Dr. C. Alberto Juan Dorta Contreras: heraldo de la ciencia abierta y la neuroinmunología en Cuba / Dr. Alberto Juan Dorta Contreras: herald of open science and neuroimmunology in Cuba

RESUMEN Esta Semblanza resume la trayectoria del Dr. Alberto Juan Dorta Contreras, eminente científico, quien dedicara su vida a la Neuroinmunología y difusión de los principios de Ciencia Abierta en Cuba. Su labor profesional se centró principalmente en la investigación básica y clínica, sobre todo, de la Inmunología con énfasis en la repercusión de las enfermedades infecciosas y el papel del sistema del complemento en el Sistema Nervioso Central. Importante ha sido, además, su función como docente en pregrado y posgrado a través de las Becas Quincke, un espacio creado por el Dr. Dorta para acercarse al mundo de la experimentación. Se desempeñó en los últimos años como director de la Revista Cubana de Investigaciones Biomédicas, la que impulsó a categorías superiores con su esfuerzo y rigor de trabajo, con lo que llegó a ocupar en este momento el primer lugar de las revistas cubanas según el ranking de Scimago. Su vida, obra y destacada trayectoria hacen que el Dr. Dorta Contreras sea un ejemplo de sacrificio, consagración, valor, honestidad, sencillez, altruismo y entrega a la ciencia y la humanidad. Por tales razones, el objetivo de esta Semblanza es destacar los aspectos más relevantes de su obra como científico y docente, apoyados en testimonios, búsqueda en bases de datos, entrevistas a estudiantes y colegas de trabajo para resumir la prolífera vida laboral del Dr.C Alberto Juan Dorta Contreras.

ABSTRACT This Semblance summarizes the career of Dr. Alberto Juan Dorta Contreras, an eminent scientist who dedicated his life to Neuroimmunology and the dissemination of open science principles in Cuba. His professional work was mainly focused on basic and clinical research, especially Immunology, with an emphasis on the impact of infectious diseases and the role of the complement system in the Central Nervous System. Also important has been his role as an undergraduate and graduate teacher in the Quincke Scholarships, a space created by Dr. Dorta to get closer to the world of experimentation. In recent years, he served as director of the Cuban Journal of Biomedical Research, which he promoted to higher categories with the effort and rigor of his work, currently occupying the first place among Cuban journals according to the Scimago ranking. His life, work and outstanding career make Dr. Dorta Contreras an example of sacrifice, dedication, value, honesty, simplicity, altruism and dedication to science and humanity. For these reasons, the objective of this article is to highlight the most relevant aspects of his work as a scientist and teacher, supported by testimonies, database searches, interviews with students and work colleagues to summarize the prolific working life of Dr C. Alberto Juan Dorta Contreras.

IgG anti-Toxoplasma gondii antibody index as a measure of the naturally-acquired immune intrathecal response in a neuroepidemiological study

Introduction: The presence of IgG anti-Toxoplasma gondii has been used as an indicator to measure the naturally-acquired immune intrathecal response due to the polyclonal and polyspecific intrathecal response developed in neuroinflammation processes. The absence of anti-Toxoplasma gondii antibodies in a subject who had been exposed to the parasite could be seeded as immunocompromised. The aim of the study is determine cases of autoimmunity and immunodeficiency. Objective: Demonstrate whether the IgG anti-Toxoplasma gondii antibody index can be used as an indicator of a population immune status seen through patients with neuroinflammatory processes. Methods: Cerebrospinal fluid (CSF) and serum samples were taken from 64 pediatric patients with intrathecal synthesis of antibodies and IgG anti-Toxoplasma gondii antibody indexes (AI) were determined. Results: The sample was divided in three intervals according to Hansotto Reiber investigations (≤0.6; 0.6-1.5; ≥1.5) and a mean interval ±1SD between 0.23 and 1.12. The groups were quite similar regarding to clinic and demographic characteristics; there were statics differences on anti-Toxoplasma gondii AI (p<0.01) and the presence of domestic animals (p=0.04). In the group with AI≥1.5, the 83.3% had positive the Measles-Rubella-Zoster reaction, indicative of active autoimmune disease. On the group with AI≤0.6 were analyzed six different variables trying to find possible cases with immunodeficiencies: risk factors to contract toxoplasmosis; subjective clinical of immunocompromise; a test to detect immunodeficiencies; response against vacunal antigens and humoral response determined by IgG levels in serum. The immunodeficiencies test was the variable with higher statistical significance (p= 0.047). Conclusions: The conclusion was that is possible to find subjects with autoimmune disorder and other ones with immunocompromise through the IgG anti-Toxoplasma gondii index by the developed investigation strategy.

