Neuroimmunology: The Immune System of the CNS

The nervous and immune systems have been historically perceived as disparate entities, separated by the blood-brain barrier (BBB) with little interaction between either system. Consequently, this shaped our perception of the central nervous system (CNS) as possessing a dampened and compartmentalised immune system with resident cells such as astrocytes assuming immune roles such as antigen presentation.

However, the role of signalling molecules of the immune system such as cytokines in CNS function and vice-versa, i.e. the role of classical neurotransmitters in modulating immune function has contributed to a paradigm shift in our understanding of our understanding of the two systems. This has in no small part been fuelled by evolving technology and analyses routes, crucially multi-parametric flow cytometry and high dimensional, automated analysis as well as the unparalleled transcriptomic resolution at the single-cell level. This article will briefly discuss the key questions confronting our understanding of the interplay of the central nervous and immune systems.

How the CNS and Immune System Effect Behaviour

The fundamental premise of neuroimmunology — defined as the cross-talk between the CNS and immune systems— warrants consideration of the evolutionary advantage of the intersection between these two disparate systems.

In this context, studies have implicated interferon-γ (IFN- γ) in modulating social behaviour, CX3CR1+ monocytes in learning-dependent dendritic spine formation, and hypothalamic lipolysis driving adaptive immunity in response to infection-induced tumour necrosis factor-α (TNF-α). This data suggests that pathogens are key drivers in the evolution of immune signals, and in turn shape CNS function. The behavioural effects that these cytokines mediate curtails the spread of pathogens through a population by inducing social withdrawal and sickness behaviour in the infected individual.

This idea is reinforced by other data demonstrating the importance of sympathetic neural signals in driving immune responses to infection through the induction of tissue-protective programmes in gut macrophages or inflammation, by modulating macrophage transcriptional programmes. The latter has spurred progress in our appreciation of trained innate immunity and role of the nervous system in imparting this “education” to immune cells. Thus, it can be interpreted that the neural input to the immune system serves to tune and elicit a highly coordinated immune response to curtail and eliminate the pathogen or inflammation and promote tissue repair.

Immune Cells of the CNS: Effector Functions & Cytokines

Given this intimate interaction that exists between the CNS and the immune system, another key question is the route of entry and exit from CNS adopted by immune cells.

Whilst previously thought that the immune privilege of the CNS implied the absence of lymphatic vessels, recent research has uncovered the existence of lymphatic vessels in the dural sinuses carrying cerebrospinal fluid (CSF)-derived immune cells and fluid. Studies investigating immune changes in response to CNS damage in ischaemic stroke have also discovered alternative routes of CNS entry wherein the recruitment of pro-inflammatory gdT cells secreting interleukin-17 (IL-17) to the ischaemic brain occurs through the leptomeninges whilst neutrophils are recruited via a breached BBB post-stroke. This has led to the notion that route of entry is dependent on the anti-inflammatory status of the infiltrating cell as contexts of stroke and spinal cord injury have demonstrated that the recruitment of beneficial (reparative) monocytes occurs via the choroid plexus.

In addition to immune cells that infiltrate the CNS during homeostasis and disease, like most other tissues, the CNS is also endowed with populations of tissue-resident macrophages like microglia, perivascular and meningeal macrophages that are embryonically seeded from yolk sac. Further, the meningeal space has also been shown to harbour a population of type 2 innate lymphoid cells (ILC2) that have been shown to be important in mediating tissue repair through their production of type 2 cytokines in an IL-33-dependent manner post-injury. Therefore, the concept of immune privilege has to be reformed to be relative, more applicable to the parenchyma and much less at the frontiers of the CNS, common to both to innate and adaptive arms and one that is compromised during inflammation.

The Neuroimmune System in Disease

The blurring of the boundaries between the CNS and the immune system means that diseases affecting one system have an inevitable impact on the other. Diseases affecting systemic immunity such as infections or autoimmune disease such as multiple sclerosis (MS) can also significantly impact CNS function including the physical damage of neuronal networks as well as cognition. This occurs predominantly through the propagation of neuroinflammation as a consequence of both myeloid and lymphoid cells from the periphery infiltrating the CNS. Specifically, in experimental models of MS, experimental autoimmune encephalomyelitis (EAE), it is thought that development of disease is facilitated by the presentation of myelin-derived antigens by antigen presenting cells to T cells at CNS interfaces and secondary lymphoid organs.

Conversely CNS disease is also capable of inflicting immune dysfunction and a classic example in this case is ischaemic stroke. Here, the disruption of cerebral blood flow results in an initial infarct that subsequently induces debilitating systemic immunosuppression, predisposing patients to infections. In experimental stroke models, studies have implicated SNS over-activation as a key mediator in increasing the susceptibility to bacterial aspiration pneumonia by modulating adaptive immunity, thus decreasing the frequency and functional responsiveness in B and T cells. Other studies have shown that even the innate arm is not spared as there is loss of in the numbers and functional capacity of NK cells to secrete cytokines as well the oxidative burst of monocytes and neutrophils. However, these findings have not translated into clinical benefits as neither prophylactic antibiotics nor sympathetic blockade appear to confer any protection from increased susceptibility to bacterial aspiration pneumonia.

Similarly, even neurodegenerative conditions such as Alzheimer’s disease (AD) have been shown to possess an immune component and therefore, it comes as no surprise that increased susceptibility to sporadic late-onset AD is linked to polymorphisms in genes of the immune system such as TREM2 and CD33. It is thought that the deposition of amyloid-b (Ab) and the development of neurofibrillary tangles of hyperphosphorylated tau are key to disease pathogenesis. However, it is only recently that we have attempted to discern the differential contributions of various immune cell populations to the progression of AD. It has now emerged that not all aspects of neuroinflammation are detrimental and that existence of T cells are key to restraining AD pathology, and their rejuvenation through checkpoint inhibitors is vital to restoring type II interferon signalling that is dampened in aging. However, it remains to be seen if these immune modulatory therapies can be translated from the bench to bedside.

The Future of Central Nervous System Immunity Studies

Whilst our appreciation of the multi-faceted interactions between the CNS and the immune system has grown, it is far from complete. We have been forced to revisit the notion of immune privilege the CNS was thought to enjoy. Similarly, we have also refined our understanding of the CNS-resident microglia, specifically, their ontogeny and relationship with monocytes and macrophages in the mononuclear phagocyte system.

But more questions remain. What is the rationale to compartmentalise CNS immunity between cells in the parenchyma and those at the border? Do CNS niches endowed with the capacity to mediate protective effects exist? What is the T cell receptor repertoire exercised by T cells in the CNS? The pursuit of answers to these questions could perhaps facilitate better understanding of the neuro-immune crosstalk and guide targeted approaches to therapeutic interventions to diseases of the CNS or immune system.

6th Oct 2021 Siddharth Krishnan, PhD, The University of Manchester

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