Distinct Autoimmune Anti-α-Synuclein Antibody Patterns in Multiple System Atrophy and Parkinson’s Disease

Abstract

Aggregation of alpha-synuclein (α-syn) is considered to be the major pathological hallmark and driving force of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Immune dysfunctions have been associated with both MSA and PD and recently we reported that the levels of natural occurring autoantibodies (NAbs) with high-affinity/avidity toward α-synuclein are reduced in MSA and PD patients. Here, we aimed to evaluate the plasma immunoglobulin (Ig) composition binding α-syn and other amyloidogenic neuropathological proteins, and to correlate them with disease severity and duration in MSA and PD patients. All participants were recruited from a single neurological unit and the plasma samples were stored for later research at the Bispebjerg Movement Disorder Biobank. All patients were diagnosed according to current consensus criteria. Using multiple variable linear regression analyses, we observed higher levels of anti-α-syn IgG1 and IgG3 NAbs in MSA vs. PD, higher levels of anti-α-syn IgG2 NAbs in PD compared to controls, whereas anti-α-syn IgG4 NAbs were reduced in PD compared to MSA and controls. Anti-α-syn IgM levels were decreased in both MSA and PD. Further our data supported that MSA patients' immune system was affected with reduced IgG1 and IgM global levels compared to PD and controls, with further reduced global IgG2 levels compared to PD. These results suggest distinct autoimmune patterns in MSA and PD. These findings suggest a specific autoimmune physiological mechanism involving responses toward α-syn, differing in neurodegenerative disease with overlapping α-syn pathology.

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease

“…The majority of studies of Igs have focused on changes in the amounts of α-syn antibodies, but the results are inconsistent and contradictory [ 112 , 113 ]. However, a study that measured the affinity of these antibodies revealed that the amount of high-affinity α-syn antibodies in the plasma of PD patients is lower than that in healthy controls, and that there are markedly fewer α-syn–antibody immunocomplexes in the plasma of PD patients.…”

“…Anti-α-syn IgM levels were also lower in PD. Increased or decreased levels of IgG subclasses are expected to be one biomarker of PD [ 112 ]. A recent study reports that the repertoire of high-affinity or -avidity IgG autoantibodies targeting a-syn is significantly reduced in PD [ 127 ].…”

Differential Circulating Levels of Naturally Occurring Antibody to α-Synuclein in Parkinson’s Disease Dementia, Alzheimer’s Disease, and Vascular Dementia

“…α-Syn exists in its soluble form and can efflux from the brain into the periphery, which may stimulate the production of NAb-α-Syn. The levels of NAb-α-Syn in PD were controversial in previous studies (Besong-Agbo et al, 2013;Folke et al, 2019). Currently, few studies have investigated the circulating levels of NAb-α-Syn in PDD.…”

Immune reactivity to neurofilaments and dipeptide repeats in ALS progression

“…In AD patients, reduced concentration in CSF of Abeta42 peptides may also reflect the accumulation of these monomers into soluble oligomers or immuno-complexes, a process leading to a possible masking of epitopes targeted by the antibodies used in most ligand-based immunoassay 23 . Levels of natural occurring autoantibodies (NAbs) with high affinity to α-synuclein have been shown to be reduced in MSA and PD patients compared to HC, suggesting a failure of this sink mechanism under pathological conditions 24 .…”