Advances in neuroimmunology最新文献

Calcium ions are critically important in many functions of the nervous system from neurotransmitter release to intracellular signal transduction. The large difference between intracellular and extracellular calcium ion concentration ([Ca²⁺]) highlights the importance of the mechanisms controlling influx and efflux of this ion. Loss of the regulatory ability of these mechanisms and the subsequent increased intracellular calcium levels may be involved in pathological events of brain trauma, stroke, epilepsy and other diseases. Ca²⁺ dynamics in the CNS ranging from ‘waves’ to ‘spirals’ are being studied because of the availability of fluorescent indicators of Ca²⁺ combined with confocal microscopy. Cellular mechanisms of Ca²⁺ signal transduction have been extensively reviewed (Tsien and Tsien, 1990; Carafoli, 1992; Berridge, 1993; Berridge and Dupont, 1994; Pozzan et al., 1994; Clapham, 1995; Ghosh and Greenberg, 1995). The aim of this review is to present the types of Ca²⁺ dynamics observed in the CNS thus far, both in normal brain function as well as in response after injury.

Central nervous system (CNS) involvement is common during human immunodeficiency virus type-1 (HIV-1) infection. The neurologic disease of the CNS most frequently observed during acquired immunodeficiency syndrome (AIDS) is HIV-1-associated cognitive/motor complex or AIDS dementia complex (ADC), which is most likely a direct consequence of HIV-1 infection of the CNS. The peripheral nervous system (PNS) is also affected in HIV-1-infected individuals and there are several features of immune- and cytokine-related pathogenesis in both the CNS and PNS that are reviewed.

Several lines of evidence demonstrate aspects of immune activation in the CNS and peripheral nervous system (PNS) of HIV-1-infected individuals. The relative paucity of HIV-1 expression in contrast to widespread functional and pathologic changes in the CNS and PNS of AIDS patients, and the lack of evidence of productive infection of HIV-1 in neuronal cells in vivo lead to the possibility of indirect or immunopathogenic mechanisms for HIV-1-related neurologic diseases.

Proposed mechanisms of neuronal and glial cell damage are injury of oligodendrocytes by tumor necrosis factor-α (TNF-α) released from activated macrophage/microglia, calcium-dependent excitoneuro-toxicity induced by gp120 HIV-1 envelope protein, N-methyl-d-aspartate (NMDA) receptor-mediated neurotoxicity by quinolinic acid (a product of activated macrophages), cell injury by HIV-1-specific cytotoxic T cells, and apoptosis of oligodendrocytes or neurons triggered by interaction between cell surface receptors and HIV-1 gp120 protein.

Common to those mechanisms is the dependence on cellular activation with expression of proinflammatory cytokines (TNF-α, interleukin-1). Amplification of activation signals through the cytokine network by macrophage/astrocyte/endothelial cell interactions, and cell-to-cell contact between activated macrophages and neural cells by upregulation of adhesion molecules dramatically enhances the toxic effect of macrophage products.

Expression of immunosuppressive cytokines such as interleukin-4, interleukin-6, and transforming growth factor-β is also increased in the CNS and PNS of HIV-1-infected patients. This may serve as neuroprotective and regenerative mechanism against insults to nervous system tissue.

Adrenocorticotropic hormone (ACTH) increases cAMP and cGMP concentrations in both adrenal and lymphoid cells, and requires extracellular Ca to have biological activity. The requirement for Ca has been difficult to characterize in terms of the channel identity and whether the committing step for steroidogenesis in the adrenal cells requires Ca. In lymphocytes, ACTH has a biphasic effect on functions such as proliferation and immunoglobin secretion. Current information is consistent with suppressive effects of high ACTH concentrations being mediated by cAMP. Stimulatory effects of ACTH concentrations are hypothesized to be mediated by Ca uptake. This review will discuss the localization of Ca signals to discrete domains within cells and the receptor- and tissue-specificity of their subcellular distribution. Considering the diversity of possible mechanisms, a hypothesis for the role of ACTH-stimulated Ca uptake during mitogen activation of T-cell lymphocytes will be presented.

