Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells

Abstract

The choroid plexus (CP) is strategically located between the peripheral blood and the cerebrospinal fluid, and is involved in the regulation of central nervous system (CNS) homeostasis. In multiple sclerosis (MS), demyelination and inflammation occur in the CNS. While experimental animal models of MS pointed to the CP as a key route for immune cell invasion of the CNS, little is known about the distribution of immune cells in the human CP during progressive phases of MS. Here, we use immunohistochemistry and confocal microscopy to explore the main immune cell populations in the CP of progressive MS patients and non-neuroinflammatory controls, in terms of abundance and location within the distinct CP compartments. We show for the first time that the CP stromal density of granulocytes and CD8+ T cells is higher in progressive MS patients compared to controls. In line with previous studies, the CP of both controls and progressive MS patients contains relatively high numbers of macrophages and dendritic cells. Moreover, we found virtually no B cells or plasma cells in the CP. MHCII+ antigenpresenting cells were often found in close proximity to T cells, suggesting constitutive CNS immune monitoring functions of the CP. Together, our data highlights the role of the CP in immune homeostasis and indicates the occurrence of mild inflammatory processes in the CP of progressive MS patients. However, our findings suggest that the CP is only marginally involved in immune cell migration into the CNS in chronic MS.

Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

“…One of the functions of the CP is the maintenance of immune homeostasis in the CNS. Although CNS inflammation is less evident in the progressive phases of MS, immune activation occurs in both the relapsingremitting and progressive MS CP [65,77]. However, we only detected a subtle alteration in the immunological profile.…”

“…CXCL2 is a chemokine for granulocytes and, interestingly, neutrophilic LCN2 is upregulated at the onset of EAE [49]. Although no neutrophil markers were differentially expressed in our RNA-seq data, our recent immunohistochemical characterization of immune cell populations in the CP showed an accumulation of granulocytes in progressive MS patients relative to controls [65]. Future studies should explore the involvement of granulocytes in CP-mediated MS pathology, including whether their release of reactive oxygen species is related to the hypoxia-like responses observed.…”

“…In the mouse model for MS, called experimental autoimmune encephalomyelitis (EAE), the first wave of immune cell infiltration is thought to occur through the CP, by means of the interaction of Th17 cells with the CP epithelium-derived chemokine CCL20 [58]. In humans, activation of immune cell populations and adhesion mechanisms have been described in the CP from MS patients [65,77]. Alterations in the BCSFB that could result in immune cell infiltration into the CNS have also been studied both in EAE and MS, with variable results [13,37].…”

Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System

“…Beside observations in EAE, not much is known about ChP macrophages in MS. Analysis of human ChP tissue revealed a high density of CD68 + MHCII + macrophages and a minor proportion of MHCII negative Iba1 + cells, with these cells present within the stroma, intercalated between epithelial cells or lying on the apical side of epithelial cells ( 63 , 64 ). However, the densities of these cells appeared comparable between progressive MS patients and healthy controls ( 64 ).…”

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…For example, the brains of progressive MS donors show a significant axonal loss in both the demyelinated and normal cortices [14], extensive subpial grey matter demyelination [10], injury to excitatory projection neurons [15], diffuse neuroaxonal metabolic abnormalities [16] and diffuse microglial activation [17]. The underlying mechanisms of these diffuse CNS pathologies in progressive MS are complex but may include transneuronal degeneration due to the destruction of efferent/afferent projections [18], B cell-rich meningeal inflammation [19], the accumulation of peripheral immune cells in the choroid plexus stroma [20], chronically active and slowly expanding lesions with smoldering inflammation [21], accelerated biological aging [22], or complement activation [23]. Different aspects of the described progressive MS pathologies can be visualized by different imaging techniques, including positron emission tomography (PET) imaging, advanced magnetic resonance imaging (MRI), brain volume measurement, optical coherence tomography (OCT), diffusion tensor imaging (DTI), or myelin water imaging (MWI) [24][25][26][27][28].…”