Zuroff Leah R, Benjamins Joyce A, Bar-Or Amit, Lisak Robert P
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Departments of Neurology and Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Neuroimmunol Neuroinflamm. 2021;8:111-133. doi: 10.20517/2347-8659.2020.35. Epub 2021 Jun 20.
Multiple sclerosis (MS) is a lifelong inflammatory demyelinating disease of the central nervous system (CNS). While there has been substantial progress in the development of therapeutic strategies for relapsing disease, the field has lagged behind in its understanding and management of progressive stages of the disease, including secondary progressive and primary progressive MS, respectively. It is now thought that distinct but temporally overlapping mechanisms underlie relapsing and progressive aspects of the disease. Relapsing disease is characterized by waves of peripheral immune cell activation and CNS infiltration leading to focal destruction of the white matter, while progressive disease is thought to be driven by chronic, low-grade multifocal inflammation contained within the CNS compartment. Specifically, peripheral B cells, T cells, and myeloid cells take up residence within niches of the inflamed CNS, such as the leptomeninges and the Virchow-Robin spaces, where complex interactions between peripheral and CNS resident cells serve to maintain these cellular aggregates and further propagate CNS injury. In particular, immune infiltrates within the meninges are tightly associated with a specific form of cortical injury, termed subpial cortical demyelination, which is thought to be a key pathologic driver of disease progression. Cortical injury in the MS brain likely occurs via a combination of multiple immune-mediated and degenerative processes, perhaps including the production of diffusible toxic mediators by peripheral immune cells retained within the meninges. A better understanding of the interplay between peripheral immune and CNS resident cells is not only relevant to our concept of the disease process, but also represents a novel target for therapeutic intervention that is more specific to progressive disease biology. This review will focus on the role of CNS-compartmentalized inflammation in the development of cortical injury in MS, with a particular emphasis on the importance of immune-CNS crosstalk in disease progression.
多发性硬化症（MS）是一种中枢神经系统（CNS）的终身性炎性脱髓鞘疾病。虽然在复发型疾病治疗策略的开发方面取得了重大进展，但该领域在对疾病进展阶段（分别包括继发进展型和原发进展型MS）的理解和管理上仍滞后。现在认为，不同但在时间上重叠的机制是疾病复发和进展方面的基础。复发型疾病的特征是外周免疫细胞激活和CNS浸润的浪潮，导致白质局灶性破坏，而进展型疾病被认为是由CNS区域内的慢性、低度多灶性炎症驱动的。具体而言，外周B细胞、T细胞和髓样细胞在炎症性CNS的特定微环境中定居，如软脑膜和Virchow-Robin间隙，外周细胞与CNS驻留细胞之间的复杂相互作用有助于维持这些细胞聚集并进一步加剧CNS损伤。特别是，脑膜内的免疫浸润与一种特定形式的皮质损伤紧密相关，称为软膜下皮质脱髓鞘，这被认为是疾病进展的关键病理驱动因素。MS脑内的皮质损伤可能是通过多种免疫介导和退行性过程的组合发生的，可能包括脑膜内保留的外周免疫细胞产生可扩散的毒性介质。更好地理解外周免疫细胞与CNS驻留细胞之间的相互作用不仅与我们对疾病过程的概念相关，而且代表了针对进展型疾病生物学更具特异性的治疗干预新靶点。本综述将重点关注CNS区域内炎症在MS皮质损伤发展中的作用，特别强调免疫与CNS相互作用在疾病进展中的重要性。
