Elsevier

Progress in Neurobiology

Volume 56, Issue 1, 1 September 1998, Pages 19-35
Progress in Neurobiology

Inflammation in the CNS: balance between immunological privilege and immune responses

https://doi.org/10.1016/S0301-0082(98)00014-8Get rights and content

Abstract

Inflammatory components play an important part in many diseases of the central nervous system (CNS). Recent evidence suggests that this may also be true of diseases which were previously considered as purely neuro-degenerative. However, it is also clear that inflammatory responses in the CNS differ in many ways from responses in non-CNS tissues.

Some of these differences have been demonstrated by the use of animal models. For example, when bacteria are injected into the brain parenchyma, they induce a typical acute inflammatory response. However, unlike in other tissues, bacteria which are not cleared from the brain parenchyma remain undetected by the immune system. Some bacteria, such as bacillus Calmette-Guérin, can persist in the brain parenchyma for months sequestered in microglia and perivascular macrophages. When an animal with an intraparenchymal bacteria deposit is later sensitised peripherally, an immune response is evoked at the site of the deposits.

The lesions induced in the CNS parenchyma are T-cell mediated and show characteristics typical of a delayed-type hypersensitivity response. The lesions produce a breakdown of the blood–brain barrier and demyelination. These immune responses are similar to those described for multiple sclerosis lesions.

The responses to bacteria are unique to the brain parenchyma. Pathogens injected into the ventricles induce inflammatory responses similar to those in other non-CNS tissues: there is an acute inflammatory response which develops spontaneously into an immune mediated response within the first week.

Introduction

Inflammation is the response of the host to tissue injury or infection. The four cardinal signs of an inflammatory response are redness, heat, swelling and pain. These signs were first described in antiquity, and they reflect complex processes by which the body responds to insult. These processes have been well described for non-CNS tissues, and work is now being done to describe the inflammatory response and its effects within the CNS. All inflammatory responses fall into two main categories: innate inflammation, which is an acute response leading in most cases to the elimination of pathogens and tissue repair; and acquired immunity, which is a secondary response. This latter response is antigen specific and is elicited by the host when innate processes have failed to clear the foreign antigen. It can be mediated by either T-cells or antibodies, or both. The type of immune response depends on the nature of the challenging antigen which will skew the response to either a cellular (T-cell) response or humoral (antibody) response.

Although injury of the nervous system has been studied extensively, until the last decade only limited work has been done on the inflammatory response in the brain itself. Such work as was done focused on immune-mediated diseases such as multiple sclerosis (MS) because the responses there appear to be more typically inflammatory, being characterised by the breakdown of the blood–brain barrier (BBB), the presence of plasma proteins, and leucocyte recruitment. However, it is now recognised that inflammatory components play an important part in a variety of CNS disorders, including trauma (Clark et al., 1994; Dusart and Schwab, 1994; Arvin et al., 1996), ischaemia (Kogure et al., 1996; Arvin et al., 1996), AIDS-related dementia (Gondelman et al., 1994) as well as diseases such as Alzheimer’s, which were previously regarded as being purely neuro-degenerative (Rogers et al., 1996). These inflammatory processes in the brain are often more subtle in their appearance, and differ from those in non-CNS tissues, e.g. in the skin.

In many of the disorders mentioned above, microglia activation, elevated levels of cytokines, and adhesion molecules are hallmarks of CNS inflammation. Microglia activation and an elevated level of cytokines such as interleukin (IL)-1 and IL-6 have been demonstrated for ischaemia (Rogers et al., 1996). Recruitment of neutrophils and macrophages has also been shown to take place following cerebral ischaemia. Both neutrophils and macrophages contribute to the breakdown of the BBB and CNS tissue damage. In animal models, the entry of these leucocytes has been inhibited with anti-MAC-1 (Chopp et al., 1994) and anti intercellular adhesion molecule 1 (ICAM-1) antibodies (Zhang et al., 1995) and this has abrogated the damage to the BBB. Microglia activation is a well-recognised feature of Alzheimer’s lesions (McGeer et al., 1993). The elevated levels of inflammatory cytokines (IL1 and IL6) and the deposition of complement components such as C1q and membrane attack complexes (C5b-9) has also been shown in these lesions. Furthermore, evidence from clinical trials, in which sufferers of Alzheimer’s disease used non-steriodal anti-inflammatory drugs (NSAIDs), suggests that these drugs inhibit the progress of the disease (McGeer and Rogers, 1992).

