From the Research Laboratory for Stereology and Neuroscience (A.K.N., J.F., S.O., B.P., S.A., T.B.), and Department of Neurology (K.S., K.W.), Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen; Neuromuscular Clinic (K.S.), Department of Neurology, Rigshospitalet, Copenhagen; Institute of Clinical Medicine (B.P.), Faculty of Health and Medical Sciences, University of Copenhagen; and Copenhagen Center for Translational Research (S.A., T.B.), Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark.
Neurol Neuroimmunol Neuroinflamm. 2020 Dec 24;8(2). doi: 10.1212/NXI.0000000000000937. Print 2021 Mar.
We hypothesize alterations in the quality and quantity of anti-43-kDa TAR DNA-binding protein (TDP-43) naturally occurring autoantibodies (NAbs) in patients with amyotrophic lateral sclerosis (ALS); therefore, we assessed relative binding properties of anti-TDP-43 NAbs composite in plasma from patients with ALS in comparison with healthy individuals.
ELISA competition assay was used to explore the apparent avidity/affinity of anti-TDP-43 NAbs in plasma from 51 normal controls and 30 patients with ALS. Furthermore, the relative levels of anti-TDP-43 NAbs within the immunoglobulin (Ig) classes of IgG (isotype IgG1-4) and IgMs were measured using classical indirect ELISA. The occurring results were hereafter correlated with the measures of disease duration and disease progression.
High-avidity/affinity anti-TDP-43 NAbs levels were significantly reduced in plasma samples from patients with ALS. In addition, a significant decrease in relative levels of anti-TDP-43 IgG3 and IgM NAbs and a significant increase in anti-TDP-43 IgG4 NAbs were observed in ALS plasma vs controls. Furthermore, a decrease in global IgM and an increase in IgG4 levels were observed in ALS. These aberrations of humoral immunity correlated with disease duration, but did not correlate with ALS Functional Rating Scale-Revised scores.
Our results may suggest TDP-43-specific immune aberrations in patients with ALS. The skewed immune profiles observed in patients with ALS could indicate a deficiency in the clearance capacity and/or blocking of TDP-43 transmission and propagation. The decrease in levels of high affinity/avidity anti-TDP-43 NAbs and IgMs correlates with disease progression and may be disease predictors.
我们假设肌萎缩侧索硬化症（ALS）患者体内抗 43kDa TAR DNA 结合蛋白（TDP-43）天然自身抗体（NAb）的质量和数量发生改变；因此，我们评估了与健康个体相比，ALS 患者血浆中抗 TDP-43 NAb 复合物的相对结合特性。
使用 ELISA 竞争测定法来探索 51 名正常对照者和 30 名 ALS 患者血浆中抗 TDP-43 NAb 的表观亲和力/亲合力。此外，使用经典间接 ELISA 测量了免疫球蛋白（Ig）类别 IgG（同种型 IgG1-4）和 IgM 内抗 TDP-43 NAb 的相对水平。随后将所得结果与疾病持续时间和疾病进展的测量值相关联。
在 ALS 患者的血浆样本中，高亲和力/亲合力的抗 TDP-43 NAb 水平显著降低。此外，与对照组相比，在 ALS 血浆中观察到抗 TDP-43 IgG3 和 IgM NAb 的相对水平显著降低，而抗 TDP-43 IgG4 NAb 的水平显著升高。此外，ALS 中观察到 IgM 总量减少和 IgG4 水平增加。这些体液免疫的异常与疾病持续时间相关，但与 ALS 功能评定量表修订版评分无关。
我们的结果可能提示 ALS 患者存在 TDP-43 特异性免疫异常。在 ALS 患者中观察到的免疫偏倚谱可能表明 TDP-43 的清除能力和/或阻断 TDP-43 传播和传播的能力不足。高水平亲和力/亲合力的抗 TDP-43 NAb 和 IgM 水平的降低与疾病进展相关，可能是疾病的预测指标。
