RESUMEN
AIMS: Experimental data suggest that systemic immune activation may create a pro-inflammatory environment with microglia activation in the central nervous system in the absence of overt inflammation, which in turn may be deleterious in conditions of neurodegenerative disease. The extent to which this is relevant for the human brain is unknown. The central aim of this study is to provide an in-depth characterization of the microglia and macrophage response to systemic inflammation. METHODS: We used recently described markers to characterize the origin and functional states of microglia/macrophages in white and grey matter in patients who died under septic conditions and compared it to those patients without systemic inflammation. RESULTS: We found pro-inflammatory microglia activation in septic patients in the white matter, with very little activation in the grey matter. Using a specific marker for resident microglia (TMEM119), we found that parenchyma microglia were activated and that there was additional recruitment of perivascular macrophages. Pro-inflammatory microglia activation occurred in the presence of homeostatic microglia cells. In contrast to inflammatory or ischaemic diseases of the brain, the anti-inflammatory microglia markers CD163 or CD206 were not expressed in acute sepsis. Furthermore, we found pronounced upregulation of inducible nitric oxide synthase not only in microglia, but also in astrocytes and endothelial cells. CONCLUSION: Our results demonstrate the pronounced effects of systemic inflammation on the human brain and have important implications for the selection of control populations for studies on microglia activation in human brain disease.
Asunto(s)
Sustancia Gris/inmunología , Macrófagos/inmunología , Microglía/inmunología , Sepsis/inmunología , Sustancia Blanca/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Sustancia Gris/patología , Humanos , Masculino , Persona de Mediana Edad , Sepsis/patología , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: Gonadal steroids may modulate disease course in multiple sclerosis (MS). OBJECTIVE: To assess the prevalence and clinical associations of hypogonadism in men with MS. METHODS: Male patients, aged 18-65 years, with relapsing-remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually. RESULTS: Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012). CONCLUSIONS: Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. A potential neuroprotective role for testosterone warrants further investigation.
Asunto(s)
Esclerosis Múltiple/sangre , Testosterona/sangre , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Estudios Transversales , Personas con Discapacidad , Progresión de la Enfermedad , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P=0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P=0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P=0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P=0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.
Asunto(s)
Encéfalo/patología , Antígenos HLA/genética , Imagen por Resonancia Magnética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Adolescente , Adulto , Alelos , Niño , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Suppression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by the oral administration of myelin basic protein (MBP) is mediated by CD8+ T cells that can be isolated from the spleens of MBP-fed animals. These cells adoptively transfer protection to naive animals subsequently immunized with MBP and complete Freund's adjuvant (CFA) and suppress in vitro MBP proliferative responses. Using a transwell system in which the modulator spleen cells from MBP-fed animals are separated by a semipermeable membrane from responder cells, MBP, or OVA-specific T cell lines, we have found that cell contact is not required for in vitro suppression to occur. In vitro suppression is dependent, however, upon antigen-specific triggering of modulator T cells. Once antigen-specific triggering occurs, suppression across the transwell is mediated by an antigen-nonspecific soluble factor that equally suppresses an MBP line or an ovalbumin (OVA) line. This phenomenon of antigen-driven bystander suppression was also demonstrated in vivo. Specifically, Lewis rats fed OVA which were then immunized with MBP/CFA plus OVA given separately subcutaneously were protected from EAE. Animals fed OVA and then immunized with MBP/CFA without OVA given subcutaneously were not protected. The protective effect of feeding OVA could be adoptively transferred by CD8+ T cells from OVA-fed animals into MBP/CFA plus OVA-injected animals. Feeding bovine serum albumin (BSA) or keyhole limpet hemocyanin did not suppress EAE in animals immunized with MBP/CFA plus OVA. EAE was suppressed, however, if BSA was fed and animals then immunized with MBP/CFA plus BSA given subcutaneously. Antigen-driven bystander suppression appears to be an important mechanism by which antigen-driven peripheral tolerance after oral administration of antigen is mediated, and presumably occurs in the microenvironment accounting for the antigen specificity of suppression generated by oral tolerization to antigens.
