Knecht Luisa, Dalsbøl Katrine, Simonsen Anja Hviid, Pilchner Falk, Ross Jean Alexander, Winge Kristian, Salvesen Lisette, Bech Sara, Hejl Anne-Mette, Løkkegaard Annemette, Hasselbalch Steen G, Dodel Richard, Aznar Susana, Waldemar Gunhild, Brudek Tomasz, Folke Jonas
Centre for Neuroscience and Stereology, Department of Neurology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Nielsine Nielsens Vej 6B, Entrance 11B, 2. floor, Copenhagen, NV, DK-2400, Denmark.
Copenhagen Center for Translational Research, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Nielsine Nielsens Vej 4B, Copenhagen, NV, DK-2400, Denmark.
J Neuroinflammation. 2024 Dec 3;21(1):317. doi: 10.1186/s12974-024-03293-3.
Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative disorders marked by protein aggregation, with AD featuring amyloid-beta (Aβ) and tau proteins, and PD alpha-synuclein (αSyn). Dementia with Lewy bodies (DLB) often presents with a mix of these pathologies. This study explores naturally occurring autoantibodies (nAbs), including Immunoglobulin (Ig)G, IgM, and IgA, which target αSyn, Aβ and tau to maintain homeostasis and were previously found altered in AD and PD patients, among others.
We extended this investigation across AD, PD and DLB patients investigating both the affinities of IgGs and levels of IgGs, IgMs and IgAs towards αSyn, Aβ and tau utilizing chemiluminescence assays. We confirmed that AD and PD patients exhibited lower levels of high-affinity anti-Aβ and anti-αSyn IgGs, respectively, than healthy controls. AD patients also showed diminished levels of high-affinity anti-αSyn IgGs, while anti-tau IgG affinities did not differ significantly across groups. However, DLB patients exhibited increased anti-αSyn IgG but decreased anti-αSyn IgM levels compared to controls and PD patients, with AD patients showing a similar pattern. Interestingly, AD patients had higher anti-Aβ IgG but lower anti-Aβ IgA levels than DLB patients. DLB patients had reduced anti-Aβ IgM levels compared to controls, and anti-tau IgG levels were lower in AD than PD patients, who had reduced anti-tau IgM levels compared to controls. AD patients uniquely showed higher anti-tau IgA levels. Significant correlations were observed between clinical measures and nAbs, with negative correlations between anti-αSyn IgG affinity and levels in DLB patients and a positive correlation with anti-αSyn IgA levels in PD patients. Disease-specific changes in nAb levels and affinity correlations were identified, highlighting altered immune responses.
This study reveals distinctive nAb profiles in AD, DLB, and PD, pinpointing specific immune deficiencies against pathological proteins. These insights into the autoreactive immune system's role in neurodegeneration suggest nAbs as potential markers for vulnerability to protein aggregation, offering new avenues for understanding and possibly diagnosing these conditions.
阿尔茨海默病（AD）和帕金森病（PD）是主要的神经退行性疾病，其特征为蛋白质聚集，AD以淀粉样β蛋白（Aβ）和tau蛋白为特征，而PD以α-突触核蛋白（αSyn）为特征。路易体痴呆（DLB）通常表现为这些病理特征的混合。本研究探索天然存在的自身抗体（nAbs），包括免疫球蛋白（Ig）G、IgM和IgA，它们靶向αSyn、Aβ和tau以维持体内平衡，此前已发现这些自身抗体在AD和PD患者等人群中发生了改变。
我们将这项研究扩展至AD、PD和DLB患者，利用化学发光测定法研究IgG的亲和力以及IgG、IgM和IgA针对αSyn、Aβ和tau的水平。我们证实，AD和PD患者分别表现出比健康对照更低水平的高亲和力抗Aβ和抗αSyn IgG。AD患者还显示出高亲和力抗αSyn IgG水平降低，而抗tau IgG亲和力在各组之间无显著差异。然而，与对照组和PD患者相比，DLB患者抗αSyn IgG水平升高但抗αSyn IgM水平降低，AD患者表现出类似模式。有趣的是，与DLB患者相比，AD患者抗Aβ IgG水平更高但抗Aβ IgA水平更低。与对照组相比，DLB患者抗Aβ IgM水平降低，AD患者抗tau IgG水平低于PD患者，而PD患者抗tau IgM水平低于对照组。AD患者独特地表现出更高的抗tau IgA水平。在临床指标与nAbs之间观察到显著相关性，DLB患者中抗αSyn IgG亲和力与水平之间呈负相关，而在PD患者中与抗αSyn IgA水平呈正相关。确定了nAb水平和亲和力相关性的疾病特异性变化，突出了免疫反应的改变。
本研究揭示了AD、DLB和PD中独特的nAb谱，确定了针对病理性蛋白质的特定免疫缺陷。这些对自身反应性免疫系统在神经退行性变中作用的见解表明，nAbs可能是易患蛋白质聚集的潜在标志物，为理解和可能诊断这些疾病提供了新途径。
