Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease

Introduction: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (alpha-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-alpha-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-alpha-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-alpha-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-alpha-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-alpha-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-alpha-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-alpha-syn IgG2 and reduced anti-alpha-syn IgG4 levels. Conclusions: Differences in the plasma/CSF distribution of anti-alpha-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 alpha-syn. The differing alpha-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.

Automated summary

The study revealed a reduction in high-affinity/avidity anti-alpha-syn IgG nAbs in CSF samples from MSA and PD patients, along with varied levels of anti-alpha-syn IgM nAbs in CSF and plasma from both patient groups. Additionally, disease-specific profiles of anti-alpha-syn IgG subclasses were observed in the CSF, with MSA patients showing increased IgG1, IgG2, and IgG3 levels, while PD patients exhibited increased IgG2 and reduced IgG4 levels.