Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: A neuropathological study

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Abstract

An immunological function has been proposed for the choroid plexus (CP). In multiple sclerosis (MS) brains, CPs show (immunohistochemistry to HLA-DR, CD3, CD20, CD68, VCAM-1, CD138) T lymphocytes in vessels and stroma, VCAM-1 expression on endothelia, intense HLA-DR immunostaining on cells in CP stroma, among CP epithelium and on epiplexus cells. CPs in control or amyotrophic lateral sclerosis brains do not show such inflammatory changes. Intense CP inflammation is observed in viral encephalitis. Changes in MS CPs suggest persisting immune activation, with intensity similar to acute encephalitis, even in MS phases in which neurodegeneration prevails. In MS, CPs could represent a site for lymphocyte entry in the CSF and for CSF antigens presentation.

Introduction

Recent studies have contributed to characterize the involvement of CNS structures outside the brain parenchyma, such as the leptomeninges and the cerebrospinal fluid (CSF), in the pathogenetic process of multiple sclerosis (MS) and Experimental Allergic Encephalomyelitis (EAE) (Kutzelnigg et al., 2005; Pedemonte et al., 2006; Magliozzi et al., 2007).

An immunological function has been proposed for the choroid plexus (CP), as a route of entry of leukocytes in the central nervous system (CNS) and as a link for antigen trafficking between the CSF and the peripheral blood (Nathanson and Chun, 1989; Kivisäkk et al., 2003). Nevertheless, studies investigating the role of the CP in MS are currently lacking, despite the importance of this structure in the interaction between the CNS and the peripheral blood, being the surface of the choroid villi of the same magnitude of the blood–brain barrier (Keep and Jones, 1990). Previous studies have suggested an involvement of the CP in EAE autoimmune inflammation (Engelhardt et al., 2001). In EAE, inflammation in the CP has been observed to precede the formation of brain perivascular inflammatory infiltrates and the development of demyelinating white matter (WM) lesions (Brown and Sawchenko, 2007).

The CP is in close contact with the CSF; the CP epithelial cells (constituting the blood–CSF barrier) form an interface between CSF and periphery, since their apical side faces the CSF and their basal side, facing fenestrated capillaries, has access to peripheral blood cells (Nathanson and Chun, 1989). The CP has been identified as one of the main routes of entry of lymphocytes in the CSF for routine immune surveillance in the normal brain (Kivisäkk et al., 2003). It has been also hypothesized that a function of the CP could be to scavenge antigens from the CSF, acting as an immunological link between CSF and blood (Nathanson and Chun, 1989). Professional antigen presenting cells have been identified within the CP, while they lack in the brain parenchyma (McMenamin, 1999); this presumably explains why adaptive immune responses are induced following injections of antigens into the brain ventricular system (while adaptive immune responses lack if antigens are injected directly in the brain parenchyma) (Lowenstein, 2002; Carson et al., 2006).

The objective of the present study is to characterize the structural and functional modifications of the CP in MS brains, in comparison to normal control brains and to brains of patients affected by other inflammatory and non-inflammatory neurological diseases.

Section snippets

Materials and methods

The CPs were evaluated in archival formalin-fixed, paraffin-embedded autoptic material, obtained from the University of Turin and the University of Genoa: 7 MS brains (3 relapsing–remitting (RR) MS, 4 secondary progressive (SP) MS), 2 control brains without abnormal findings at histopathological examination, 2 brains from patients affected by non-autoimmune inflammatory neurological diseases (acute viral encephalitis), and 6 brains from patients affected by amyotrophic lateral sclerosis (ALS),

Extent, distribution and inflammatory activity of demyelinating lesions in the MS brains

WM and GM demyelinating lesions were observed in all the MS brains included in this study. The extent of WM demyelination ranged from 4.5% to 75% of the total WM area in the coronal section (mean 21.5%; median 12.5%). The extent of GM demyelination ranged from 1.5% to 49.5% of the total GM area in the coronal section (mean 12.7%; median 3%) (Table 1). A typical periventricular distribution of WM lesions was observed in all MS brains.

Most of WM demyelinating lesions were chronic inactive;

Discussion

An important immunological function of the CP has been hypothesized, both in the routine immune surveillance of the CNS and in CNS inflammation, such as in EAE (Nathanson and Chun, 1989; Engelhardt et al., 2001; Kivisäkk et al., 2003; Engelhardt and Ransohoff, 2005, Brown and Sawchenko, 2007).

Hereby we present the first data, as far as we know, on the involvement of the CP in MS, in comparison to normal control brains and to brains of patients affected by other neurological diseases, either

Acknowledgment

This study was supported by: Compagnia di San Paolo, Turin. Grant number 2004.1424.

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