Cytokine expression in the brain during the acquired immunodeficiency syndrome

Abstract

The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin-1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV-seropositive and -seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin-1 and -6, tumor necrosis factor-alpha and -beta, and interferon gamma. Levels of soluble CD4, CD8, and interleukin-2 receptor, as well as interferon gamma, tumor necrosis factor-alpha, beta 2-microglobulin, neopterin, and interleukin-6 and -1 beta were assayed in the cerebrospinal fluid and plasma of many of these individuals during life. The HIV-seropositive group included individuals without neurological disease, those with CNS opportunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present on microglial cells, which were frequently positive for tumor necrosis factor-alpha. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin-1 and interferon gamma and less frequently for tumor necrosis factor and interleukin-6. There were gliosis and significant increases in MHC class II antigen, interleukin-1, and tumor necrosis factor-alpha in HIV-positive patients compared to HIV-negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, beta 2-microglobulin, and neopterin. There was no correlation in HIV-positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of "immune activation" in the brains of HIV-positive compared to HIV-negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.

Cytokine-Stimulated, But Not HIV-Infected, Human Monocyte-Derived Macrophages Produce Neurotoxic Levels of l-Cysteine

“…As alluded to previously, TNF-␣ and IL-1␤ are elevated in the brain, spinal cord, and cerebrospinal fluid of AIDS patients (47,48). Importantly, the amount of TNF-␣ present in brain parenchyma at postmortem appears to correlate with the degree of dementia determined preagonally (47). Our findings suggest therefore that at least one pathway for the neuronal injury observed in HAD may be cytokine-induced release of macrophage toxins such as cysteine.…”

“…In fact, previous studies have shown that gp120 stimulates the secretion of both TNF-␣ and IL-1␤ by human monocytic cells (26,27). As alluded to previously, TNF-␣ and IL-1␤ are elevated in the brain, spinal cord, and cerebrospinal fluid of AIDS patients (47,48). Importantly, the amount of TNF-␣ present in brain parenchyma at postmortem appears to correlate with the degree of dementia determined preagonally (47).…”

“…2). This is relevant to HAD because cytokines (especially TNF-␣) have been found to be elevated in the brains and cerebrospinal fluid of patients with cognitive dysfunction and may herald the neurodegenerative process (47,48). Several previous studies have demonstrated the release of putative neurotoxins by both gp120-stimulated and HIV-infected monocytic cells (7-9, 11, 12, 19, 24, 25, 45, 46).…”

Microglial and Astrocyte Chemokines Regulate Monocyte Migration through the Blood-Brain Barrier in Human Immunodeficiency Virus-1 Encephalitis

“…For example, activation of microglia and diffuse microgliosis were previously shown to correlate with ventricular expansion and neuropathological changes in HAD. 15,46,47 The discordance, in select patients, between the level of pathology and the clinical course of disease may be related to several factors. These include genetic susceptibilities to dementia in patient subpopulations, peripheral immune activation, and limitations of autopsy tissue analyses.…”

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

“…Viral particles, however, are not the only mediators of CNS dysfunction and neuron toxicity. HIV-induced encephalitis is associated with immune activation of glial cells that results in alterations of normal cell biology, notably secretory functions (41)(42)(43)(44)(45). Improper regulation of these factors can lead to impaired cellular functioning, modified neurotransmitter action, amplified inflammation and neuronal damage.…”