What is the blood–brain barrier (not)?

Abstract

(preferred mode of contact) This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. The immune privilege of the central nervous system is indispensable for damage limitation during inflammation in a sensitive organ with poor regenerative capacity.It is a longstanding notion which has down the years acquired a lack of precision in its definition and a number of misconceptions. In this article we address these issues and re-define CNS immune privilege in the light of recent data. We show how it is far from absolute and how it varies with age and brain region. Immune privilege in the CNS is often mis-attributed wholly to the blood-brain barrier. We discuss the pivotal role of the specialization of the brain's afferent arm in adaptive immunity, which results in a lack of cell-mediated antigen drainage to the cervical lymph nodes although soluble drainage to these nodes is well described. It is now increasingly recognized how immune privilege is actively maintained as a result of the immunoregulatory characteristics of the CNS resident cells and their microenvironment. Immune privilege down the agesPrivilege: "a right, advantage, or immunity granted to or enjoyed by a person, or class of persons, beyond the common advantages of others" [1].The concept of "immune privilege" in the central nervous system (CNS) has a long history. That antigens trapped within the brain parenchyma evade systemic immunological recognition has been shown as early as 1921 in Japan. Back then, Y Shirai observed that rat sarcoma grew well when transplanted into the mouse brain parenchyma, but not when implanted subcutaneously or intramuscularly [2]. Murphy and Strum extended these findings in 1923 by demonstrating that if recipient spleen was cotransplanted with the foreign tumour in the brain parenchyma, it inhibited the tumour growth [3]. This showed that the survival of the foreign tumour within the brain parenchyma was occurring as a result of disconnection from the systemic immune system. These were the first indications of what was later to be termed "immunological privilege" by Billingham and Boswell [4]. Over the years, these observations have been shown to hold true for tissue grafts [5], bacteria [6], viruses [7] and vectors [8], which all evaded immune recognition when delivered to the brain parenchyma. Around the same time as the brain's "immune privilege" was being discovered, the blood-brain barrier (BBB) was under study, and the two concepts grew together. This had two consequences.First, the brain's "immune privilege" assumed a more absolute meaning, rendering it too strong a descriptive term for the brain's relationship with the immune system (Box 1).Secondly, "immune privilege" was inappropriately wholly attributed to the BBB (see previous article), whereas other features such as the specialization of afferent communication from CNS to nearby lymphatic organs and the nature of the CNS microenvironment are much more pertinent (Box 1). In this article, we aim to upd...

Blood—Brain Barrier Breakdown Involves Four Distinct Stages of Vascular Damage in Various Models of Experimental Focal Cerebral Ischemia

“…4,5 As part of the NVU, the endothelial layer and interendothelial belts of tight junctions (TJs) have been considered to be primarily responsible to regulate the permeability toward blood-sourced hydrophilic molecules into the brain parenchyma. [6][7][8] On the molecular level, TJs consist of three transmembrane protein families, which comprise junction-associated proteins, claudins, and occludin all of which are linked to the cytoskeleton via zonula occludens (ZO) proteins. 5,9 As these sealing structures are responsible for the maintenance of the BBB under physiologic conditions, loss of BBB function after stroke or associated with reperfusion is consequently attributed to dysfunctional TJs leading to an increased permeability of affected vessels, although respective data are often derived from in vitro models.…”

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

“…This early finding naturally inspired a discussion as to what could constitute the morphological substrate of this barrier (1). With the advent of the electron microscope it became clear that the blood-brain interface is composed of endothelia and pericytes, surrounded by a basal lamina and perivascular endfeet of astrocytes.…”

Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology

“…Importantly, the immune privilege of the brain is restricted to the parenchyma, whereas the ventricles, choroid plexus, meninges, and cerebrospinal fluid display the full range of innate and adaptive immune responses, because they contain the requisite immune structures and cells (3,(9)(10)(11). Soluble antigen will diffuse from the brain parenchyma to the ventricles, will be taken up by DCs, which migrate to the cervical lymph nodes, and will initiate an immune response (12)(13)(14).…”