RESUMEN
BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
Asunto(s)
Esclerosis Múltiple/patología , Adulto , Estudios de Cohortes , Progresión de la Enfermedad , Endonucleasas , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/análisis , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/líquido cefalorraquídeo , Proteínas Nucleares/análisis , Bandas Oligoclonales/genética , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Análisis de Supervivencia , Vitamina D/sangreRESUMEN
Death rules our lives. In this short paper, we summarize new insights into molecular mechanisms of neurodegeneration. Here we review the most important processes of cell death: apoptosis and oncosis. We focus on autophagy, which is pivotal for neuronal homeostasis, in the context of neurodegeneration, infection and immunity. Its dysfunction has been linked to several neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's diseases. Our understanding is still incomplete, but may highlight attractive new avenues for the development of treatment strategies to combat neurodegenerative diseases.
Asunto(s)
Apoptosis , Autofagia , Enfermedades Virales del Sistema Nervioso Central/fisiopatología , Sistema Nervioso Central/fisiología , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/fisiología , Animales , Enfermedades Virales del Sistema Nervioso Central/inmunología , Humanos , Ratones , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/virologíaRESUMEN
OBJECTIVE: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain. METHODS: White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization. RESULTS: We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro. CONCLUSION: These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/patogenicidad , Inmunidad Innata , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/virología , Activación Viral/inmunología , Latencia del Virus/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/patología , Células HEK293 , Herpesvirus Humano 4/inmunología , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Interferón-alfa/biosíntesis , Esclerosis Múltiple/patologíaRESUMEN
The recent success of therapies directed at B cells has highlighted their potential as central players in multiple sclerosis (MS) pathogenesis. Exciting new data showed that B cell depletion led to reduced clinical and magnetic resonance imaging (MRI) evidence of disease activity. However, the mechanisms of action remain unknown, but could involve autoantibody production, antigen presentation and/or cytokine production by B cells. Another exciting line of investigation in the field of MS comes from latent infection of memory B cells by Epstein-Barr virus (EBV). These cells are hijacked as 'Trojan horses' and 'smuggle' the virus into the central nervous system (CNS). Thus, these new anti B cell treatments will also be likely to have anti-viral effects. We briefly review recent findings in the field of MS pathogenesis, and highlight promising new targets for therapeutic intervention in MS.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/fisiología , Esclerosis Múltiple/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/inmunología , Subgrupos de Linfocitos B/virología , Movimiento Celular , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Ensayos Clínicos Fase II como Asunto , Células Clonales/inmunología , Células Clonales/patología , Infecciones por Virus de Epstein-Barr/virología , Humanos , Depleción Linfocítica , Modelos Inmunológicos , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Esclerosis Múltiple/virología , Bandas Oligoclonales/líquido cefalorraquídeoRESUMEN
In this study, we have compared the effector functions and fate of a number of human CTL clones in vitro or ex vivo following contact with variant peptides presented either on the cell surface or in a soluble multimeric format. In the presence of CD8 coreceptor binding, there is a good correlation between TCR signaling, killing of the targets, and FasL-mediated CTL apoptosis. Blocking CD8 binding using alpha3 domain mutants of MHC class I results in much reduced signaling and reduced killing of the targets. Surprisingly, however, FasL expression is induced to a similar degree on these CTLs, and apoptosis of CTL is unaffected. The ability to divorce these events may allow the deletion of antigen-specific and pathological CTL populations without the deleterious effects induced by full CTL activation.
