEMRA and TEM cells, while CD8 central memory (TCM) and naïve cells were already more-active and transcriptionally-reprogrammed. Our work provides a comprehensive map of dysregulated peripheral immunity in iPD, proposing candidates for early diagnosis and treatments.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Capelle, Christophe M; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg ; Faculty of Science, Technology and Medicine, University of Luxembourg, 2 Av. de Université, L-4365, Esch-sur-Alzette, Luxembourg ; Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8049, Zurich, Switzerland
Ciré, Séverine ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg ; Eligo Bioscience, 111 Av. de France, 75013, Paris, France
Hedin, Fanny; National Cytometry Platform, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
HANSEN, Maxime ; University of Luxembourg ; Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), 4 Rue Nicolas Ernest Barblé, L-1210, Luxembourg, Luxembourg
PAVELKA, Lukas ; University of Luxembourg ; Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), 4 Rue Nicolas Ernest Barblé, L-1210, Luxembourg, Luxembourg ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), 1A-B Rue Thomas Edison, L-1445, Strassen, Luxembourg
KYRIAKIS, Dimitrios ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Integrative Cell Signalling > Team Alexander SKUPIN ; Icahn School of Medicine at Mount Sinai, New York, NY, 10029-5674, USA
Hunewald, Oliver ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
Konstantinou, Maria; National Cytometry Platform, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
Revets, Dominique; National Cytometry Platform, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
TSLAF, Vera ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), 1A-B Rue Thomas Edison, L-1445, Strassen, Luxembourg
Marques, Tainá M ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), 1A-B Rue Thomas Edison, L-1445, Strassen, Luxembourg
GOMES, Clarissa ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
BARON, Alexandre ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
Domingues, Olivia; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
Gomez, Mario; National Cytometry Platform, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
Zeng, Ni ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg ; Faculty of Science, Technology and Medicine, University of Luxembourg, 2 Av. de Université, L-4365, Esch-sur-Alzette, Luxembourg
BETSOU, Fay ; University of Luxembourg ; Integrated Biobank of Luxembourg (IBBL), Luxembourg Institute of Health (LIH), 1 Rue Louis Rech, L-3555, Dudelange, Luxembourg ; CRBIP, Institut Pasteur, Université Paris Cité, Paris, France
SKUPIN, Alexander ; University of Luxembourg ; Department of Neurosciences, University California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0662, USA
COSMA, Antonio ; University of Luxembourg ; National Cytometry Platform, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg
Balling, Rudi ; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Av. du Swing, L-4367, Belvaux, Luxembourg ; Institute of Molecular Psychiatry, University of Bonn, Venusberg-Campus 1, D-53127, Bonn, Germany
Krüger, Rejko; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Av. du Swing, L-4367, Belvaux, Luxembourg ; Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), 4 Rue Nicolas Ernest Barblé, L-1210, Luxembourg, Luxembourg ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), 1A-B Rue Thomas Edison, L-1445, Strassen, Luxembourg
OLLERT, Markus ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg. Markus.ollert@lih.lu ; Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis (ORCA), University of Southern Denmark, Odense, 5000C, Denmark. Markus.ollert@lih.lu
Hefeng, Feng Q ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 Rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg. feng.he@lih.lu ; Data Integration and Analysis Unit, Luxembourg Institute of Health (LIH), L-1445, Strassen, Luxembourg. feng.he@lih.lu
Fonds National de la Recherche Luxembourg Integrated BioBank of Luxembourg
Funding text :
We thank all the anonymous participants of the Luxembourg Parkinson’s Study for their support of our research and acknowledge the joint effort of the National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) Consortium members generally contributing to the Luxembourg Parkinson’s Study (the full list of consortium members are provided in Supplementary Note ). We thank the CIEC of LIH (especially Daniela Valoura Esteves), the processing and biorepository teams of IBBL (especially Wim Ammerlann and Sabrina Saracino) and the LuxGen sequencing platform (especially Arnaud Muller and Nathalie Nicot) for their support. This study was initially supported by the Luxembourg Personalized Medicine Consortium (PMC) (CoPImmunoPD, PMC/2018/01, F.Q.H.). The study was also partially supported by Luxembourg National Research Fund (FNR) CORE program grant (CORE/14/BM/8231540/GeDES, F.Q.H.), Luxembourg Government via the CoVaLux programme (M.O.), FNR AFR-RIKEN bilateral programme (TregBAR, 11228353, F.Q.H., R.B. and M.O.) and several PRIDE programme grants (PRIDE/11012546/NEXTIMMUNE, PRIDE/10907093/CRITICS and PRIDE/14254520/i2TRON, F.Q.H., R.K., M.O.) and an individual AFR grant (PHD-2015-1/9989160, N.Z. via the group of F.Q.H.). The Luxembourg Parkinson’s study is funded within NCER-PD by FNR (R.K., NCER13/BM/11264123). R.K. was further supported by an Excellence Grant in Research within the FNR PEARL programme (P13/6682797). D.K. was supported by FNR through PRIDE17/12244779/PARK-QC. We also thank Fondation Jean Think for their kind support (F.Q.H.). Some icons in several schematic figures (a and were created with BioRender.com.We thank all the anonymous participants of the Luxembourg Parkinson’s Study for their support of our research and acknowledge the joint effort of the National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) Consortium members generally contributing to the Luxembourg Parkinson’s Study (the full list of consortium members are provided in Supplementary Note 1). We thank the CIEC of LIH (especially Daniela Valoura Esteves), the processing and biorepository teams of IBBL (especially Wim Ammerlann and Sabrina Saracino) and the LuxGen sequencing platform (especially Arnaud Muller and Nathalie Nicot) for their support. This study was initially supported by the Luxembourg Personalized Medicine Consortium (PMC) (CoPImmunoPD, PMC/2018/01, F.Q.H.). The study was also partially supported by Luxembourg National Research Fund (FNR) CORE program grant (CORE/14/BM/8231540/GeDES, F.Q.H.), Luxembourg Government via the CoVaLux programme (M.O.), FNR AFR-RIKEN bilateral programme (TregBAR, 11228353, F.Q.H., R.B. and M.O.) and several PRIDE programme grants (PRIDE/11012546/NEXTIMMUNE, PRIDE/10907093/CRITICS and PRIDE/14254520/i2TRON, F.Q.H., R.K., M.O.) and an individual AFR grant (PHD-2015-1/9989160, N.Z. via the group of F.Q.H.). The Luxembourg Parkinson’s study is funded within NCER-PD by FNR (R.K., NCER13/BM/11264123). R.K. was further supported by an Excellence Grant in Research within the FNR PEARL programme (P13/6682797). D.K. was supported by FNR through PRIDE17/12244779/PARK-QC. We also thank Fondation Jean Think for their kind support (F.Q.H.). Some icons in several schematic figures (1 a and 6a) were created with BioRender.com.
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