Vascular, glial, and lymphatic immune gateways of the central nervous system.

Britta Engelhardt,Ingo Bechmann,Roxana O Carare,Roy O Weller,Jon D Laman,Alexander Flügel

doi:10.1007/s00401-016-1606-5

Abstract

Immune privilege of the central nervous system (CNS) has been ascribed to the presence of a blood–brain barrier and the lack of lymphatic vessels within the CNS parenchyma. However, immune reactions occur within the CNS and it is clear that the CNS has a unique relationship with the immune system. Recent developments in high-resolution imaging techniques have prompted a reassessment of the relationships between the CNS and the immune system. This review will take these developments into account in describing our present understanding of the anatomical connections of the CNS fluid drainage pathways towards regional lymph nodes and our current concept of immune cell trafficking into the CNS during immunosurveillance and neuroinflammation. Cerebrospinal fluid (CSF) and interstitial fluid are the two major components that drain from the CNS to regional lymph nodes. CSF drains via lymphatic vessels and appears to carry antigen-presenting cells. Interstitial fluid from the CNS parenchyma, on the other hand, drains to lymph nodes via narrow and restricted basement membrane pathways within the walls of cerebral capillaries and arteries that do not allow traffic of antigen-presenting cells. Lymphocytes targeting the CNS enter by a two-step process entailing receptor-mediated crossing of vascular endothelium and enzyme-mediated penetration of the glia limitans that covers the CNS. The contribution of the pathways into and out of the CNS as initiators or contributors to neurological disorders, such as multiple sclerosis and Alzheimer’s disease, will be discussed. Furthermore, we propose a clear nomenclature allowing improved precision when describing the CNS-specific communication pathways with the immune system.

Highlights

The central nervous system (CNS), comprising the brain, spinal cord, and neural parts of the eye, has a unique relationship with the immune system that has been referred to as immune privilege
We examine the possible mechanisms involved in immunological diseases of the CNS, how lymphatic drainage pathways are involved in the aetiology of Alzheimer’s disease and we revisit the concept of immune privilege
Drainage of interstitial fluid from the CNS parenchyma to regional lymph nodes Experimental studies have shown that soluble tracers injected in minute amounts (0.5 μL) into the parenchyma of grey matter areas in the mouse brain initially diffuse through the extracellular spaces (ECS) and rapidly enter the basement membranes of cerebral capillaries and drain directly via basement membranes in the tunica media of arterioles and arteries out of the brain to cervical lymph nodes [24, 26, 33] (Figs. 1, 2c, 3, 4)

Summary

Introduction

The central nervous system (CNS), comprising the brain, spinal cord, and neural parts of the eye, has a unique relationship with the immune system that has been referred to as immune privilege. As a sequel to the grafting experiments, it was shown that if the same allografts were subsequently grafted on to the skin, allografts in the brain were rapidly rejected [29, 86] It appears, that immunization in peripheral tissues precipitates immunological rejection of foreign tissue in the CNS. T lymphocyte-mediated immune responses, such as those involved in the rejection of skin allografts, in the elimination of microorganisms and in autoimmune disorders, may only occur in the CNS in individuals that have been initially immunised by antigen in peripheral tissues.Immunological reactions comprise two major components: an innate response and an adaptive response. The leptomeningeal and perivascular compartments of the CNS harbour professional APC, such as macrophages and dendritic cells (DC), that, without activating signals, constitutively express MHC class I and class II molecules and constantly present self-antigens and may promote. Further progress into the brain parenchyma requires MMP-dependent penetraƟon of the perivascular glia limitans

Perivascular and paravascular

Not APCs

Conclusions

Findings

Compliance with ethical standards