Intrathecal Inflammation in Progressive Multiple Sclerosis

Salvatore Monaco,Richard Reynolds,Richard Nicholas,Roberta Magliozzi

doi:10.3390/ijms21218217

Abstract

Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy. These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid. In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations. The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid. This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles. Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance. In addition, “double hit” damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow–Robin spaces and the periventricular ependymal barrier. An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood–cerebrospinal fluid barrier and inflammation in the choroid plexus. Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS.

Highlights

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by white matter and gray matter demyelination, axonal loss, and neurodegeneration [1]
Whilst acute cellular inflammation with breakdown of the blood–brain barrier (BBB) is observed in RRMS, progressive disease is associated with compartmentalized chronic inflammation at leptomeninges and brain parenchyma, in the presence of an intact BBB [3]
The latter include the meninges and the cerebrospinal fluid (CSF), which is in part secreted by epithelial cells of the choroid plexuses (CP) of the brain’s ventricles, and the remaining half contributed by the interstitial fluid of the brain and by the secretory epithelium of ependymal cells lining the cerebral ventricles [5,6]

Summary

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by white matter and gray matter demyelination, axonal loss, and neurodegeneration [1]. Recent research on MS has provided insights into pathogenetic mechanisms governing the progressive forms of the disease, which are characterized by increasing disability, neurodegeneration, and gray matter atrophy These changes are thought to be the effect of mechanisms triggered by compartmentalized chronic innate and adaptive immune responses in the brain parenchyma and CSF-filled regions and associated cells lining these areas [4]. At different interfaces between the blood–CNS and blood–non-neural tissues, including meningeal membranes and choroid plexuses, blood vessels display distinctive cellular properties and biochemical mechanisms that provide the basis for anatomical and immunological barriers These barriers, encompassing the BBB, the blood–meningeal barrier (BMB), and the blood–CSF (B-CSF) barrier, regulate the active transport of small molecules while restricting the inward passage of cells and large molecules [7]. Insight into pathogenetic mechanisms of MS has been gained from neuropathological studies of post-mortem tissues and molecular proteomic analysis of blood/CSF [9,10], and this review describes current knowledge about the role of intrathecal inflammation compartmentalized in the CSF and non-neural tissues

Meningeal Inflammation

Subpial Lesions

CSF Inflammation

Findings

Choroid Plexus Inflammation