The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis

Britta Engelhardt,Martina Schulz

doi:10.1186/1743-8454-2-8

Abstract

BackgroundDuring inflammatory conditions of the central nervous system (CNS), such as in multiple sclerosis or in its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells migrate from the blood stream into the CNS parenchyma and into the cerebrospinal fluid (CSF) spaces. The endothelial blood-brain barrier (BBB) has been considered the most obvious entry site for circulating immune cells. Recently, the choroid plexus has been considered as an alternative entry site for circulating lymphocytes into the CSF. The choroid plexus, belongs to the circumventricular organs (CVOs) localized in the walls of the ventricles. Other CVOs, which similar to the choroid plexus lack an endothelial BBB, have not been considered as possible entry sites for immune cells into the CNS parenchyma or the CSF. Here we asked, whether CVOs are involved in the recruitment of inflammatory cells into the brain during EAE.MethodsWe performed an extensive immunohistological study on the area postrema (AP), the subfornical organ (SFO), the organum vasculosum of the lamina terminalis (OVLT) and the median eminence (ME) in frozen brain sections from healthy SJL mice and mice suffering from EAE. Expression of cell adhesion molecules, the presence of leukocyte subpopulations and the detection of major histocompatibility complex antigen expression was compared.ResultsSimilar changes were observed for all four CVOs included in this study. During EAE significantly increased numbers of CD45+ leukocytes were detected within the four CVOs investigated, the majority of which stained positive for the macrophage markers F4/80 and Mac-1. The adhesion molecules ICAM-1 and VCAM-1 were upregulated on the fenestrated capillaries within the CVOs. A considerable upregulation of MHC class I throughout the CVOs and positive immunostaining for MHC class II on perivascular cells additionally documented the immune activation of the CVOs during EAE. A significant enrichment of inflammatory infiltrates was observed in close vicinity to the CVOs.ConclusionOur data indicate that the CVOs are a site for the entry of immune cells into the CNS and CSF and consequently are involved in the inflammatory process in the CNS during EAE.

Highlights

During inflammatory conditions of the central nervous system (CNS), such as in multiple sclerosis or in its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells migrate from the blood stream into the CNS parenchyma and into the cerebrospinal fluid (CSF) spaces
The MECA-32 antigen was absent on the mature cerebral endothelium, whereas it remained present on vessels outside of the CNS and the microvessels within the choroid plexus and the circumventricular organs (CVOs, Figures 1, 2, 3, 4, 5, 6, 7, 8)
In the present study we investigated four CVOs, namely the subfornical organ (SFO), the area postrema (AP), the

Summary

Introduction

During inflammatory conditions of the central nervous system (CNS), such as in multiple sclerosis or in its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells migrate from the blood stream into the CNS parenchyma and into the cerebrospinal fluid (CSF) spaces. The endothelial blood-brain barrier (BBB) has been considered the most obvious entry site for circulating immune cells. Other CVOs, which similar to the choroid plexus lack an endothelial BBB, have not been considered as possible entry sites for immune cells into the CNS parenchyma or the CSF. In multiple sclerosis and in its animal model, experimental autoimmune encephalomyelitis (EAE), inflammatory cells obtain access to the central nervous system (CNS) parenchyma and the cerebrospinal fluid (CSF) and initiate the events leading to signs of paralysis. The endothelial blood-brain barrier (BBB) has been considered the obvious place for entry for circulating lymphocytes into the CNS. The barrier is located at the level of the choroid plexus epithelial cells, which form tight junctions inhibiting paracellular diffusion of water soluble molecules [4]

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