Introducción: La presencia de IgG anti-Toxoplasma gondii se ha utilizado como indicador para medir la respuesta inmune intratecal adquirida naturalmente, debido a la respuesta intratecal poliespecífica y policlonal que se produce en los procesos neuroinflamatorios. La ausencia de anticuerpos anti-Toxoplasma gondii en un sujeto que ha estado expuesto al parásito se puede ver como un caso de inmunocompromiso. Objetivo: Determinar casos de autoinmunidad e inmunodeficiencia. Métodos: Se tomaron muestras de líquido cefalorraquídeo (LCR) y suero de 64 pacientes pediátricos con síntesis intratecal de anticuerpos y se determinaron los índices de anticuerpos (IA) IgG anti-Toxoplasma gondii. Resultados: La muestra se dividió en tres intervalos según las investigaciones de Hansotto Reiber (·0,6; 0,6-1,5; ·1,5) y un intervalo medio ±1DE entre 0,23 y 1,12. Los grupos eran bastante similares en cuanto a sus características clínicas y demográficas, pero mostraban diferencias estadísticas en sus índices de anticuerpos anti-Toxoplasma gondii (p< 0,01) y la presencia de animales domésticos (p= 0,04). En el grupo con IA·1,5, el 83,3% tuvo una reacción positiva al sarampión-rubéola-zóster, lo que indica la presencia de enfermedad autoinmune activa. En el grupo con IA·0,6 se analizaron seis variables diferentes, tratando de encontrar posibles casos de inmunodeficiencia: factores de riesgo de contraer toxoplasmosis, historia clínica subjetiva de inmunocompromiso, una prueba para detectar inmunodeficiencias, respuesta ante antígenos vacunales y respuesta humoral determinada por niveles de IgG en suero. La prueba de inmunodeficiencias fue la variable que mostró la mayor significación estadística (p= 0,047). Conclusiones: Se concluye que es posible encontrar sujetos con trastornos autoinmunes y otros con inmunocompromiso a partir del índice de IgG anti- Toxoplasma gondii siguiendo la estrategia de investigación elaborada.

Neuroimmunological approach for evaluation of viral measles, mumps and rubella (MMR) triple vaccine

Introduction: During the neuroinflammatory processes there are a poly-specific and polyclonal activation in the cerebrospinal fluid. It means that there can be quantified antibodies against all the components of the vaccines may have received. Objective: To evaluate the immune response against measles, mumps and rubella in vaccinated pediatric patients. Methods: All the serum and cerebrospinal fluid (CSF) paired samples from pediatric patients with neurological symptoms, that were submitted to hospitals from Havana City and were performed a lumbar puncture, were collected. Serum and CSF IgG, albumin were measured by immune-diffusion techniques using NOR and LC Partigen Immunoplates (Siemens, Marburg) and specific antibodies against measles, mumps and rubella were quantified by ELISA kits (Enzygnost, Siemens, Marburg). Reibergrams were employed in order to determine if there was IgG intrathecal synthesis. Later on, antibody index against the specific virus were calculated. Results: In all the neuroimmune inflammation process were found antibody index against measles, mumps and rubella in a different ample confidence variation among the different virus. Antibodies against mumps are significantly different from the other ones. It could be due to a natural different immune response or due to a deficient vaccine quality lot. Also it was possible to identify six pediatric patients that had no immune antibody index at all. It coincides with a transient hypogammaglobulinemia of infancy in such patients. Conclusions: This neuroimmunological approach can be used to evaluate the immune status in pediatric population.

