Advances in neuroimmunology最新文献

The pathogenesis of the acquired immuno-deficiency syndrome (AIDS) dementia complex (ADC) is unknown. However, recent work indicates that neurons and astrocytes are functionally compromised by exposure to viral components or cellular factors released from HIV-1-infected macrophages/microglia. We show that exposure of primary cultured rat astrocytes to the major HIV envelope glycoprotein gp120 results in alterations of ion and solute transport that may contribute to neuronal cell injury.

This review aims to summarize recent work related to the pathogenesis and possible treatment of neuronal injury in the acquired immunodeficiency syndrome (AIDS), especially with reference to potential neurotoxic substances released by HIV-infected or gp120-stimulated macrophages/microglia. Approximately a third of adults and half of children with AIDS eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews recent evidence suggesting that at least part of the neuronal injury observed in the brains of AIDS patients is related to excessive influx of Ca²⁺ after the release of potentially noxious substances from HIV-infected or gp120-stimulated macrophages/microglia.

There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, i.e. arachidonic acid and its metabolites, as well as platelet-activating factor. Other candidate toxins include nitric oxide (NO·), superoxide anion (02·⁻), and the N-methyl-scd-aspartate (NMDA) agonist, cysteine. Similarly, macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites, and cysteine. These factors can lead to increased glutamate release or decreased glutamate re-uptake. In addition, interferon-γ (IFN-γ) stimulation of macrophages induces release of the NMDA-like agonist, quinolinate. HIV-infected or gp120-stimulated macrophages also produce cytokines, including TNF-α and ILI-β, which contribute to astrocytosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca²⁺ channels and NMDA receptor-operated channels with resultant generation of free radicals, and therefore offers hope for future pharmacological intervention.

Continuous intravenous administration of zidovudine (AZT) has been reported to improve cognitive function in HIV-infected pediatric patients (Pizzo et al., 1988). The effects of long-term zidovudine treatment in the perinatally infected pediatric population, including antiviral efficacy and effects on cognitive and motor function has not been systematically examined. These questions were addressed in rhesus macaque infants infected at birth with SIV_SMM/B670, a primate model for infantile HIV infection and disease (Eiden et al., 1993a). Continuous or intermittent administration of AZT during the first 6 months following infection resulted in about a doubling of lifespan, a delay in the occurrence of motor impairment, and lower virus burden and quinolinic acid levels in cerebrospinal fluid (CSF) following administration of the antiviral drug.

Experiments carried out by indirect immunofluorescence and unlabelled antibody enzyme procedures revealed the presence of morphine-like immunoreactive material in the perikarya, fibers, and terminals of neurons in different, discrete areas of rat and human brain. The monoclonal and polyclonal anti-morphine antibodies used do not distinguish between morphine and codeine. Endogenous morphine seems to be stored in neurons as the 3-ethereal sulphate conjugate. This possibility is supported by the finding that, although active uptake of [³H]morphine has not been detected in brain synaptosomes, long-term i.c.v. injection of the tritiated opiate results in the accumulation of radioactivity inside the same neurons in which the endogenous alkaloids have been detected. Finally, striatal slices exposed to high K⁺ concentrations showed a rapid disappearance of the morphine-like immunoreactive material from neurons, indicating that endogenous alkaloids are released from neurons by depolarization.

Many studies have examined the relationship between stress and immunity, however, only a few have explored associations between stress and Immoral immunity. In our review of this literature, three ways of characterizing the response of the humoral immunity system to stress were identified: total immunoglobulins, antibody to latent viruses and antibody to vaccines. These studies provide some support for the hypothesis that stress affects humoral immunity, particularly response to latent virus, but further research is required to confirm these observations. Several directions for future research are proposed.

In order to detect latent infection in neurons or other cell types in formalin-fixed brain tissue, we performed polymerase chain reaction amplification with incorporation of digoxigenin-conjugated deoxynucleotides, followed by in situ hybridization with biotinylated probes. The use of this two-step technique in brain tissue from a child with severe HIV-1 encephalitis revealed signal in both nuclear and perinuclear regions of cells identified as monocytes and astrocytes, and also in perineuronal satellite cells of glial morphology, but HIV-1 infection of neurons was not detected.

The pathological hallmark of HIV infection in brain is productive viral replication in cells of mononuclear phagocyte lineage including brain macrophages, microglia and multinucleated giant cells (Koenig et al., 1986; Wiley et al., 1986; Gabuzda et al., 1986; Stoler et al., 1986). These cells secrete viral and cell encoded neurotoxins that lead to neuronal injury, glial proliferation and myelin pallor during advancing disease (Genis et al., 1992; Giulian et al., 1990, 1993; Pulliam et al., 1991). The apparent paradox between the distribution and numbers of virus infected cells and brain tissue pathology support indirect mechanisms for CNS damage (Epstein, 1993; Geleziunas et al., 1992; Merrill and Chen, 1992; Michaels et al., 1988; Price et al., 1988). First, brain macrophages and microglia can produce neurotoxins by secretion of viral proteins (for example, gp120) (Dawson et al., 1991; Merrill et al., 1989; Lipton et al., 1990; Lipton, 1993). Second, HIV primes macrophages for immune activation to produce neurotoxins including: cytokines (TNF(α and IL-1β), eicosanoids, quinolinate and nitric oxide (NO). Chronic immune stimulation mediated by opportunistic infections and chronic interferon gamma (IFNγ) production (in and outside the CNS) continues the process of macrophage activation leading to progressive neural injury. The hyperresponsiveness of HIV-infected macrophages to activation results in production of cellular factors that activate uninfected macrophages. This suggests that HIV-infected macrophages are both perpetrators and amplifiers for neurotoxic activities.

The interrelationships of patterns of change and variability between baseline and after 6 months of anti-retroviral therapy in neurocognitive, brain imaging, and immune measures were studied in 77 children with symptomatic HIV disease.

Overall improvement in CNS structure/function after 6 months of anti-retroviral therapy was limited; new intracerebral calcifications tended to occur and old ones tended to progress in young children with vertically acquired HIV infection, despite treatment. Substantial inter-individual differences in change were however observed. Factors which explained part of the variance in the magnitude and direction of change were baseline structural and functional abnormalities, rating of degree of CNS penetration of the drug protocol, and concurrent changes on other variables. These preliminary data suggest that CNS specific effects of therapies as well as pretreatment status of CNS function/structure need to be taken into consideration when evaluating future trials of anti-retroviral therapy for children with symptomatic HIV infection.