Asunto(s)
Encefalomielitis Autoinmune Experimental/prevención & control , Inmunoterapia Adoptiva , Proteína Básica de Mielina/uso terapéutico , Linfocitos T/inmunología , Administración Oral , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Cobayas , Hipersensibilidad Tardía , Proteína Básica de Mielina/administración & dosificación , Ovalbúmina/inmunología , Ratas , Ratas Endogámicas Lew , Albúmina Sérica Bovina/inmunología , Bazo/inmunologíaRESUMEN
The S1 genome segment of reovirus is linked to type specificity as determined by neutralization antibody. This gene segment codes for a minor outer capsid polypeptide (sigma1). Therefore, sigma1 is the peptide responsible for induction of neutralization antibody and confers type specificity. This biologic property of reovirus was defined using hybrid recombinants clones between reovirus types 1 and 3 and 2 and 3.
Asunto(s)
Antígenos Virales , Genes Virales , Reoviridae/genética , Anticuerpos Antivirales , Especificidad de Anticuerpos , ARN Viral/genética , ARN Viral/inmunología , Reoviridae/inmunologíaRESUMEN
Experimental autoimmune encephalomyelitis (EAE) in the Lewis rat is a self-limited inflammatory process localized to the central nervous system that is induced by the injection of myelin basic protein (MBP) in adjuvant. Oral administration of MBP suppresses EAE, and this suppression is mediated by CD8+ T cells that adoptively transfer protection and suppress both in vitro and in vivo by the release of transforming growth factor (TGF) beta after antigen-specific triggering. Furthermore, oral tolerance to MBP is enhanced by the concomitant oral administration of lipopolysaccharide (LPS). The present study was undertaken to determine whether the disease course in EAE and its suppression by oral tolerization to MBP is associated with distinct patterns of cytokine expression in the target organ. Detailed immunohistology of the brain was performed at the peak of clinical disease (day 14 after immunization) and after recovery (day 18) in control (ovalbumin [OVA]-fed), MBP-fed, and MBP plus LPS-fed animals. Brains from OVA-fed animals at the peak of disease showed perivascular infiltration with activated mononuclear cells which secreted the inflammatory cytokines interleukins (IL) 1, 2, 6, 8, TNF-alpha, and interferon gamma. The inhibitory cytokines TGF-beta and IL-4, and prostaglandin E2 (PGE2) were absent. In MBP orally tolerized animals there was a marked reduction of the perivascular infiltrate and downregulation of all inflammatory cytokines. In addition, there was upregulation of the inhibitory cytokine TGF-beta. In MBP plus LPS orally tolerized animals, in addition to upregulation of TGF-beta and reduction of inflammatory cytokines, there was enhanced expression of IL-4 and PGE2, presumably secondary to activation of an additional population of immunoregulatory cells. In OVA-fed animals that had recovered (day 18), staining for inflammatory cytokines diminished, and there was the appearance of TGF-beta and IL-4. These results suggest that suppression of EAE, either induced by oral tolerization or that which occurs during natural recovery is related to the secretion of inhibitory cytokines or factors that actively suppress the inflammatory process in the target organ.
