Johansson Emil, Freuchet Antoine, Williams Gregory P, Michealis Tanner, Frazier April, Litvan Irene, Goldman Jennifer G, Alcalay Roy N, Standaert David G, Amara Amy W, Stover Natividad, Fon Edward A, Postuma Ronald B, Sidney John, Sulzer David, Lindestam Arlehamn Cecilia S, Sette Alessandro
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, USA.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
NPJ Parkinsons Dis. 2025 May 26;11(1):137. doi: 10.1038/s41531-025-01001-3.
A role of the immune system in Parkinson's disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells in the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and α-synuclein (α-syn), two Lewy body-associated proteins. Further, T cell reactivity towards α-syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown. Here, we investigated T cell responses towards PINK1 and α-syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.
由于黑质中活化胶质细胞和浸润性T细胞的频率增加，免疫系统在帕金森病（PD）进展中的作用早已受到怀疑。此前有报道称，PD供体对两种路易小体相关蛋白PINK1和α-突触核蛋白（α-syn）的T细胞反应增强。此外，对α-syn的T细胞反应性在疾病发作时最强，这表明自身反应性T细胞可能在PD发病机制中起作用。然而，前驱期PD是否存在T细胞自身反应性尚不清楚。在这里，我们研究了与PD和健康对照供体相比，有患PD高风险的供体（即前驱期PD：遗传风险、嗅觉减退和/或快速眼动睡眠行为障碍）对PINK1和α-syn的T细胞反应。在前驱期PD中检测到对这两种自身抗原的T细胞反应性，其水平与临床诊断为PD的个体中检测到的水平相当。与男性PD发病率增加一致，我们发现男性PD患者（而非女性）与健康对照相比T细胞反应性升高。然而，在前驱期PD供体中，男性和女性的T细胞反应均升高。这些反应性的不同趋势凸显了进一步研究生物性别对神经炎症和PD进展影响的必要性。
