Inflammation in the CNS: balance between immunological privilege and immune responses
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.
References (131)
- et al.
The morbid anatomy of the demyelinative diseases
Am. J. Med.
(1952) - et al.
Cellular environment and apoptosis: tissue microenvironment control activated T-cell death
Immunol. Today
(1997) - et al.
Multiple sclerosis: variations on a theme
Immunol. Today
(1997) - et al.
The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues
Neuroscience
(1992) - et al.
The role of inflammation and cytokines in brain injury
Neurosci. Biobehav. Rev.
(1996) - et al.
Overriding the brain’s intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines
Neuroscience
(1996) - et al.
Signals and receptors involved in recruitment of inflammatory cells
J. Biol. Chem.
(1995) - et al.
Evidence for an early inflammatory response in the central nervous system of mice with scrapie
Neuroscience
(1996) - et al.
Through and beyond the wall: late steps in leukocyte transendothelial migration
Immunol. Today
(1997) Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity
Cell
(1991)
Adenovirus gene transfer causes inflammation in the brain
Neuroscience
Microglia present myelin antigens to T cells after phagocytosis of oligodendrocytes
Cell. Immunol.
Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view
Immunol. Today
Expression of ICAM-1, VCAM-1, L-selectin, and leukosialin in the mouse central nervous system during the induction and remission stages of experimental allergic encephalomyelitis
J. Neuroimmunol.
Blood–brain barrier breakdown and increased intercellular adhesion molecule (ICAM-1/CD54) expression after Semliki Forest (A7) virus infection facilitates the development of experimental allergic encephalomyelitis
J. Neuroimmunol.
Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury
Neurosci. Lett.
Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders
J. Neuroimmunol.
Reactivity of serum IgG-GM1 antibodies with the lipopolysaccharide fractions of Campylobacter jejuni isolates from patients with Guillain–Barrésyndrome
J. Neuroimmunol.
Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid
J. Neuroimmunol.
Effect of bacillus Calmette–Guerin inoculation on numbers of dendritic cells in bronchoalveolar lavages of rats
Immunobiology
Microglia are the major cell type expressing MHC class II in human white matter
J. Neurol. Sci.
The injured cell: the role of the dendritic cell system as a sentinel receptor pathway
Immunol. Today
Ia expression and antigen presentation by glia: strain and cell type-specific differences among rat astrocytes and microglia
J. Neuroimmunol.
Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain
Neuroscience
Turnover of resident microglia in the normal adult mouse brain
Neuroscience
Embryonic neural transplants across a major histocompatibility barrier: survival and specificity of innervation
Brain Res.
Lymphocyte migration into brain modelled in vitro: control by lymphocyte activation, cytokines and antigen
Cell. Immunol.
The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents
Neuroscience
Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens
J. Neuroimmunol.
Demyelination in the central nervous system following a delayed-type hypersensitivity response to bacillus Calmette-Guérin
Neuroscience
The potential role of dendritic cells in immune mediated inflammatory responses in the central nervous system
Neuroscience
Ultrastructural studies of an immune-mediated inflammatory response in the CNS parenchyma directed against a non-CNS antigen
Neuroscience
Recombinant human tumour necrosis factor alpha constricts pial arterioles and increases blood–brain barrier permeability in newborn piglets
Neurosci. Lett.
Lipopolysaccharide intracerebral administration induces minimal inflammatory reaction in rat brain
Brain Res.
Macrophages and the nervous system
Int. Rev. Cytol.
Macrophages and inflammation in the central nervous system
Trends Neurosci.
Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein
Biochem. Biophys. Res. Commun.
The Norton Lecture: a review of the oligodendrocyte in the multiple sclerosis lesion
J. Neuroimmunol.
Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood-brain barrier permeability in rats
Brain
New insights into the mobilization and phagocytic activity of dendritic cells
J. Exp. Med.
The long standing multiple sclerosis lesion. A quantitative MRI and electron microscopy study
Brain
Surface expression of α4 integrin by CD4 T cells is required for their entry into brain parenchyma
J. Exp. Med.
Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis
J. Neurosci. Res.
Human chemokines: an update
A. Rev. Immunol.
Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS
J. Neurocytol.
Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammogen or during acute neuronal degeneration
J. Neurocytol.
Recombinant human adenovirus with rat MIP-2 gene insertion causes prolonged PMN recruitment to the murine brain
Eur. J. Neurosci.
Origin and kinetics of pulmonary macrophages during an inflammatory reaction induced by intra-alveolar administration of aerosolized heat-killed BCG
Am. Rev. Respir. Dis.
The MRC OX-62 antigen: a useful marker in the purification of rat veiled cells with the biochemical properties of an Integrin
J. Exp. Med.
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