Trends in Immunology
Volume 28, Issue 1, January 2007, Pages 5-11
Journal home page for Trends in Immunology

Opinion
What is the blood–brain barrier (not)?

https://doi.org/10.1016/j.it.2006.11.007Get rights and content

In 1900, summarizing his experiments with toxins and Ehrlich's earlier observations with intravital dyes, the Berlin physician Lewandowski concluded that ‘brain capillaries must hold back certain molecules’. Illustrating this phenomenon with persuasive beauty, the subsequently evolving metaphor of a ‘Bluthirnschranke’ (blood–brain barrier, BBB) gained wide acceptance, but the extension of its meaning into the context of inhibiting leukocyte recruitment into the brain is imprecise. On the basis of the original work by Ehrlich, Lewandowski and Goldmann we re-define the BBB as a capillary barrier for solutes, and clarify that leukocyte recruitment requires two differentially regulated steps: (i) passage across postcapillary venules into Virchow–Robin spaces, and (ii) subsequent progression across the glia limitans into the neuropil. We propose that the second step frequently involves perivascular antigen-recognition and the induction of ectoenzymes, for example matrix metalloproteinases (MMPs).

‘The metaphor is often smarter than the poet’ (Heiner Müller).

Section snippets

Anatomical misconceptions have been sources of confusion

Leukocyte recruitment into the brain is an important topic in neuroimmunology. A deeper understanding of its regulation might provide clues for treating diseases such as multiple sclerosis (MS) [1]. However, numerous studies in the field suffer from an inappropriate view or understanding of the blood–brain barrier (BBB). Terms including ‘leukocytes cross the blood–brain barrier’ often leave open the question of whether these cells passed the vascular wall to reside in perivascular

Ehrlich's unwanted finding

For the following, it is helpful to distinguish between the phenomenon and its interpretation(s). The phenomenon was first noted by Ehrlich [2] in a series of experiments designed to compare the oxygen consumptions of different organs. To this end, Ehrlich used ‘intravital dyes’, the colours of which changed with their redox state. His incidental, but seminal, observation (which, in fact, was unwanted as it spoiled his studies) was that some of the dyes, following injection into veins, arteries

How the concept of a BBB was taken over by neuroimmunologists

Medawar [26] observed that immune tolerance to grafts in the brain breaks down when a second graft of the same tissue is inserted under the skin. He concluded that ‘skin homografts transplanted to brain submit to, but cannot elicit, an immune state’ and proposed that this ‘is consistent with the view that a lymphatic drainage system is required to create a state of immunity, but not necessary to enforce a response to it.’ It is noteworthy that functional drainage through the cribriform plate

The two steps in neuroinflammation

Pre- and post-capillary vessels are accompanied by leptomeningeal protrusions from the surface of the brain forming the perivascular spaces. Thus, the vessel wall of postcapillary venules is separated from the neuropil by an additional compartment, which is connected to the subpial and subarachnoid space and partly filled with cerebrospinal fluid (Figure 1). Therefore, cells crossing the vessel wall do not enter the neuropil directly, but have performed the first step of migration from the

Acknowledgements

I.B. thanks the Deutsche Forschungsgemeinschaft (DFG) (SFB 507 B-16) for financial support, and Josef Priller, Frauke Zipp and Robert Nitsch for years of enjoyable and helpful collaboration. Owing to space limitations, some of the relevant literature has not been mentioned. We extend our apologies to the authors concerned.

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