Jonas Folke1, Rasmus Rydbirk2, Annemette Løkkegaard3, Anne-Mette Hejl3, Kristian Winge4, Charlotte Starhof3, Lisette Salvesen3, Lars Østergaard Pedersen5, Susana Aznar6, Bente Pakkenberg7, Tomasz Brudek6. 1. Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Nielsine Nielsens Vej 6B, entrance 11B, DK-2400, Copenhagen, NW, Denmark; Copenhagen Center for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Nielsine Nielsens Vej, 4B, entrance 80, DK-2400, Copenhagen, NW, Denmark. Electronic address: Jonas.folke@regionh.dk. 2. Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen, N, Denmark. 3. Department of Neurology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Ebba Lunds Vej 44, DK-2400, Copenhagen, NW, Denmark. 4. Department of Neurology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Ebba Lunds Vej 44, DK-2400, Copenhagen, NW, Denmark; Novo Nordisk Foundation, Tuborg Havnevej 19, DK-2900, Hellerup, Denmark. 5. H. Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark. 6. Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Nielsine Nielsens Vej 6B, entrance 11B, DK-2400, Copenhagen, NW, Denmark; Copenhagen Center for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Nielsine Nielsens Vej, 4B, entrance 80, DK-2400, Copenhagen, NW, Denmark. 7. Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Nielsine Nielsens Vej 6B, entrance 11B, DK-2400, Copenhagen, NW, Denmark; Institute of Clinical Medicine, Faculty of Health, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, N, Denmark.
Abstract
INTRODUCTION: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. METHODS: Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. RESULTS: Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. CONCLUSIONS: Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.
INTRODUCTION: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. METHODS: Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. RESULTS: Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. CONCLUSIONS: Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.
Authors: Rasmus Rydbirk; Ole Østergaard; Jesper V Olsen; Susana Aznar; Jonas Folke; Casper Hempel; Brian DellaValle; Thomas L Andresen; Annemette Løkkegaard; Anne-Mette Hejl; Matthias Bode; Morten Blaabjerg; Mette Møller; Erik H Danielsen; Lisette Salvesen; Charlotte C Starhof; Sara Bech; Kristian Winge; Jørgen Rungby; Bente Pakkenberg; Tomasz Brudek Journal: Cell Mol Life Sci Date: 2022-06-03 Impact factor: 9.207