Immunological function of the blood-cerebrospinal fluid barrier.

Abstract

Because the brain lacks a true lymphatic system, it is unclear how peripheral lymphocytes recognize foreign antigens present in the central nervous system. This report demonstrates that the choroid plexus, which constitutes the blood-cerebrospinal fluid barrier, is able to present foreign antigen to, and stimulate the proliferation of, peripheral helper T lymphocytes through an Ia-dependent, major histocompatibility complex-restricted mechanism. Furthermore, in vivo, choroid plexus epithelial cells have access to, and are capable of taking up, virus-sized particles injected elsewhere into the cerebrospinal fluid. Thus these data suggest that the bloodcerebrospinal fluid barrier may play a role in immunological communication between the central nervous system and periphery, a function relevant to the initiation of immunological responses to central nervous system infections and autoimmune processes and for the surveillance of tumor cells in the cerebrospinal fluid.During disease states, the brain contains immunoglobulinproducing plasma cells and T lymphocytes (1,2). These cells, which are normally present in only small numbers, appear to enter the central nervous system (CNS) from the systemic circulation (3). Surprisingly, little is known about how this immune process is initiated; particularly, how, at a time when lymphocytes are largely absent from the brain, foreign antigens in the CNS are recognized and processed for presentation to helper T cells (a necessary step for the initiation of most types of cellular-and humoral-mediated immunity). In the periphery, interaction among lymphocytes, antigen-presenting cells (e.g., macrophages), and antigen is facilitated by a highly developed lymphatic drainage system. However, the brain parenchyma, itself, contains no comparable lymph system and, furthermore, is largely isolated from the systemic circulation by the blood-brain and bloodcerebrospinal fluid (CSF) barriers. Even with the help of endogenous CNS antigen-presenting cells, such as microglia or astrocytes (4-8), it is unclear how antigens present in the CNS can interact with unstimulated lymphocytes located in the periphery.Prior studies have suggested that foreign substances present in brain extracellular fluid can move by bulk flow into the CSF (9, 10), which itselfundergoes a slow movement through the lateral, third, and fourth ventricles, into the cisterna magna. It occurred to us that the choroid plexuses (which also contribute to CSF formation) might be well-suited to detect foreign antigens present in the CSF and to communicate this information to the periphery. Choroid plexus tissue not only comes in close contact with CSF in the ventricular cavities but also is strategically present at the narrow foramina through which the CSF passes from lateral to third ventricles and from fourth ventricle to cisterna magna. In addition, the tightly joined choroid epithelial cells (constituting the blood-CSF barrier) form an interface between CSF and periphery, since their apical side faces the CSF and thei...

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

“…As discussed above these myeloid cells are distinct from the myeloid subsets in the CSF spaces. Interestingly, choroid plexus stroma dendritic cells can also reside between choroid plexus epithelial cells and extend their dendrites into the CSF filled ventricles [133], where they might take up CSF antigens for presentation to T cells in the choroid plexus stroma [101]. This is supported by the observation that T cells found in the choroid plexus stroma are enriched for CNS-specific effector/memory CD4 + T cells [10] (Fig.…”

“…A myeloid population is present in the choroid plexus: stromal macrophages, stromal dendritic cells, stromal myeloid progenitors [100,101,133], and epiplexus Kolmer cells located at the apical surface of the choroidal epithelium (Fig. 3d).…”

“…While there is no direct evidence for immune cell entry from the dura mater across the arachnoid membrane into the subarachnoid space, accumulating evidence points to immune cell entry into the CNS ventricles via the choroid plexuses [36,101,114,129]. A key function of both the arachnoid and the choroid plexuses in regulating CNS immunity is, however, suggested by the high amount of MHC class II expressing myeloid cells found strategically positioned on either side of the barriers.…”

“…An important immunological function of the choroid plexus in its entity has long been proposed [36,101,144] and has been underscored by numerous descriptions of the high numbers of MHC class II expressing bone marrow-derived macrophages and dendritic cells [101,133] residing in the highly vascularized choroid plexus stroma that is exposed to blood component due to the lack of an endothelial barrier (Fig. 6).…”

The Distributional Nexus of Choroid Plexus to Cerebrospinal Fluid, Ependyma and Brain

“…Drug-metabolizing enzymes in the BCSFB transform xenobiotics that might harm the brain if left unmetabolized. Fourth, an immune-type function is subserved by CP through the activity of antigen-presenting cells in the epithelial lining (Nathanson and Chun 1989), thereby permitting immune surveillance of CSF. Normally just a few immune cells migrate from plasma into ventricles to monitor CSF immunologic status.…”