Asunto(s)
Apoptosis/inmunología , Antígeno HLA-A2/inmunología , Antígenos HLA-B/inmunología , Activación de Linfocitos/inmunología , Péptidos/inmunología , Linfocitos T Citotóxicos/inmunología , Proteínas Virales , Linfocitos T CD8-positivos/inmunología , Proteína Ligando Fas , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Antígenos VIH/genética , Antígenos VIH/inmunología , Antígeno HLA-A2/genética , Antígenos HLA-B/genética , Antígeno HLA-B44 , Humanos , Virus de la Influenza A/genética , Virus de la Influenza A/inmunología , Glicoproteínas de Membrana/inmunología , Proteínas de la Membrana/inmunología , Mutagénesis , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fosforilación , Receptores de Antígenos de Linfocitos T/inmunología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/inmunología , Microglobulina beta-2/genética , Microglobulina beta-2/inmunología , Receptor fas/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia HumanaRESUMEN
Engineered MHC-peptide targets capable of inducing recognition by CTL may prove useful in designing vaccines for infectious disease and cancer. We tested whether peptides directly linked to beta2-microglobulin (beta2m) could complex with human HLA class I heavy chain, and could be recognized by human CTL, both as soluble reagents and as cell surface constituents. An HLA-A2-restricted peptide epitope was physically linked to the N terminus of human beta2m. This fusion protein refolded efficiently in vitro with HLA-A2 heavy chain, and when multimerized, the resultant complexes ("fusamers") bound specifically to appropriate CTL clones. These fused peptide/MHC complexes were as efficient as standard tetrameric peptide/MHC complexes in recognizing antigen-specific CTL. When the fusion protein was delivered to target cells using a retroviral vector, these cells were recognized and killed by appropriate CTL clones. Efficient sensitization to CTL lysis was achieved in TAP-negative and beta2m-negative cell lines, as well as in unmutated B cell lines, proving that such constructs may be effective in inducing CTL even when the MHC class I pathway has been disrupted. Specific peptides covalently linked to beta2m and delivered via retroviral vectors may be useful reagents for in vivo priming of CTL against epitopes of clinical relevance.
Asunto(s)
Presentación de Antígeno , Antígenos de Histocompatibilidad Clase I/fisiología , Neoplasias/terapia , Proteínas Recombinantes de Fusión/inmunología , Linfocitos T Citotóxicos/inmunología , Microglobulina beta-2/inmunología , Línea Celular , Citotoxicidad Inmunológica , Terapia Genética , Antígenos de Histocompatibilidad Clase I/química , Humanos , Neoplasias/inmunología , Retroviridae/genética , Microglobulina beta-2/genéticaRESUMEN
The water exchange on [Ru(CO)(H2O-eq)4(H2O-ax)](tos)2 (1), [Ru(CO)2(H2O-eq)2(H2O-ax)2](tos)2 (2), and [Ru(CO)3(H2O)3](ClO4)2 (3), the 17O exchange between the bulk water and the carbonyl oxygens have been studied by 17O NMR spectroscopy, and the X-ray crystallographic structures of 1 and 2 have been determined. The water exchange of equatorially and axially coordinated water molecules on 1 and 2 follow an Id mechanism and are characterized by keq298 (s-1), delta H++ (kJ/mol), and delta S++ (J/(mol K)) of (2.54 +/- 0.05) x 10(-6), 111.6 +/- 0.4, and 22.4 +/- 1 (1-eq); (3.54 +/- 0.02) x 10(-2) and 81 (1-ax); (1.58 +/- 0.14) x 10(-7), 120.3 +/- 2, and 28.4 +/- 4 (2-eq); and (4.53 +/- 0.08) x 10(-4), 97.9 +/- 1, and 19.3 +/- 3 (2-ax). The observed reactivities correlate with the strength of the Ru-OH2 bonds, as expressed by their length obtained by X-ray studies: 2.079 (1-eq), 2.140 (1-ax), 2.073 (2-eq), and 2.110 (2-ax) A. 3 is strongly acidic witha pKa of -0.14 at 262 K. Therefore, the acid-dependent water exchange can take place through 3 or Ru(CO)3(H2O)3OH+ with an estimated keq298 of 10(-4)/10(-3) s-1 and kOH262 of 0.053 +/- 0.006 s-1. The 17O exchange rate between the bulk water and the carbonyl oxygens increases from 1 to 2 to 3. For 1 an upper limit of 10(-8) s-1 was estimated. For 2, no acid dependence of kRuCO between 0.1 and 1 m Htos was observed. At 312.6 K, in 0.1 and 1 m Htos, kRuCO = (1.18 +/- 0.03) x 10(-4). For the tricarbonyl complex, the exchange can proceed through 3 or Ru(CO)3(H2O)2OH+ with kRuCO and kRuOHCO of, respectively, 0.003 +/- 0.002 and 0.024 +/- 0.003 s-1, with a ruthenacarboxylic acid intermediate.
