RESUMO
In recent years, autoimmune encephalitis associated with antibodies against neuronal cell surface proteins has become a well-recognized phenomenon. Here, we describe clinical features and diagnosis of these conditions before turning to the mechanisms by which autoantibodies are generated and cause disease. The clinical syndrome typically evolves in a subacute fashion and is quite variable, although short-term memory loss, behavioral changes, and seizures are common. Laboratory and imaging parameters of inflammation are typically less overtly deranged than in infectious encephalitis. While the most common antibodies found are to the NMDA receptor or LGI1 protein, a growing number of autoantibodies have been described. Established triggers include tumors and infections, although in many cases neither is identified. It is becoming increasingly clear that host immunogenetics can play a part in disease susceptibility, with a prominent role of HLA haplotype in certain syndromes. Antibodies cause disease by several mechanisms, including direct blocking of ligand binding sites, receptor internalization, and activation of complement, governed in part by the subtype of IgG antibody present. Although in vitro and in vivo models have contributed to our understanding of the mechanisms of disease, numerous gaps in our knowledge of the immunopathogenesis remain, and newer disease models are needed. Insights gained from such approaches will inform our basic understanding of disease and will likely also translate into diagnostic and therapeutic advances.
Assuntos
Encefalite , Doença de Hashimoto , Autoanticorpos , Doença de Hashimoto/diagnóstico , Humanos , Neurônios/metabolismo , Receptores de N-Metil-D-AspartatoAssuntos
Doenças Cerebelares/induzido quimicamente , Neoplasias Cerebelares/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Síndrome Miastênica de Lambert-Eaton/induzido quimicamente , Degeneração Neural/induzido quimicamente , Tumores Neuroendócrinos/terapia , Nivolumabe/efeitos adversos , Amifampridina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Canais de Cálcio Tipo P , Canais de Cálcio Tipo Q , Doenças Cerebelares/tratamento farmacológico , Doenças Cerebelares/imunologia , Doenças Cerebelares/fisiopatologia , Neoplasias Cerebelares/secundário , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Síndrome Miastênica de Lambert-Eaton/imunologia , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Linfonodos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Degeneração Neural/tratamento farmacológico , Degeneração Neural/imunologia , Degeneração Neural/fisiopatologia , Tumores Neuroendócrinos/secundário , Fármacos Neuromusculares/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prednisona/uso terapêutico , Radiocirurgia , Radioterapia , Rituximab/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/secundário , Carcinoma de Pequenas Células do Pulmão/terapia , Tomografia Computadorizada por Raios XRESUMO
Previous studies showed that persons living with HIV (PLWH) demonstrate higher brain prefrontal cortex neuroinflammation and immunoproteasome expression compared to HIV-negative individuals; these associate positively with HIV levels. Lower expression of the antioxidant enzyme heme oxygenase 1 (HO-1) was observed in PLWH with HIV-associated neurocognitive impairment (HIV-NCI) compared to neurocognitively normal PLWH. We hypothesized that similar expression patterns occur throughout cortical, subcortical, and brainstem regions in PLWH, and that neuroinflammation and immunoproteasome expression associate with lower expression of neuronal markers. We analyzed autopsied brains (15 regions) from 9 PLWH without HIV-NCI and 7 matched HIV-negative individuals. Using Western blot and RT-qPCR, we quantified synaptic, inflammatory, immunoproteasome, endothelial, and antioxidant biomarkers, including HO-1 and its isoform heme oxygenase 2 (HO-2). In these PLWH without HIV-NCI, we observed higher expression of neuroinflammatory, endothelial, and immunoproteasome markers in multiple cortical and subcortical regions compared to HIV-negative individuals, suggesting a global brain inflammatory response to HIV. Several regions, including posterior cingulate cortex, globus pallidus, and cerebellum, showed a distinct pattern of higher type I interferon (IFN)-stimulated gene and immunoproteasome expression. PLWH without HIV-NCI also had (i) stable or higher HO-1 expression and positive associations between (ii) HO-1 and HIV levels (CSF, plasma) and (iii) HO-1 expression and neuroinflammation, in multiple cortical, subcortical, and brainstem regions. We observed no differences in synaptic marker expression, suggesting little, if any, associated neuronal injury. We speculate that this may reflect a neuroprotective effect of a concurrent HO-1 antioxidant response despite global neuroinflammation, which will require further investigation.
