Brain borders at the central stage of neuroimmunology, 2022, Rustenhoven et al.

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Brain borders at the central stage of neuroimmunology
Rustenhoven, Justin; Kipnis, Jonathan

The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.

Link | PDF (Nature) paywalled

 

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Paywalled, so a few summary quotes —

It is increasingly apparent that the tissues of the CNS have unique immunological mechanisms that reflect the complexity of the tissue that they protect, rather than a distinct immune privilege. In particular, recent observations have demonstrated the importance of the brain borders—the meninges, choroid plexus, CNS-draining lymph nodes, perivascular spaces and the skull and vertebral bone marrow—in immune surveillance. In these compartments, various aspects of the immune system can sample CNS antigens, shape B cell tolerance, protect the brain from pathogenic insults, manipulate behavioural paradigms and provide bespoke immune cells to the brain during health and in response to diverse insults.

Despite the presence of an arachnoid barrier layer, the CSF reaches the dura mater. Through yet undefined routes—possibly perivascular pathways along cerebral veins that traverse the arachnoid mater—CSF constantly effluxes to the dura mater, largely restricted to sites surrounding the dural sinuses. These observations have been confirmed in rodent models using live imaging of fluorescent tracers, human studies using gadolinium-based MRI and mass spectrometry analysis of human samples demonstrating the presence of CNS-enriched antigens in the parasagittal dura.

The meninges are constantly bathed in antigenic matter arising from the CNS. This enables another fundamental feature of the adaptive immune response—elimination of autoreactive B cells. The dura mater contains a large proportion of mature B cells under steady-state conditions. Recent work has also demonstrated that this tissue contains developing B cells—including pro-, pre- and immature B cells—a function previously believed to be restricted to the bone marrow.

During development in the bone marrow, immature self-reactive B cells exposed to self-antigens undergo elimination via central tolerance to avoid autoimmunity. Intriguingly, B cells that recognize MOG—a component of CNS myelin that is largely restricted to the brain—were eliminated specifically in the dura mater, but not in peripheral bone marrow, demonstrating an additional site for immune tolerance.

 

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The lack of a lymphatic network in the CNS was previously thought to underlie the mechanism of immune privilege. However, the dura mater contains a lymphatic network that is evolutionarily conserved and is capable of draining the CNS via the CSF.

Recently, an unexpected role has been demonstrated for perivascular macrophages in controlling CSF dynamics under homeostasis. Depletion of perivascular and leptomeningeal macrophages (collectively referred to as parenchymal border macrophages) [...] resulted in impaired arterial pulsation, which is a driving force for CSF influx from peri-arterial spaces. Ultimately, this resulted in impaired CSF and brain ISF [interstitial fluid] exchange and impaired removal of CNS waste.

Similar to the dura mater, the choroid plexus endothelium is fenes- trated and displays low levels of tight junctions and abundant adhesion molecule expression. Short-lived cells such as neutrophils and monocytes are present in the choroid plexus, suggesting continuous homeostatic trafficking from the permissive blood vessels, and diverse chemokines are present under steady-state conditions that could recruit myeloid population.

The classical dogma of CSF drainage described its direct passage into the dural sinuses via arachnoid granulations. Such a route would remove CSF with its CNS-derived antigenic matter directly into blood, rather than lymph, negating any potential for immunological surveillance of this fluid. Several recent observations have begun to describe alternative CSF drainage pathways, and indeed fluorescent tracers injected into CSF appear in lymphatic circulation before their appearance in the blood.

Exactly which lymph nodes CSF drains to in humans remains unclear. However, molecular tracers used as a surrogate for CSF movement can be observed in the lymphatics at the brain borders of humans and human cervical lymph nodes demonstrate the presence of the CNS-enriched myelin protein MOG.

Neuro-immune interactions are increasingly recognized in diverse brain disorders. Although there has been a substantial focus on microglia—the resident macrophages of the brain—the brain borders represent highly active immunological sites that shape homeostatic brain functions and may be critical in the pathophysiology of diverse neurological diseases.