Introducción: Durante los procesos neuroinflamatorios se produce una activación poliespecífica y policlonal en el líquido cefalorraquídeo. Eso significa que pueden existir anticuerpos cuantificados contra todos los componentes de las vacunas que se reciban. Objetivo: Evaluar la respuesta inmune contra el sarampión, las paperas y la rubéola en pacientes pediátricos vacunados. Métodos: Se recogieron muestras pareadas de suero y líquido cefalorraquídeo (LCR) de pacientes pediátricos con síntomas neurológicos mediante punciones lumbares realizadas en hospitales de Ciudad de La Habana. El IgG y la albúmina del suero y el LCR fueron medidos con técnicas de inmunodifusión usando inmunoplacas Partigen NOR y LC (Siemens, Marburgo). Los anticuerpos específicos contra el sarampión, la parotiditis y la rubéola se cuantificaron con dispositivos para ELISA (Enzygnost, Siemens, Marburgo). Se utilizaron reibergramas para determinar la presencia de síntesis intratecal de IgG. Seguidamente se calculó el índice de anticuerpos contra el virus específico. Resultados: En todos los procesos de inflamación neuroinmune se encontraron índices de anticuerpos contra el sarampión, la parotiditis y la rubéola con una variación amplia y diferente entre los distintos virus. Los anticuerpos contra la parotiditis son significativamente diferentes a los demás, lo que puede deberse a una respuesta inmune natural distinta o a una deficiente calidad de las vacunas. También fue posible identificar a seis pacientes pediátricos en los que no se observó ningún índice de anticuerpos inmunes, en coincidencia con la presencia de hipogammaglobulinemia transitoria infantil en esos pacientes. Conclusiones: El enfoque neuroinmunológico que se describe puede usarse para evaluar el estado inmunológico de la población pediátrica.

Antibody Index in neuroimmunoepidemiological studies

The evaluation of the neuroimmunoepidemiological response from the reibergram allows the determination of the specific antibody index for a determined etiological agent. This evaluation has served to know the behavior of the neuroimmune response in pediatric patients to different herpesviruses, evaluate the effectiveness of vaccination campaigns and find a response that helps in the diagnosis of various processes that affect this system(AU)

Neurobrucelosis evaluada por reibergrama. Presentación de un caso / Neurobrucellosis evaluated by reibergram. A case report

Introducción: La brucelosis es una enfermedad zoonótica y endémica en muchas partes del mundo. La causa principal de la infección se produce por la ingestión de leche no pasteurizada o por el contacto con animales infectados. La neurobrucelosis incluye afecciones en el sistema nervioso central y periférico. Las principales manifestaciones clínicas son la meningitis, la encefalitis, la neuritis óptica y la periférica. Objetivo: Evaluar, mediante reibergrama, la dinámica intratecal de las clases mayores de inmunoglobulinas y el estado de la barrera sangre/LCR de un paciente con neurobrucelosis. Presentación del caso: Los niveles de IgA, IgM. IgG y albúmina en suero y líquido cefalorraquídeo fueron cuantificados por inmunodifusión. Los resultados fueron colocados en el reibergrama correspondiente. El paciente mostró síntesis intratecal de las tres clases mayores de inmunoglobulinas, sin disfunción de la barrera sangre/LCR. Conclusión: El estudio neuroinmunológico del líquido cefalorraquídeo puede indicar el curso activo de la respuesta inmune intratecal contra el patógeno, donde la síntesis intratecal de inmunoglobulinas y el funcionamiento de la barrera sangre/líquido cefalorraquídeo constituyeron los principales marcadores en el diagnóstico de la neuroinflamación(AU)

