Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain.
Section of Biochemistry, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Immunology. 2021 Oct;164(2):358-371. doi: 10.1111/imm.13377. Epub 2021 Jun 20.
Increasing evidence indicates that peripheral immune cells play a prominent role in neurodegeneration connected to protein misfolding, which are associated with formation of aberrant aggregates, including soluble protein misfolded oligomers. The precise links, however, between the physicochemical features of diverse oligomers and their effects on the immune system, particularly on adaptive immunity, remain currently unexplored, due partly to the transient and heterogeneous nature of the oligomers themselves. To overcome these limitations, we took advantage of two stable and well-characterized types of model oligomers (A and B), formed by HypF-N bacterial protein, type B oligomers displaying lower solvent-exposed hydrophobicity. Exposure to oligomers of human peripheral blood mononuclear cells (PBMCs) revealed differential effects, with type B, but not type A, oligomers leading to a reduction in CD4 cells. Type A oligomers promoted enhanced differentiation towards CD4 CD25 FoxP3 Tregs and displayed a higher suppressive effect on lymphocyte proliferation than Tregs treated with oligomers B or untreated cells. Moreover, our results reveal Th1 and Th17 lymphocyte differentiation mediated by type A oligomers and a differential balance of TGF-β, IL-6, IL-23, IFN-γ and IL-10 mediators. These results indicate that type B oligomers recapitulate some of the biological responses associated with Parkinson's disease in peripheral immunocompetent cells, while type A oligomers resemble responses associated with Alzheimer's disease. We anticipate that further studies characterizing the differential effects of protein misfolded oligomers on the peripheral immune system may lead to the development of blood-based diagnostics, which could report on the type and properties of oligomers present in patients.
越来越多的证据表明，外周免疫细胞在与蛋白质错误折叠相关的神经退行性变中发挥着重要作用，这些错误折叠与异常聚集的形成有关，包括可溶性蛋白质错误折叠的寡聚物。然而，由于寡聚物本身具有瞬态和异质性，不同寡聚物的物理化学特性与其对免疫系统的影响，特别是对适应性免疫系统的影响之间的确切联系仍未得到探索。为了克服这些限制，我们利用两种稳定且特征良好的模型寡聚物（A 和 B），它们由 HypF-N 细菌蛋白形成，B 型寡聚物显示出较低的溶剂暴露疏水性。暴露于人外周血单核细胞（PBMC）的寡聚物显示出不同的影响，B 型寡聚物但不是 A 型寡聚物导致 CD4 细胞减少。A 型寡聚物促进向 CD4 CD25 FoxP3 Treg 的分化，并显示出比 B 型寡聚物或未处理细胞处理的 Treg 更高的淋巴细胞增殖抑制作用。此外，我们的结果揭示了 A 型寡聚物介导的 Th1 和 Th17 淋巴细胞分化以及 TGF-β、IL-6、IL-23、IFN-γ 和 IL-10 介质的不同平衡。这些结果表明，B 型寡聚物再现了与外周免疫细胞中帕金森病相关的一些生物学反应，而 A 型寡聚物类似于与阿尔茨海默病相关的反应。我们预计，进一步表征蛋白质错误折叠寡聚物对周围免疫系统的差异影响的研究可能会导致开发基于血液的诊断方法，该方法可以报告患者体内存在的寡聚物的类型和特性。
