Centre for Neuroscience & Stereology, Department of Neurology, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital, DK-2400 Copenhagen NV, Denmark.
Copenhagen Center for Translational Research, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital, DK-2400 Copenhagen NV, Denmark.
Int J Mol Sci. 2022 Jun 12;23(12):6554. doi: 10.3390/ijms23126554.
Multiple-system trophy (MSA) and Parkinson's Disease (PD) are both progressive, neurodegenerative diseases characterized by neuropathological deposition of aggregated alpha-synuclein (αSyn). The causes behind this aggregation are still unknown. We have reported aberrancies in MSA and PD patients in naturally occurring autoantibodies (nAbs) against αSyn (anti-αSyn-nAbs), which are important partakers in anti-aggregatory processes, immune-mediated clearance, and anti-inflammatory functions. To elaborate further on the timeline of autoimmune aberrancies towards αSyn, we investigated here the Immunoglobulin (Ig) affinity profile and subclass composition (IgG-total, IgG1-4 and IgM) of anti-αSyn-nAbs in serum samples from prodromal (p) phases of MSA and PD. Using an electrochemiluminescence competition immunoassay, we confirmed that the repertoire of high-affinity anti-αSyn-nAbs is significantly reduced in pMSA and pPD. Further, we demonstrated that pPD had increased anti-αSyn IgG-total levels compared to pMSA and controls, concordant with increased anti-αSyn IgG1 levels in pPD. Anti-αSyn IgG2 and IgG4 levels were reduced in pMSA and pPD compared with controls, whereas anti-αSyn IgG3 levels were reduced in pMSA compared to pPD and controls. The results indicate that the impaired reactivity towards αSyn occurs prior to disease onset. The apparent lack of high-affinity anti-αSyn nAbs may result in reduced clearance of αSyn, leading to aggregation of the protein. Thus, this study provides novel insights into possible causes behind the pathogenesis in synucleinopathies such as MSA and PD.
多系统萎缩症（MSA）和帕金森病（PD）都是进行性神经退行性疾病，其特征为聚集的α-突触核蛋白（αSyn）的神经病理学沉积。导致这种聚集的原因尚不清楚。我们已经报道了 MSA 和 PD 患者中天然存在的针对 αSyn 的自身抗体（nAbs）（抗-αSyn-nAbs）的异常，这些抗体是抗聚集过程、免疫介导清除和抗炎功能的重要参与者。为了更详细地阐述针对 αSyn 的自身免疫异常的时间进程，我们在此研究了 MSA 和 PD 的前驱期（p）阶段血清样本中抗-αSyn-nAbs 的免疫球蛋白（Ig）亲和力谱和亚类组成（总 IgG、IgG1-4 和 IgM）。我们使用电化学发光竞争免疫分析法证实，高亲和力抗-αSyn-nAbs 的 repertoire 在 pMSA 和 pPD 中显著减少。此外，我们证明与 pMSA 和对照组相比，pPD 具有更高的抗-αSyn IgG 总水平，并且 pPD 中的抗-αSyn IgG1 水平也增加。与对照组相比，pMSA 和 pPD 中的抗-αSyn IgG2 和 IgG4 水平降低，而 pMSA 中的抗-αSyn IgG3 水平与 pPD 和对照组相比降低。这些结果表明，针对 αSyn 的反应受损发生在疾病发作之前。缺乏高亲和力的抗-αSyn nAbs 可能导致 αSyn 的清除减少，从而导致蛋白聚集。因此，这项研究为 MSA 和 PD 等突触核蛋白病的发病机制背后的可能原因提供了新的见解。