Introduction: Brucellosis is a zoonotic and an endemic disease in many areas around the world. The main cause of infection is the intake of unpasteurized milk or the contact with infected animals. Neurobrucellosis includes pathologic conditions in the central and peripheral nervous systems. The main clinical manifestations are meningitis, encephalitis, optical neuritis, and peripheral neuritis. Objective: To evaluate, through reibergram, the intrathecal dynamics of the major immunoglobulin classes and the blood-CSF barrier function in one patient with neurobrucellosis. Case report: IgA, IgM, IgG and albumin levels in serum and cerebrospinal fluid were quantified by using a radial immunodiffusion technique. Results were placed in the corresponding reibergram. The patient showed evidences of intrathecal synthesis of the three major immunoglobulins without blood-CSF barrier dysfunction. Conclusion: The neuroimmunological study of cerebrospinal fluid can indicate the active course of the intrathecal immune response against this pathogen, where the intrathecal synthesis of immunoglobulins and blood-cerebrospinal fluid barrier function constitute the main markers in the diagnosis of neuroinflammation(AU)

Neuroinflamación: el ying-yang de la neuroinmunología / Neuroinflammation: the ying-yang of neuroimmunology

Resumen El área de la neuroinmunología es un campo que se encuentra en gran desarrollo y que tiene como objetivo el entender las interacciones fisiológicas entre el sistema nervioso central (SNC) y el sistema inmune periférico, llegándose a encontrar que estas relaciones son más importantes de lo que se creía y que por lo tanto son 2 sistemas íntimamente conectados y con una gran dinámica. Por otro lado, la neuroinflamación es activada después de cualquier reto inmunológico, tanto dentro como fuera del SNC, y que puede llevar a generar tanto respuestas enfocadas a la limitación del daño y la restauración del tejido, como a ser un riesgo para el desarrollo de enfermedades neurodegenerativas en el caso de que este estímulo permanezca de manera crónica.

Abstract The field of neuroimmunology has recently had a development, and its primary goal is to understand the physiological interactions between the central nervous system (CNS) and the peripheral immune system. Various data has found that these relations are more important than what was previously thought. Also, that both systems are highly dynamic and are intimately connected. On the other hand, neuroinflammation is activated after any immune challenge, both inside and outside the CNS, leading to responses focused on limiting tissue damage and restoration; as well as being a risk for developing neurodegenerative diseases when this stimulus remains chronic.

Neuroinmunología de la meningoencefalitis por Cryptococcus neoformans. Presentación de un caso / Neuroimmunology of meningoencephalitis by Cryptococcus neoformans. A case report

Introducción: la meningitis/meningoencefalitis criptococócica es una forma infrecuente de infección del sistema nervioso central, producida por Cryptococcus neoformans. Objetivo: mostrar la respuesta neuroinmunológica, a través del reibergrama, en un paciente con meningoencefalitis crónica por Cryptococcus neoformans. Presentación del caso: se cuantificaron los niveles de IgA, IgM, IgG y albúmina en suero y líquido cefalorraquídeo a partir de las cinco punciones lumbares que se le realizó a la paciente y se confeccionó el reibergrama correspondiente. Se comprobó la ocurrencia de síntesis intratecal de, por lo menos, dos clases de inmunoglobulinas mayores, se observó un porciento mayor de síntesis intratecal de IgG. No existió disfunción de la barrera sangre/líquido cefalorraquídeo. Conclusiones: el estudio neuroinmunológico del líquido cefalorraquídeo indica la cronicidad de la entidad. La síntesis intratecal de inmunoglobulinas y el estado de la barrera sangre/líquido cefalorraquídeo constituyen elementos claves en el diagnóstico de la neuroinflamación(AU)