RESUMEN
The propensity of HIV-1 for genetic variation, a consequence of error-prone reverse transcription combined with high rates of replication, is thought to contribute to the establishment of persistent infection in the host despite the presence of a vigorous antiviral immune response. Protective immunity to viruses is mediated primarily by cytotoxic T lymphocytes, which recognize viral peptides of 8-11 amino acids bound to major histocompatibility complex class I molecules on the surface of infected cells. In this review we examine the mechanisms by which mutation within peptide antigen-encoding regions of the viral genome enables HIV-1 to evade recognition by virus-specific cytotoxic T lymphocytes. The discussion is relevant to other genetically unstable viruses and more generally to intracellular pathogens of variable antigenicity.
Asunto(s)
Variación Antigénica , Antígenos VIH/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Linfocitos T Citotóxicos/inmunología , VIH-1/genética , Humanos , Activación de Linfocitos , Péptidos/inmunologíaRESUMEN
Immune evasion by the human immunodeficiency virus (HIV) is unexplained but may involve the mutation of viral antigens. When cytotoxic T lymphocytes engaged CD4-positive cells that were acutely infected with HIV bearing natural variant epitopes in reverse transcriptase, substantial inhibition of specific antiviral lysis was observed. Mutant viruses capable of these transactive effects could facilitate the persistence of a broad range of HIV variants in the face of an active and specific immune response.
Asunto(s)
Citotoxicidad Inmunológica , Antígenos VIH/inmunología , VIH-1/inmunología , Tolerancia Inmunológica , ADN Polimerasa Dirigida por ARN/inmunología , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Variación Antigénica , Secuencia de Bases , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Línea Celular , Epítopos/genética , Antígenos VIH/genética , Transcriptasa Inversa del VIH , VIH-1/enzimología , VIH-1/genética , Antígeno HLA-B8/inmunología , Humanos , Datos de Secuencia Molecular , ADN Polimerasa Dirigida por ARN/genética , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
Cytotoxic T lymphocytes (CTL) directed against human immunodeficiency virus (HIV)-1 are detectable in the majority of infected individuals, and their early appearance as the initial viremia is suppressed is thought to represent a potent antiviral response. Variation which arises in CTL epitopes can affect recognition by CTL, and we have observed previously that variant epitopes in HIV-1 gag which arise in HIV-1-seropositive donors may act as T cell receptor (TCR) antagonists of their own CTL (Klenerman et al., Nature 1994, 369: 403). The most important question arising from these observations is the extent of these immune escape mechanisms in vivo. Here we show that fresh, uncultured lymphocytes taken directly from HIV-1-infected patients are susceptible to TCR antagonism by variants present within their own virus. In contrast to HLA Class II-restricted T cell responses, where anergy may be induced, we find that in vitro, natural variants may stimulate and sustain growth of CTL. These CTL lines retain lytic specificity exclusively for the original peptide. If this represents events in vivo, natural HIV altered peptide ligands (APL) have the capacity to inhibit the range of CTL directed against an epitope, not simply those clones selected in vitro. Partial activation of CTL by APL could also act to drive an ineffectual CTL response incapable of lysing infected cells bearing these natural antigenic variants. Distortion of lymphocyte populations and function by APL might represent a further mechanism of immune evasion by HIV.
Asunto(s)
VIH/inmunología , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Secuencia de Bases , Cartilla de ADN/química , Epítopos , Humanos , Inmunidad Celular , Ligandos , Activación de Linfocitos , Masculino , Datos de Secuencia Molecular , Péptidos/química , Péptidos/inmunologíaRESUMEN
alpha 2-Macroglobulin is cleaved by human immunodeficiency virus-1 protease. The cleavage site is the Phe684-Tyr685 bond in the "bait region", an exposed part of alpha 2-macroglobulin, creating the "F-form". The methylamine derivative of alpha 2-macroglobulin is also cleaved at the same bond. The homologous chicken ovomacroglobulin does not form an F-form structure with the protease, although, F-form generation by other enzymes is known. This is possibly due to the lack of a suitable cleavage sequence in the corresponding region of ovomacroglobulin. In human alpha 2-macroglobulin, the interdomain segment between the main part of the molecule and the receptor-binding C-terminal domain is not cleaved by the HIV protease although typical cleavage sequences occur. In AIDS, therefore, HIV protease from infected cells in unlikely to interfere with receptor-binding of alpha 2-macroglobulin.