IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Curr Med Chem. 2011;18(12):1775-84. doi: 10.2174/092986711795496881.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss underlying progressive clinical disability. The chronic inflammatory tissue damage involving myelin and axons is driven by autoreactive T cells and represents a key mechanism in the immunopathogenesis of MS. Over the last few years, evidence from MS and experimental models of neuroinflammation has suggested that autoimmune responses could exert neuroprotective effects through the release of neurotrophins by autoreactive T cells. Specifically, the role of the Brain-derived neurotrophic factor (BDNF) in facilitating brain tissue repair in experimental traumatic injury has been well recognized. Support for this hypothesis comes from recent studies showing that glatiramer acetate, a currently approved treatment for MS, promotes the expansion of T cell clones crossing the blood-brain barrier and releasing BDNF in situ. A small subset of autoreactive T cells expresses the high-affinity full-length receptor for BDNF (TrkB-TK) in the periphery. In MS patients, T cells show reduced susceptibility to activation-induced apoptosis, a crucial mechanism eliminating autoreactive T clones and contributing to peripheral immunologic tolerance. These findings suggest the existence of a dual effect exerted by BDNF, which not only provides neuroprotection in the CNS but also promotes the survival of autoreactive T cells through an autocrine/paracrine loop. The aim of this review is to discuss the neuroprotective effects of currently approved immunomodulatory treatments for MS and their role in regulating neurotrophin production. We will also describe novel therapeutic strategies arising from new insights on "neuroprotective autoimmunity".
多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症性疾病，其特征是炎症、脱髓鞘和轴突丢失，导致进行性临床残疾。涉及髓鞘和轴突的慢性炎症性组织损伤是由自身反应性 T 细胞驱动的，是 MS 免疫发病机制的关键机制。在过去的几年中，来自 MS 和神经炎症实验模型的证据表明，自身免疫反应可以通过自身反应性 T 细胞释放神经营养因子来发挥神经保护作用。具体来说，脑源性神经营养因子（BDNF）在促进实验性创伤性损伤中的脑组织修复中的作用已得到充分认识。这一假设的证据来自最近的研究，这些研究表明，目前批准用于 MS 的治疗药物醋酸格拉替雷能够促进穿过血脑屏障的 T 细胞克隆的扩张，并在原位释放 BDNF。一小部分自身反应性 T 细胞在周围表达 BDNF 的高亲和力全长受体（TrkB-TK）。在 MS 患者中，T 细胞对激活诱导的细胞凋亡的敏感性降低，这是消除自身反应性 T 克隆并有助于外周免疫耐受的关键机制。这些发现表明 BDNF 发挥双重作用，不仅在中枢神经系统中提供神经保护，而且通过自分泌/旁分泌环促进自身反应性 T 细胞的存活。本综述的目的是讨论目前批准用于 MS 的免疫调节治疗的神经保护作用及其在调节神经营养因子产生中的作用。我们还将描述“神经保护性自身免疫”新见解带来的新治疗策略。