Introduction: Meningitis/meningoencephalitis is a non-frequent central nervous system infection produced by Cryptococcus neoformans. Objective: To show the neuroimmunological response using reibergram in a patient with chronic meningoencephalitis due to Cryptococcus neoformans. Case presentation: Serum and cerebrospinal fluid IgA, IgM, IgG and albumin levels were quantified in a patient suffering from the disease by means of five lumbar punctures during her evolution; the results were plotted in their corresponding reibergram. Syntheses of at least two intrathecal major immunoglobulin were confirmed. A percent bigger of IgG intrathecal synthesis was observed. There is no blood-brain barrier dysfunction. Conclusion: Intrathecal immunoglobulin synthesis and blood-brain barrier situation constitute key element in the neuro-inflammation diagnosis(AU)

Central Nervous System-Peripheral Immune System Dialogue in Neurological Disorders: Possible Application of Neuroimmunology in Urology / 대한배뇨장애요실금학회지

Previous concepts of immune-privileged sites obscured the role of peripheral immune cells in neurological disorders and excluded the consideration of the potential benefits of immunotherapy. Recently, however, numerous studies have demonstrated that the blood-brain barrier in the central nervous system is an educational barrier rather than an absolute barrier to peripheral immune cells. Emerging knowledge of immune-privileged sites suggests that peripheral immune cells can infiltrate these sites via educative gates and that crosstalk can occur between infiltrating immune cells and the central nervous system parenchyma. This concept can be expanded to the testis, which has long been considered an immune-privileged site, and to neurogenic bladder dysfunction. Thus, we propose that the relationship between peripheral immune cells, the brain, and the urologic system should be considered as an additional possible mechanism in urologic diseases, and that immunotherapy might be an alternative therapeutic strategy in treating neurogenic bladder dysfunction.

Association of interleukin-10 levels with age of onset and duration of illness in patients with major depressive disorder

Objective: To investigate peripheral levels of interleukin-10 (IL-10) in patients with major depressive disorder (MDD) and bipolar disorder (BD) and evaluate the relationship between IL-10, age of disease onset, and duration of illness. Methods: Case-control study nested in a population-based cohort of 231 individuals (age 18-24 years) living in Pelotas, state of Rio Grande do Sul, Brazil. Participants were screened for psychopathology using the Mini-International Neuropsychiatric Interview (MINI) and the Structured Clinical Interview for DSM-IV (SCID-I). Serum IL-10 was measured using commercially available immunoassay kits. Results: Peripheral levels of IL-10 were not significantly different in individuals with MDD or BD as compared to controls. However, higher IL-10 levels were found in MDD patients with a later disease onset as compared with controls or early-onset patients. In addition, IL-10 levels correlated negatively with illness duration in the MDD group. In the BD group, age of onset and duration of illness did not correlate with IL-10 levels. Conclusion: Higher levels of IL-10 are correlated with late onset of MDD symptoms. Moreover, levels of this cytokine might decrease with disease progression, suggesting that an anti-inflammatory balance may be involved in the onset of depressive symptoms and disease progression in susceptible individuals.

Central nervous system lupus:an update / 医学研究生学报

At present, central nervous system involvement is the most common in neuropsychiatric lupus.This article discus-ses the research status of central nervous system lupus in the past few years which include characteristics of clinical presentation, etio-pathological mechanism, neuroimaging diagnosis and therapeutic strategy.Actually, the advanced technology, especially neuroimmu-nology and neuroimaging, in combination with early diagnosis, effective assessment and treat to target strategy could decrease global disease activity, ameliorate quality of life and increase life expectancy.Furthermore, the prospective researches should be paid more attention in lupus registries, neuropsychiatric questionnaires, damage index and improvement of severe refractory cases in clinic.