Asunto(s)
Química Encefálica , Citocinas/análisis , Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica , Interleucina-4/análisis , Proteína Básica de Mielina/inmunología , Prostaglandinas E/análisis , Factor de Crecimiento Transformador beta/análisis , Animales , Regulación hacia Abajo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Lipopolisacáridos , Ovalbúmina/inmunología , Ratas , Ratas Endogámicas Lew , Regulación hacia ArribaRESUMEN
Monocyte recruitment to the central nervous system (CNS) is a necessary step in the development of pathologic inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Monocyte chemoattractant protein (MCP)-1, a potent agonist for directed monocyte migration, has been implicated in the pathogenesis of EAE. Here we report that deficiency in CC chemokine receptor (CCR)2, the receptor for MCP-1, confers resistance to EAE induced with a peptide derived from myelin oligodendrocyte glycoprotein peptide 35-55 (MOGp35-55). CCR2(-/)- mice immunized with MOGp35-55 failed to develop mononuclear cell inflammatory infiltrates in the CNS and failed to increase CNS levels of the chemokines RANTES (regulated on activation, normal T cell expressed and secreted), MCP-1, and interferon (IFN)-inducible protein 10 (IP-10) as well the chemokine receptors CCR1, CCR2, and CCR5. Additionally, T cells from CCR2(-/)- immunized mice showed decreased antigen-induced proliferation and production of IFN-gamma compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE. These data indicate that CCR2 plays a necessary and nonredundant role in the pathogenesis of EAE.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Receptores de Quimiocina/inmunología , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Quimiocina CCL2/biosíntesis , Quimiocina CCL5/biosíntesis , Quimiocina CXCL10 , Quimiocinas CXC/biosíntesis , Inmunidad Innata/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Receptores CCR2 , Receptores CCR5/biosíntesis , Receptores de Quimiocina/genética , Linfocitos T/inmunologíaRESUMEN
Equal numbers of CD4+ T cells recognizing myelin basic protein (MBP) and proteolipid protein (PLP) are found in the circulation of normal individuals and multiple sclerosis (MS) patients. We hypothesized that if myelin-reactive T cells are critical for the pathogenesis of MS, they would exist in a different state of activation as compared with myelin-reactive T cells cloned from the blood of normal individuals. This was investigated in a total of 62 subjects with definitive MS. While there were no differences in the frequencies of MBP- and PLP-reactive T cells after primary antigen stimulation, the frequency of MBP or PLP but not tetanus toxoid-reactive T cells generated after primary recombinant interleukin (rIL-2) stimulation was significantly higher in MS patients as compared with control individuals. Primary rIL-2-stimulated MBP-reactive T cell lines were CD4+ and recognized MBP epitopes 84-102 and 143-168 similar to MBP-reactive T cell lines generated with primary MBP stimulation. In the cerebrospinal fluid (CSF) of MS patients, MBP-reactive T cells generated with primary rIL-2 stimulation accounted for 7% of the IL-2-responsive cells, greater than 10-fold higher than paired blood samples, and these T cells also selectively recognized MBP peptides 84-102 and 143-168. In striking contrast, MBP-reactive T cells were not detected in CSF obtained from patients with other neurologic diseases. These results provide definitive in vitro evidence of an absolute difference in the activation state of myelin-reactive T cells in the central nervous system of patients with MS and provide evidence of a pathogenic role of autoreactive T cells in the disease.
Asunto(s)
Interleucina-2/farmacología , Esclerosis Múltiple/inmunología , Proteína Básica de Mielina/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Adulto , Antígenos CD/sangre , Antígenos CD/líquido cefalorraquídeo , Línea Celular , Femenino , Citometría de Flujo , Antígenos HLA-DQ/sangre , Antígenos HLA-DQ/líquido cefalorraquídeo , Antígenos HLA-DR/sangre , Antígenos HLA-DR/líquido cefalorraquídeo , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/líquido cefalorraquídeo , Proteínas de la Mielina/inmunología , Proteína Proteolipídica de la Mielina , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/inmunología , Proteínas Recombinantes/farmacología , Linfocitos T/efectos de los fármacosRESUMEN
We have investigated the T cell populations in the cerebrospinal fluid (CSF) of chronic progressive multiple sclerosis (MS) patients. Individual T cells from the CSF and blood were cloned before expansion and their clonotypes were defined by analysis of rearranged T cell receptor beta chain and gamma chain genes. 87 T cell clones from blood and CSF of two patients with chronic progressive MS were examined for common TCR gene rearrangement patterns. In one patient, 18 of 28 CSF-derived T cell clones demonstrated common TCR gene rearrangements indicating oligoclonal T cell populations; in the blood, two patterns were found twice among 26 T cell clones. In another patient, 5 of 27 CSF-derived clones had common TCR gene rearrangement patterns. In contrast, no common beta chain rearrangement pattern was found among 67 T cell clones derived from the blood or CSF of a patient with subacute sclerosing panencephalitis, among 20 clones from the CSF of a patient with herpes zoster meningoencephalitis, or among 66 clones from a normal subject. A subject with atypical, fatal MS of 8-mo duration was also studied and did not have oligoclonal T cells in the CSF or blood. These results demonstrate that distinct oligoclonal T cell populations can be found in the CSF immune compartment of subjects with nonmalignant inflammatory disease and they can create a new avenue for the investigation of the specificity of the T cell response within the central nervous system.
