Brain Behav Immun. 2014 Feb;36:9-14.

Afferent and efferent immunological pathways of the brain. Anatomy, function and failure.

Carare RO1, Hawkes CA2, Weller RO2.
  • 1Faculty of Medicine, University of Southampton, UK. Electronic address: rcn@soton.ac.uk.
  • 2Faculty of Medicine, University of Southampton, UK.

 

Abstract

Immunological privilege appears to be a product of unique lymphatic drainage systems for the brain and receptor-mediated entry of inflammatory cells through the blood-brain barrier. Most organs of the body have well-defined lymphatic vessels that carry extracellular fluid, antigen presenting cells, lymphocytes, neoplastic cells and even bacteria to regional lymph nodes. The brain has no such conventional lymphatics, but has perivascular pathways that drain interstitial fluid (ISF) from brain parenchyma and cerebrospinal fluid (CSF) from the subarachnoid space to cervical lymph nodes. ISF and solutes drain along narrow, ∼100 nm-thick basement membranes within the walls of cerebral capillaries and arteries to cervical lymph nodes; this pathway does not allow traffic of lymphocytes or antigen presenting cells from brain to lymph nodes. Although CSF drains into blood through arachnoid villi, CSF also drains from the subarachnoid space through channels in the cribriform plate of the ethmoid bone into nasal lymphatics and thence to cervical lymph nodes. This pathway does allow the traffic of lymphocytes and antigen presenting cells from CSF to cervical lymph nodes. Efferent pathways by which lymphocytes enter the brain are regulated by selected integrins on lymphocytes and selective receptors on vascular endothelial cells. Here we review: (1) the structure and function of afferent lymphatic drainage of ISF and CSF, (2) mechanisms involved in the efferent pathways by which lymphocytes enter the brain and (3) the failure of lymphatic drainage of the brain parenchyma with age and the role of such failure in the pathogenesis of Alzheimer’s disease.

KEYWORDS: Alzheimer’s disease; BM; Blood–brain barrier; Brain; CSF; IC; Interstitial fluid; Lymphatic drainage; Neuroimmunology; SMC; basement membrane (green contains tracer); immune complexes derived from the blood and entrapped in basement membranes of the perivascular drainage pathways; smooth muscle cell in the tunica media of the artery

PMID: 24145049

 

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fig1

Figure 1: Diagram of perivascular drainage of interstitial fluid from the brain along the basement membranes of capillaries and arteries. Interstitial fluid from the extracellular spaces of the brain enter basement membranes (green) of capillaries and drainage continues along the tortuous basement membranes arranged between the circumferentially arranged smooth muscle cells (red). Perivascular drainage occurs in minutes after intracerebral injection and is in the direction opposite to that of arterial blood flow into the brain (red arrow). Diagram drawn by Miss Roxana Aldea, BSc Physics, PhD student in Complexity interdisciplinary science, supervised by Dr Carare RO and Richardson G.

Lymphatic drainage of the brain and the pathogenesis of neurodegenerative diseases

Apart from the blood, there are two fluids associated with the brain: cerebrospinal fluid (CSF and interstitial fluid (ISF). CSF drains through arachnoid villi into the blood and via routes adjacent to olfactory nerves into the nasal mucosa and cervical lymphatics [1]. This route permits the drainage of antigen presenting cells from the subarachnoid space into the lymphatic system. The brain parenchyma is not endowed with traditional lymphatic vessels. For the last 50 years different physiological studies have shown that interstitial fluid drains from the brain along perivascular pathways into cervical lymphatics [2]. Using refined injection techniques and confocal microscopy, our group has demonstrated that drainage of interstitial fluid and solutes from the brain occurs along 100-150 nm-wide basement membranes in the walls of cerebral capillaries and arteries Fig 1). Older experimental studies suggest that only 10-15% of solutes draining by this route escape into the CSF [3]. We have demonstrated that injection of soluble Aβ into the brain parenchyma of young mice results in its rapid elimination along the walls of capillaries and arteries [4]. Our theoretical modelling studies suggest that the motive force for perivascular lymphatic drainage is derived from vascular pulsations and biochemical interactions with basement membranes [5, 6]. With increasing age and arteriosclerosis, cerebral arteries become stiffer [7] and the amplitude of pulsations decreases with the probable decline in the motive force that is reflected in reduced efficiency of lymphatic drainage of the brain as shown in aged mice [4].

Our working hypothesis is that the deposition of amyloid plaques in the human brain with age and Alzheimer’s disease reflects a failure of elimination of Aβ from the brain. Several mechanisms for the elimination of Aβ from the brain have been defined: degradation by enzymes such as neprilysin [8], receptor-mediated absorption into the blood [9], passage into the CSF [10] in addition to perivascular lymphatic drainage [11]. Reduction in neprilysin activity and failure of absorption of Aβ into the blood with age [8, 9] may divert more Aβ along perivascular lymphatic drainage pathways [8, 12]. As arteries age, lymphatic drainage becomes less efficient [4] and Aβ is deposited in basement membranes of arteries and capillaries as cerebral amyloid angiopathy (CAA), which further impairs perivascular lymphatic drainage [13], Fig 2. APOE ε4 is also associated with impaired perivascular lymphatic drainage as demonstrated in mice expressing human ApoE ε4 [14].

As a result of the failure of elimination of Aβ from the brain associated with ageing of cerebral arteries and CAA there is loss of homoeostasis of the extracellular environment in the brain as reflected in the rise of soluble Aβ in Alzheimer’s disease [15]. It is likely that there is also failure of elimination of soluble metabolites other than Aβ adding further to the loss of homoeostasis of the neuronal environment. The association of CAA with accumulation of fluid in the subcortical white matter reported after recent therapeutic trials in Alzheimer’s disease suggests that drainage of fluid is ultimately impaired [16, 17].

We are working in an interdisciplinary manner to demonstrate that changes in extracellular matrix and artery walls due to age, genotype, diet [18] or different patterns of innervation or branching of blood vessels could have a marked effect upon the extracellular environment of brain tissue leading especially to failure of elimination of Aβ from the extracellular space but also to failure of elimination of other metabolites and loss of homeostasis. Our mission is to clarify the exact factors that are responsible for efficient drainage along basement membranes of capillaries and arteries in order to identify new therapeutic targets for cerebral amyloid angiopathy and Alzheimer’s disease.

Figure 2

Figure 2: This is an image from a case of Alzheimer’s Disease, assessing the pattern of deposition of amyloid (red) within the walls of arteries at the surface of the brain. Amyloid (red) is deposited within the channels in the walls of blood vessels and sometimes completely replaces the normal components of the artery (arrow). In other arteries, amyloid remains exclusively deposited within its drainage pathways. The Carare group investigates the factors that prevent the normal elimination of amyloid and toxins from the ageing brain, in order to design therapeutic strategies that facilitate the elimination of amyloid along the artery walls. Smooth muscle in the artery walls is green. Collagen IV, a normal component of the arterial walls and helping the elimination of amyloid, is blue. Tissue from patient with Alzheimer’s disease, diagnosed by Prof Johannes Attems, University of Newcastle, tissue from Newcastle Brain Tissue Resource.

 

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