A human astrocytoma cell line is highly susceptible to infection with Trypanosoma cruzi

Astrocytes play a vital role in neuronal protection, homeostasis, vascular interchange and the local immune response. Some viruses and parasites can cross the blood-brain barrier and infect glia. Trypanosoma cruzi, the aetiological agent of Chagas disease, can seriously compromise the central nervous system, mainly in immune-suppressed individuals, but also during the acute phase of the infection. In this report, the infective capacity of T. cruzi in a human astrocyte tumour-derived cell line was studied. Astrocytes exposed to trypomastigotes (1:10 ratio) produced intracellular amastigotes and new trypomastigotes emerged by day 4 post-infection (p.i.). At day 6 p.i., 93% of the cells were infected. Using flow cytometry, changes were observed in both the expression of major histocompatibility complex class I and II molecules and the chemokine secretion pattern of astrocytes exposed to the parasite. Blocking the low-density lipoprotein receptor on astrocytes did not reduce parasite intracellular infection. Thus, T. cruzi can infect astrocytes and modulate the immune response during central nervous system infection.

El futuro de la depresión: una enfermedad sistémica neuroendócrina, inflamatoria y neurodegenerativa compleja / The future of depression: a complex neuroendocrine, inflammatory and neurodegenerative systemic illness

Los modelos neurobiológicos de la depresión han evolucionado más allá de la teoría monoaminérgica, que fue construida luego del advenimiento de las drogas antidepresivas en la década de 1950. Actualmente se considera que la depresión implica una amplia gama de neurotransmisores, incluyendo a la dopamina y el glutamato, y a prácticamente la totalidad del sistema nervioso central. La evidencia emergente está redefiniendo la depresión como una enfermedad crónica y sistémica que puede deteriorar la función neuroendocrina, los ritmos biológicos y las respuestas inmunes, y como una enfermedad que, de no ser tratada, puede conducir a la demencia. Diferentes abordajes de investigación, desde la biología molecular hasta los estudios clínicos, han ofrecido tanto nuevos conocimientos acerca de los mecanismos fisiológicos implicados como también indicios para desarrollar terapias antidepresivas efectivas en respuesta a los mismos. Además de los métodos ya bien establecidos, como los inhibidores de la recaptación de monoaminas y la terapia cognitivo-conductual, estos pueden incluir drogas anti-inflamatorias no esteroides, prescripción de ejercicio físico, tratamientos somáticos y toda una nueva generación de drogas antidepresivas dotadas de modos de acción originales. A medida que el manejo de la depresión se torna cada vez más multifacético, los médicos serán capaces de optimizar los resultados clínicos para sus pacientes integrando sinérgicamente las múltiples opciones terapéuticas disponibles.

Neurobiological models of depression have evolved far beyond the monoamine theory that was construed following the advent of antidepressant drugs in the 1950s. Depression is now seen to implicate a wide range of neurotransmitters, including dopamine and glutamate, and virtually the entire central nervous system. Emerging evidence is redefining depression as a chronic and systemic illness that may impair neuroendocrine function, biological rhythms and immune responses, and one which may lead to dementia if left untreated. Different research approaches, from molecular biology to clinical studies, have offered new insights into the physiological mechanisms involved as well as indications of how effective antidepressant therapies may develop in response to these. In addition to well-established methods, like monoamine reuptake inhibitors and cognitive behavioral therapy, these may include non-steroid anti-inflammatory drugs, prescription of physical exercise, somatic treatments and a whole new generation of antidepressant drugs endowed with original modes of action. As the management of depression becomes increasingly multifaceted, clinicians will be able to optimize clinical outcomes for their patients by synergistically integrating the multiple therapeutic options available.

Hydrogen Peroxide Upregulates TNF-Related Apoptosis-Inducing Ligand (TRAIL) Expression in Human Astroglial Cells, and Augments Apoptosis of T Cells

The brain is particularly vulnerable to oxygen free radicals, and these radicals have been implicated in the pathology of several neurological disorders. In this study, the modulation of TNF-related apoptosis-inducing ligand (TRAIL) expression by oxidative stress was shown in LN215 cells, an astroglioma cell line. Hydrogen peroxide (H2O2) treatment increased TRAIL expression in LN215 cells and H2O2-induced TRAIL augmented apoptosis in Peer cells, a cell line sensitive to TRAIL- mediated cell death. Our findings suggest that the upregulation of TRAIL in astroglial cells may abrogate immune cell effector functions.

