B lymphocyte responses in Parkinson's disease and their possible significance in disease progression.
B lymphocyte responses in Parkinson's disease and their possible significance in disease progression.
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DOI：
10.1093/braincomms/fcad060
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发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
炎症与帕金森病的发病机制有关。我们假设B淋巴细胞参与帕金森病的进展。我们测量了快速眼动睡眠行为障碍（n = 79）、早期帕金森病（n = 50）和匹配对照（n = 50）患者血清中α -突触核蛋白和tau抗体。快速眼动睡眠行为障碍病例按进展为帕金森病的风险进行分层（低风险= 30，高风险= 49）。我们还测量了肿瘤坏死因子受体家族的b细胞活化因子、c反应蛋白和总免疫球蛋白g。我们发现，在帕金森病转化高风险的快速眼动睡眠行为障碍患者中，α -突触核蛋白原纤维抗体水平升高（方差分析，P < 0.001），而在低风险患者中，S129D肽特异性抗体水平较低（方差分析，P < 0.001）。因此，在帕金森氏病发生之前，就可以检测到对α -突触核蛋白的早期体液反应。使用流式细胞术对早期帕金森病患者和匹配对照（每组n = 41）进行外周B淋巴细胞表型分析显示，帕金森病患者的B细胞减少，特别是在早期痴呆的高风险人群中[t(3) = 2.87, P = 0.01]。调节性B细胞比例越大的患者运动评分越高[F(4,24) = 3.612, P = 0.019]，提示其在帕金森病中具有保护作用。相比之下，在体外刺激后，从痴呆症风险较高的帕金森病患者分离的B细胞有更大的细胞因子（白细胞介素6和白细胞介素10）反应。我们评估了α -突触核蛋白转基因帕金森病小鼠模型的外周血淋巴细胞：它们也有减少的B细胞，这表明这与α -突触核蛋白病理有关。在基于毒素的帕金森病小鼠模型中，B细胞缺乏或耗竭导致更差的病理和行为结果，支持B细胞在多巴胺能细胞损失中起早期保护作用的结论。总之，我们发现B细胞区室的变化与快速眼动睡眠行为障碍（α -突触核蛋白抗体较高）和早期帕金森病（B淋巴细胞水平较低，对刺激反应更强）的疾病进展风险相关。调节性B细胞在小鼠模型中发挥保护作用，可能通过减轻炎症和多巴胺能细胞损失。因此，B细胞可能以复杂的方式参与帕金森病的发病机制，因此值得考虑作为治疗靶点。Scott等人报道，B淋巴细胞的变化与帕金森病的进展有关，包括前驱疾病中纤维α -突触核蛋白抗体的增加、B细胞的减少和调节性B细胞的保护作用。有些变化是保护性的；其他可能有助于疾病的发病机制。
Inflammation contributes to Parkinson’s disease pathogenesis. We hypothesized that B lymphocytes are involved in Parkinson’s disease progression. We measured antibodies to alpha-synuclein and tau in serum from patients with rapid eye movement sleep behaviour disorder (n = 79), early Parkinson’s disease (n = 50) and matched controls (n = 50). Rapid eye movement sleep behaviour disorder cases were stratified by risk of progression to Parkinson’s disease (low risk = 30, high risk = 49). We also measured B-cell activating factor of the tumour necrosis factor receptor family, C-reactive protein and total immunoglobulin G. We found elevated levels of antibodies to alpha-synuclein fibrils in rapid eye movement sleep behaviour disorder patients at high risk of Parkinson’s disease conversion (ANOVA, P < 0.001) and lower S129D peptide-specific antibodies in those at low risk (ANOVA, P < 0.001). An early humoral response to alpha-synuclein is therefore detectable prior to the development of Parkinson’s disease. Peripheral B lymphocyte phenotyping using flow cytometry in early Parkinson’s disease patients and matched controls (n = 41 per group) revealed reduced B cells in Parkinson’s disease, particularly in those at higher risk of developing an early dementia [t(3) = 2.87, P = 0.01]. Patients with a greater proportion of regulatory B cells had better motor scores [F(4,24) = 3.612, P = 0.019], suggesting they have a protective role in Parkinson’s disease. In contrast, B cells isolated from Parkinson’s disease patients at higher risk of dementia had greater cytokine (interleukin 6 and interleukin 10) responses following in vitro stimulation. We assessed peripheral blood lymphocytes in alpha-synuclein transgenic mouse models of Parkinson’s disease: they also had reduced B cells, suggesting this is related to alpha-synuclein pathology. In a toxin-based mouse model of Parkinson’s disease, B-cell deficiency or depletion resulted in worse pathological and behavioural outcomes, supporting the conclusion that B cells play an early protective role in dopaminergic cell loss. In conclusion, we found changes in the B-cell compartment associated with risk of disease progression in rapid eye movement sleep behaviour disorder (higher alpha-synuclein antibodies) and early Parkinson’s disease (lower levels of B lymphocytes that were more reactive to stimulation). Regulatory B cells play a protective role in a mouse model, potentially by attenuating inflammation and dopaminergic cell loss. B cells are therefore likely to be involved in the pathogenesis of Parkinson’s disease, albeit in a complex way, and thus warrant consideration as a therapeutic target. Scott et al. report that there are changes in B lymphocytes that are associated with progression in Parkinson’s disease including increased antibodies to fibrillar alpha-synuclein in prodromal disease, decreased B cells and a protective effect of regulatory B cells. Some changes are protective; others may contribute to disease pathogenesis.
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影响因子：
6.1
作者：
Thomas Broome S;Louangaphay K;Keay KA;Leggio GM;Musumeci G;Castorina A
通讯作者：
Castorina A
影响因子：
3.3
作者：
Gruden, Marina A.;Sewell, Robert D. E.;Morozova-Roche, Ludmilla A.
通讯作者：
Morozova-Roche, Ludmilla A.
影响因子：
7.1
作者：
Kouli A;Camacho M;Allinson K;Williams-Gray CH
通讯作者：
Williams-Gray CH
影响因子：
15.1
作者：
Kedmi M;Bar-Shira A;Gurevich T;Giladi N;Orr-Urtreger A
通讯作者：
Orr-Urtreger A
DOI：
10.1084/jem.20111675
发表时间：
2012-05-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Barr TA;Shen P;Brown S;Lampropoulou V;Roch T;Lawrie S;Fan B;O'Connor RA;Anderton SM;Bar-Or A;Fillatreau S;Gray D
通讯作者：
Gray D