Involvement of the choroid plexus in central nervous system inflammation

Abstract

During inflammatory conditions in the central nervous system (CNS), immune cells immigrate into the CNS and can be detected in the CNS parenchyma and in the cerebrospinal fluid (CSF). The most comprehensively investigated model for CNS inflammation is experimental autoimmune encephalomyelitis (EAE), which is considered the prototype model for the human disease multiple sclerosis (MS). In EAE autoagressive CD4+, T cells gain access to the CNS and initiate the molecular and cellular events leading to edema, inflammation, and demyelination in the CNS. The endothelial blood‐brain barrier (BBB) has been considered the obvious place of entry for the circulating immune cells into the CNS. A role of the choroid plexus in the pathogenesis of EAE or MS, i.e., as an alternative entry site for circulating lymphocytes directly into the CSF, has not been seriously considered before. However, during EAE, we observed massive ultrastructural changes within the choroid plexus, which are different from changes observed during hypoxia. Using immunohistochemistry and in situ hybridization, we observed expression of VCAM‐1 and ICAM‐1 in the choroid plexus and demonstrated their upregulation and also de novo expression of MAdCAM‐1 during EAE. Ultrastructural studies revealed polar localization of ICAM‐1, VCAM‐1, and MAdCAM‐1 on the apical surface of choroid plexus epithelial cells and their complete absence on the fenestrated endothelial cells within the choroid plexus parenchyme. Furthermore, ICAM‐1, VCAM‐1, and MAdCAM‐1 expressed in choroid plexus epithelium mediated binding of lymphocytes via their known ligands. In vitro, choroid plexus epithelial cells can be induced to express ICAM‐1, VCAM‐1, MAdCAM‐1, and, additionally, MHC class I and II molecules on their surface. Taken together, our observations imply a previously unappreciated function of the choroid plexus in the immunosurveillance of the CNS. Microsc. Res. Tech. 52:112–129, 2001. © 2001 Wiley‐Liss, Inc.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…As cells from the adaptive immune system can be detected in the CSF but not in the CNS parenchyma in healthy individuals, the choroid plexuses and arachnoid which form the interfaces between the blood and CSF have recently moved into the focus of attention as the neuroimmune gateways regulating CNS immunosurveillance [41]. At the choroid plexuses, several cell types participate to immunosurveillance and neuroinflammation, and the choroidal responses to inflammatory stimuli are multiple.…”

“…The immunoregulatory function of the choroid plexuses has further been supported by local expression of complement proteins and their regulators (summarized in [41]). Overall, in absence of neuroinflammation the choroid plexuses thus seem to play an underestimated role in maintaining CNS immunity and may be critical structures ensuring local activation of CNS-specific T cells and their controlled subsequent migration across the choroidal epithelium allowing them to enter into the CSF niches of the CNS.…”

“…In neurological disorders as different as brain trauma [155], perinatal inflammation triggered by bacterial components [151], and experimental autoimmune encephalomyelitis (EAE) [41], the balanced cytokine and chemokine milieu within the choroid plexuses changes rapidly and may thus directly contribute to altered immune cell activation and their subsequent trafficking across the inflamed BCSFB into the CNS. Increased numbers of T cells and B cells are found in the CSF of patients with CNS infections or multiple sclerosis [3,16].…”

“…EAE is accompanied by significant morphological changes of the choroid plexuses, which are characterized by loss of apical microvilli and mitochondrial alterations in the choroid plexus epithelium and appearance of a higher number of electron dense, i.e. "dark cells" in the epithelium [41].…”

“…Granulocytes [41] and myeloid cells taking up circulating very small superparamagnetic iron oxide particles (VSOP) accumulate in the stroma of the choroid plexuses prior to the onset of EAE [41,93]. Interestingly, VSOP accumulation is undetectable in the non-inflamed CNS suggesting that the resident myeloid cells in the choroid plexus stroma require an inflammatory stimulus to actively phagocytose VSOPs.…”