Asunto(s)
Líquido Cefalorraquídeo/patología , Esclerosis Múltiple/líquido cefalorraquídeo , Linfocitos T/patología , Líquido Cefalorraquídeo/inmunología , Células Clonales/inmunología , Células Clonales/patología , Herpes Zóster/líquido cefalorraquídeo , Humanos , Meningoencefalitis/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Receptores de Antígenos de Linfocitos T/genética , Panencefalitis Esclerosante Subaguda/líquido cefalorraquídeo , Linfocitos T/inmunologíaRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system that can be induced in a number of species by immunization with myelin basic protein (MBP) in adjuvant, and serves as an experimental model for the study of multiple sclerosis. The role of the thymus in acquired tolerance in autoimmune models has not been thoroughly investigated. In this study, we examined the effects of intrathymic injection of MBP or its major encephalitogenic peptide on the course of EAE in Lewis rats. A single intrathymic injection of MBP 48 h pre- but not postimmunization protects animals from actively induced EAE. An intact MBP-primed thymus was required up to 10 d postimmunization, as thymectomy on days 1, 2, and 7 postimmunization abrogated the protective effect, whereas thymectomy on day 10 did not. The proliferative response of primed lymphocytes was significantly reduced in animals that were intrathymically injected with MBP. Protection against clinical EAE was induced by thymic injection of the major encephalitogenic region (residues 71-90) but not a nonencephalitogenic (21-40) MBP epitope. Immunohistologic examination of the brain from rats intrathymically injected with encephalitogenic peptide showed markedly reduced cellular infiltrate and virtual absence of activation and inflammatory cytokines as compared with rats intrathymically injected with the nonencephalitogenic peptide. These results indicate that the thymus may play an active role in acquired systemic immunologic tolerance in T cell-mediated experimental autoimmune diseases. This effect may be mediated by a process of clonal inactivation of autoreactive T cell clones circulating through the thymus.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica , Proteína Básica de Mielina/inmunología , Timo/inmunología , Animales , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/prevención & control , Encéfalo/metabolismo , División Celular , Células Cultivadas , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/prevención & control , Epítopos , Femenino , Cobayas , Inmunohistoquímica , Ganglios Linfáticos/citología , Proteína Básica de Mielina/administración & dosificación , Ratas , Ratas Endogámicas Lew , Timectomía , VacunaciónRESUMEN
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease that can be induced in laboratory animals by immunization with the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP). We analyzed the role of the T cell receptor (TCR) repertoire in susceptibility to EAE induced by these two autoantigens. Autoreactive T cells induced after immunization with MBP use a limited set of TCR. In contrast, we demonstrate that T cell clones that recognize the encephalitogenic PLP epitope (PLP 139-151) use diverse TCR genes. When the TCR repertoire is limited by introduction of a novel rearranged TCR V beta 8.2 chain in transgenic SJL mice, EAE could be induced in the transgenic mice by immunization with the encephalitogenic epitopes of PLP, but not with the encephalitogenic epitope of MBP. Thus, skewing the TCR repertoire affects the susceptibility to EAE by immunization with MBP but not with PLP. These data demonstrate the biological consequences of the usage of a more diverse T cell repertoire in the development of an autoimmune disease.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN , Susceptibilidad a Enfermedades , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Receptores de Antígenos de Linfocitos T alfa-beta/inmunologíaRESUMEN