Understanding of Neuroimmunology: Multiple sclerosis and Guillain-Barre syndrome

Neuroimmunology is a rapidly expanding field in the medicine and there has been great advancement in the understanding of the pathogenesis of autoimmune diseases during the past decade. In neurology, immune mechanism has been implicated in the pathogenesis of more than twenty neurological diseases. The understanding of the immunological mechanism of these diseases has helped clinicians in management of these diseases. In many neurological diseases with immunological deterioration, multiple sclerosis and Guillain-Barre syndrome are relatively common diseases that share common features like demyelination. But multiple sclerosis is a disease of central nervous system and Guillain-Barre syndrome is a syndrome developed in peripheral nervous system. This review will describe the recent advances in clinical immunology with regard to general aspects of autoimmune diseases of neurological system, pathogenesis of two common autoimmune diseases, multiple sclerosis and Guillain-Barre syndrome.

The Role of the Ubiquitin-Proteasome Pathway in Neurodegenerative Disorders

Impaired function of the Ubiquitin (Ub)/proteasome pathway is one of the molecular mechanisms underlying aging process and neurodegenerative disorders such as Parkinson's Disease and Alzheimer's Disease (AD). Among many vital cellular functions, the Ub/proteasome pathway regulates immune responses via mediating activation of NF-kappa B by pro-inflammatory signals. Dysfunction of this pathway may aberrantly affect the signaling of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), which are abundantly present in AD brains. To address this, chemokine expression was measured as a readout for IL-1beta and TNF-alpha signaling in human astrocytes. Proteasome inhibitors, MG-132 and lactacystin, suppressed IL-1beta and TNF-alpha-induced expression of MCP-1, RANTES and IP-10, but not that of IL-8. In addition, human astrocytes underwent apoptotic cell death upon treatment with IL-1beta and TNF-alpha only in the presence of the proteasome inhibitors. These results suggest that inhibition of the Ub/proteasome pathway dysregulates pro-inflammatory cytokine signaling in human astrocytes, leading to divergent chemokine expression and enhanced cell death. Therefore, we propose that the immuno-pathologic role of astrocytes in AD brains should be re-evaluated under the circumstances of impaired function of the Ub/proteasome pathway.

Effects of Cycloheximide and Dexamethasone on Fas - Mediated Apopthsis in Primary Human Astrocytes / 대한면역학회지

Astrocytes are major glial cells in central nervous system (CNS) and are known to express death receptors or ligands that can induce apoptosis of astrocytes or other brain cells. We have previously confirmed that cultured human astrocytes express fas and fas ligand and their expression may be regulated by various cytokines found in CNS. Because fas can rnediate cell death known as apoptosis, we investigated fas-mediated cell death in cultured human astrocytes and evaluated factors that may influence the fas-mediated apoptosis in astrocytes. Pretreatment of interferon-r and TNF-a increased cell death in astrocytes. Cell death induced by fas ligation was confirmed as apoptosis by phosphatidylserine translocation in cell membrane. Cycloheximide, protein synthesis inhibitor, potentiated fas-mediated cell death. However, buthionine sulfoxine did not potentiate fas-mediated apoptosis. Dexamethasone blocked cell death in dose-dependent and time-dependent manners. These findings collectively show that fas expressed on cultured human fetal astrocytes can induce apoptotic cell death after pretreatment of interferon-r and/or TNF-a. Therefore, the fas-fas ligand system in CNS may regulate the glial degeneration and may participate the neuronal loss in certain conditions. Furthermore, fas-mediated apoptosis of astrocytes can be potentiated by protein synthesis inhibitors and can be blocked by dexamethasone.