Assuntos
Córtex Cerebral/metabolismo , Disfunção Cognitiva/genética , Infecções por HIV/genética , HIV-1/patogenicidade , Heme Oxigenase-1/genética , Idoso , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/virologia , Autopsia , Biomarcadores/metabolismo , Tronco Encefálico/metabolismo , Tronco Encefálico/virologia , Estudos de Casos e Controles , Núcleo Caudado/metabolismo , Núcleo Caudado/virologia , Córtex Cerebral/virologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/virologia , Feminino , Regulação da Expressão Gênica , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Heme Oxigenase-1/metabolismo , Humanos , Inflamação , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
OBJECTIVE: To determine whether regulatory variations in the heme oxygenase-1 (HO-1) promoter (GT) n dinucleotide repeat length could identify unique population genetic risks for neurocognitive impairment (NCI) in persons living with HIV (PLWH), we genotyped 528 neurocognitively assessed PLWH of European American and African American descent and linked genotypes to cognitive status. METHODS: In this cross-sectional study of PLWH (the CNS HIV Antiretroviral Therapy Effect Research cohort), we determined HO-1 (GT) n repeat lengths in 276 African Americans and 252 European Americans. Using validated criteria for HIV-associated NCI (HIV NCI), we found associations between allele length genotypes and HIV NCI and between genotypes and plasma markers of monocyte activation and inflammation. For comparison of HO-1 (GT) n allele frequencies with another population of African ancestry, we determined HO-1 (GT) n allele lengths in African PLWH from Botswana (n = 428). RESULTS: PLWH with short HO-1 (GT) n alleles had a lower risk for HIV NCI (OR = 0.63, 95% CI: 0.42-0.94). People of African ancestry had a lower prevalence of short alleles and higher prevalence of long alleles compared with European Americans, and in subgroup analyses, the protective effect of the short allele was observed in African Americans and not in European Americans. CONCLUSIONS: Our study identified the short HO-1 (GT) n allele as partially protective against developing HIV NCI. It further suggests that this clinical protective effect is particularly relevant in persons of African ancestry, where the lower prevalence of short HO-1 (GT) n alleles may limit induction of HO-1 expression in response to inflammation and oxidative stress. Therapeutic strategies that enhance HO-1 expression may decrease HIV-associated neuroinflammation and limit HIV NCI.
Assuntos
Negro ou Afro-Americano/genética , Infecções por HIV/complicações , Heme Oxigenase-1/genética , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/genética , População Branca/genética , Adulto , Negro ou Afro-Americano/etnologia , Estudos Transversais , Repetições de Dinucleotídeos/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/etnologia , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Fatores de Proteção , População Branca/etnologiaRESUMO
Induction of the detoxifying enzyme heme oxygenase-1 (HO-1) is a critical protective host response to cellular injury associated with inflammation and oxidative stress. We previously found that HO-1 protein expression is reduced in brains of HIV-infected individuals with HIV-associated neurocognitive disorders (HAND) and in HIV-infected macrophages, where this reduction associates with enhanced glutamate release and neurotoxicity. Because HIV-infected macrophages are a small component of the cellular content of the brain, the reduction of macrophage HO-1 expression likely accounts for a small portion of brain HO-1 loss in HIV infection. We therefore investigated the contribution of astrocytes, the major pool of brain HO-1. We identified immunoproteasome-mediated HO-1 degradation in astrocytes as a second possible mechanism of brain HO-1 loss in HIV infection. We demonstrate that prolonged exposure of human fetal astrocytes to interferon-gamma (IFNγ), an HIV-associated CNS immune activator, selectively reduces expression of HO-1 protein without a concomitant reduction in HO-1 RNA, increases expression of immunoproteasome subunits, and decreases expression of constitutive proteasome subunits, consistent with a shift towards increased immunoproteasome activity. In HIV-infected brain HO-1 protein reduction also associates with increased HO-1 RNA expression and increased immunoproteasome expression. Finally, we show that IFNγ treatment of astrocytic cells reduces HO-1 protein half-life in a proteasome-dependent manner. Our data thus suggest unique causal links among HIV infection, IFNγ-mediated immunoproteasome induction, and enhanced HO-1 degradation, which likely contribute to neurocognitive impairment in HAND. Such IFNγ-mediated HO-1 degradation should be further investigated for a role in neurodegeneration in inflammatory brain conditions. BRIEF SUMMARY: Kovacsics et al. identify immunoproteasome degradation of heme oxygenase-1 (HO-1) in interferon gamma-stimulated astrocytes as a plausible mechanism for the observed loss of HO-1 protein expression in the brains of HIV-infected individuals, which likely contributes to the neurocognitive impairment in HIV-associated neurocognitive disorders.
Assuntos
Antivirais/farmacologia , Astrócitos/efeitos dos fármacos , Infecções por HIV/patologia , Heme Oxigenase-1/metabolismo , Interferon gama/farmacologia , Córtex Pré-Frontal/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Astrócitos/enzimologia , Astrócitos/virologia , Células Cultivadas , Estudos de Coortes , Inibidores de Cisteína Proteinase/farmacologia , Feminino , Feto , Heme Oxigenase-1/genética , Humanos , Leupeptinas/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , NAD(P)H Desidrogenase (Quinona)/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , RNA/metabolismo , Fatores de TempoRESUMO
UNLABELLED: Expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIV-positive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses. In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genes nef, vpr, or vpu but rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIV-infected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis. IMPORTANCE: The continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART.
Assuntos
Anemia Hemolítica/virologia , Ácido Glutâmico/toxicidade , Transtornos do Crescimento/virologia , HIV-1/patogenicidade , HIV-2/patogenicidade , Heme Oxigenase-1/deficiência , Distúrbios do Metabolismo do Ferro/virologia , Macrófagos/virologia , Anemia Hemolítica/genética , Anemia Hemolítica/imunologia , Animais , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Farmacorresistência Viral/imunologia , Expressão Gênica , Ácido Glutâmico/biossíntese , Transtornos do Crescimento/genética , Transtornos do Crescimento/imunologia , HIV-1/imunologia , HIV-2/imunologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Humanos , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neuroglia/virologia , Fenótipo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/imunologia , Replicação Viral/efeitos dos fármacos , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/genética , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/imunologiaRESUMO
Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.