Sleep responds to a variety of stressors, but the precise mechanisms whereby these alterations occur are not known. Ample evidence, however, testifies to corticotropin-releasing hormone (CRH) being uniquely situated to contribute to stressor-induced alterations in sleep. Behavioral responses to most stressors include periods of increased arousal and waking, regardless of whether the stressor is psychological in nature or results in physical insult. Furthermore, a large body of evidence suggests that CRH may also contribute to the regulation and maintenance of physiological waking. In this paper we hypothesize that CRH mediates waking, particularly after periods of exposure to acute stressors. The complex interactions of multiple systems determine the behavioral response to a particular stressor. As such, many factors determine the time course and duration of response, including stressor type, and the status of a particular system at the time of stressor presentation. We briefly review data indicating that CRH mediates physiological and behavioral responses to stressors, and present new data supporting the hypothesis that CRH may also be involved in the physiological regulation of waking.

Narcolepsy is a neurological disorder known to be associated with human leukocyte antigen (HLA)-DQB1 ∗0602 in humans. In a canine model, the disorder is also genetically linked to a gene of high homology with the human μ-switch-like immunoglobulin (Ig) gene (current LOD score 13.6 at 0% recombination). Since association with HLA or other immune function polymorphic genes (T cell receptor of Ig, mainly) is a hallmark of most autoimmune diseases, it is proposed that autoimmunity may also play a role in the development of narcolepsy. Arguments for and against this hypothesis are reviewed. It is shown that both on the basis of the most recent molecular studies, and because of some of its clinical features, narcolepsy may be an autoimmune disorder. However, neither systemic nor central nervous system (CNS) evidence of any autoimmune abnormality have ever been found. To reconcile this discrepancy, it is suggested that the pathological immune process involved in narcolepsy could be difficult to detect because it is restricted to a very small region of the brain or targets a low abundance neuroeffector. Alternatively, it is possible that a more fundamental relationship is involved between sleep generation and immune regulation. The pathophysiology of narcolepsy may then involve new CNS-immune mechanisms that may shed new light on the sleep process itself.

Common perceptions that the desire for sleep is increased during mild infectious diseases like colds and ‘the flu’ have fostered beliefs that sleep promotes recovery from infectious disease and that lack of sleep increases susceptibility to infections. However, until recently, the relationship between infectious disease and vigilance received relatively little systematic study. At present, several model systems provide evidence that infectious disease is accompanied by alterations in sleep. Indeed, increased sleepiness, like fever and anorexia, may be viewed as a facet of the acute phase response to infectious challenge. Recent studies also suggest that sleep, sleep deprivation and infectious disease may be related via mechanisms of the immune system (Fig. 1). Data are now accumulating to address questions such as whether immune processes alter sleep, whether sleep or sleep deprivation influences immune competence, and whether sleep facilitates recovery from infectious disease.

Many of the known roles of arginine (e.g. in immune function, wound healing, and protection against ammonia intoxication) are mediated by a metabolic pathway synthesising nitric oxide (NO) in the liver. Contrary to some of the current views, liver-produced NO may be basically beneficial, as it exerts both protective actions against tissue injury and cytotoxic effects on invading microorganisms, parasites, or tumor cells.

An ongoing equilibrium between NO and other NO-reactive compounds (e.g. O₂ and non-heme iron-sulphur-containing moieties) appears to be important in this respect, even under critical conditions. Thus, NO may prevent liver tissue harm from oxidant stress. Only when this putative counterbalance is upset by an uncontrolled, prolonged and/or massive production of NO, liver tissue damage may occur leading to hepatic inflammation or even tumor development. Moreover, the currently available data support the working hypothesis that hepatocytes partake not only to immunoregulatory processes, but even to immune defence mechanisms. Thus, the liver constitutes an excellent model for investigations into the crosstalks regulating the production of NO which take place among not only the various networks operating inside a single hepatic cell, but even the individual types of liver cells.