Finally, microglia activation has been shown in prion diseases such as scrapie (Williams et al., 1994a, Williams et al., 1994b; Betmouni et al., 1996), and a new study has shown the recruitment of T-cells in the mouse scrapie model. The presence of these T-cells correlated directly with that of activated microglia and the progress of the disease (Betmouni et al., 1996).

In this review we will highlight recent experimental work on a newly-developed animal model based on responses to bacillus Calmette-Guérin (BCG), which has opened the possibility of studying aspects of CNS inflammation which have not previously been examined. The model has allowed study of the processes leading to both innate and acquired immunity in the CNS. Use of the model has also demonstrated that there are clear differences in inflammatory responses to pathogens in different CNS compartments.

Section snippets

Overview of acute inflammatory responses to proinflammatory stimuli in the CNS

It is now evident that acute/innate inflammatory responses in the CNS are different from responses in non-neuronal tissues. A number of studies have explored inflammatory responses in the murine CNS using different proinflammatory agents such as bacteria endotoxin (lipopolysaccharide, LPS) (Andersson et al., 1992; Montero-Menei et al., 1994) or proinflammatory cytokines IL-1β and tumour necrosis factor-α (TNF-α) (Anthony et al., 1997). A direct comparison with inflammatory responses in non-CNS

Microglia and other macrophages in the brain

One of the first responses to injury or infection in any tissue is mounted by resident macrophages. In the brain, the largest population of these macrophages are microglia. They reside in the brain parenchyma and therefore behind the BBB. Microglia are derived from bone marrow, and populate the brain early in development (Perry and Gordon, 1991). They are a homogeneous population of cells, and in different parts of the brain they differ slightly in their morphology (Lawson et al., 1990, Lawson

The blood-brain barrier and lymphatic drainage

The BBB and the lack of a conventional lymphatic drainage contributes to the unique environment of the CNS. The BBB contains tight junctions between cerebral endothelium which are impermeable to large macromolecules (Schlosshauer, 1993). However, it is not totally impermeable to all cells. Through the BBB there is a constant, although slow, migration of monocytes into the brain parenchyma which then differentiate into microglia (Lawson et al., 1992) or perivascular macrophages (Hickey and

Principle of antigen priming

It has been argued above that immune responses in the brain are substantially different to those in the periphery. This is also true of antigen presentation. Therefore, before describing the mechanisms of the induction of immune responses to antigens sequestered in the CNS, it is well worth reviewing the well-documented evidence for this process in the periphery (see also schematic drawing in Fig. 4). When it comes to primary immune responses, dendritic cells have a special place (Steinman, 1991

Priming of the immune system to antigens sequestered in the central nervous system

To discuss this topic we have to start by asking questions, such as: (1) Are APCs associated with the CNS able to prime the immune system? (2) In what situations can the priming take place?

The original studies of Hart and Fabre (1981)suggested that there were no dendritic cells associated with the brain. However, their study was done using anti-MHC class II antibody and morphological criteria, since there were no antibodies specific for dendritic cells which they could use for

The relevance of the delayed-type hypersensitivity model in studies of multiple sclerosis

In the following sections it will be argued that the DTH model which we have described will be useful to study certain aspects of the pathology of MS.

The balance between immunological privilege of the central nervous system and inflammatory responses

The original assumption that the CNS is immunologically privileged has been questioned in recent years. It is now clear that the CNS parenchyma is not refractory or devoid of immunological reactions. Immune responses play an important role in the pathology of MS, viral encephalomyelitis, or in the pathology of corresponding animal models such as EAE. Also, although the BBB restricts the entry of many macromolecules and cells into the CNS parenchyma under normal physiological conditions, this

Acknowledgements

This work has been supported by the British Multiple Sclerosis Society. The author would like to thank Professor Hugh Perry for his help during the preparation of this review. I would also like to thank Dr N. Gregson for his contribution to the research described in this review.

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