Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA.
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226.
Crit Rev Immunol. 2023;43(1):1-11. doi: 10.1615/CritRevImmunol.2023047235.
Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.
肌萎缩侧索硬化症（ALS）是一种神经系统疾病，其特征是大脑和脊髓中的运动神经元逐渐丧失。迄今为止，尚未建立有效的治疗策略，因此，迫切需要有效的治疗方法来阻止疾病的发展并逆转其引起的病理变化。尽管 ALS 的病因尚不清楚，但似乎是异质性的。目前已经发现超过 20 个基因与 ALS 相关。家族病史仅在 10%的 ALS 患者中发现，但在其余 90%的患者中未发现与家族病史有关。最常见的遗传原因是 C9orf72 基因扩增和超氧化物歧化酶 1、TDP-43 和 FUS 的突变。在我们最近的研究中，我们还发现 ALS 患者的 TDP43 和 FUS 突变。为了了解疾病的发病机制，我们的任务是分析 ALS 患者所有关键免疫效应物的表型和功能，并将其与基因健康的双胞胎或健康个体进行比较。我们的研究表明，NK 和 CD8+T 细胞毒性免疫效应物的功能激活显著增加，并且不仅在 ALS 患者的效应细胞中，而且在血清中也释放出大量 IFN-γ。对 ALS 患者 CD8+T 细胞介导的 IFN-γ分泌的纵向分析表明，IFN-γ分泌持续增加，并伴有一定的下降期，这与某些治疗方法相吻合；然而，这些效果在很大程度上是短暂的。N-乙酰半胱氨酸（NAC）是一种已被使用的治疗方法，它被认为可以阻止细胞死亡；然而，即使这种治疗能够阻断大多数促炎细胞因子、趋化因子和生长因子的释放，它也无法阻断 IFN-γ和 TNF-α，这两种细胞因子我们之前已经证明可以诱导细胞分化。在这篇综述中，我们讨论了细胞毒性效应细胞，特别是原始 NK 细胞、超激活 NK 细胞（sNK），以及 sNK 细胞在 CD8+T 细胞向记忆/效应 T 细胞分化中的扩增和功能激活在 ALS 发病机制中的作用。还讨论了潜在的新靶向治疗策略。