Experimental autoimmune encephalomyelitis (EAE), an experimental model for the study of multiple sclerosis, is an autoimmune disease of the central nervous system that can be induced in a number of species by immunization with myelin basic protein (MBP). MBP-reactive CD4+ T cells, predominantly expressing the V beta 8.2 T cell receptor (TCR), migrate from the peripheral lymphoid organs and initiate the inflammatory response in the brain. We have previously shown that a single intrathymic injection of MBP or its major encephalitogenic peptide (p71-90), but not a nonencephalitogenic peptide (p21-40), induces antigen-specific systemic tolerance and inhibits the induction of EAE in Lewis rats. In this study, we investigated the mechanisms of induction and maintenance of acquired thymic tolerance in this model. First, we investigated which thymic cell is responsible for "induction" of systemic tolerance. Thymic dendritic-enriched cells, isolated by plastic adherence, when incubated in vitro with p71-90 and injected intravenously into Lewis rats, were capable of preventing the development of EAE, but his protection was lost in thymectomized recipients. In addition, intravenous injection of thymic dendritic cells isolated from animals that had been previously injected intrathymically with p71-90 but not p21-40 also prevented the development of EAE. Second, to determine the "effector" mechanisms involved in acquired thymic tolerance, we compared TCR expression in the brains of animals with actively induced EAE with TCR expression in animals that received intrathymic injection of p71-90 or p21-40. Using a semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) technique, we found increased expression of CD4 and V beta 8.2 message in brains of immunized animals compared with those of naive animals. In animals intrathymically injected with p71-90 but not p21-40, CD4 and V beta 8.2 transcript levels were significantly reduced compared with immunized controls. Immunohistologic studies of brain tissue and spleens with specific V beta 8.2 and control V beta 10 monoclonal antibodies confirmed these observations in vivo. These findings, taken together with recent data demonstrating that activated T cells circulate through the thymus, suggest that interaction of thymic dendritic cells with specific TCR of activated peripheral T cells can lead to inactivation of these antigen-specific cells and confirm the role of V beta 8.2-expressing T cells in EAE.
Asunto(s)
Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Linfocitos T/inmunología , Timo/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Secuencia de Bases , Encéfalo/inmunología , Cartilla de ADN/química , Encefalomielitis Autoinmune Experimental/patología , Femenino , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Tolerancia Inmunológica , Inmunización Pasiva , Masculino , Datos de Secuencia Molecular , Proteína Básica de Mielina/química , Proteína Básica de Mielina/inmunología , Péptidos/administración & dosificación , Péptidos/inmunología , Ratas , Ratas Endogámicas Lew , Bazo/citología , TimectomíaRESUMEN
A xenogeneic antiserum raised to antireovirus immunoglobulin was used to define an idiotypic determinant present on antibodies to reovirus type 3 hemagglutinin. The same idiotype was identified on nonimmune lymphoid cells and on neuronal cells that specifically bind the hemagglutinin of type 3 reovirus. This idiotypic determinant, called Id3, is shared by (a) a monoclonal antibody to the neutralization site of hemagglutinin from type 3 reovirus; (b) BALB/c serum antibodies to the hemagglutinin of reovirus type 3; (c) R1.1, a murine thymoma cell line that binds reovirus type 3; (d) primary cultures of murine neuronal cells. The presence of an idiotype shared by antihemagglutinin antibodies and by structures on nonlymphoid cells suggests a general relationship between disparate receptors that recognize a common determinant. Furthermore, this suggests a novel approach for the study of viral receptor interactions and for analysis of mechanisms of autoimmune responses.
Asunto(s)
Hemaglutininas/inmunología , Idiotipos de Inmunoglobulinas/inmunología , Linfocitos/inmunología , Reoviridae/inmunología , Animales , Anticuerpos Antivirales/biosíntesis , Especificidad de Anticuerpos , Sitios de Unión de Anticuerpos , Epítopos , Ligamiento Genético , Hemaglutininas/genética , Sueros Inmunes/farmacología , Idiotipos de Inmunoglobulinas/genética , Orthoreovirus Mamífero 3/genética , Orthoreovirus Mamífero 3/inmunología , Ratones , Ratones Endogámicos BALB C , Neuronas/inmunología , Conejos , Reoviridae/genéticaRESUMEN
Viruses that infect ependyma cause ependymitis in humans and hydrocephalus in experimental animals. We report that reovirus type 1 (which induces hydrocephalus in mice) binds to the surface of isolated human and murine ciliated ependymal cells. With the use of recombinant viral clones, the binding property was mapped to the type 1 viral hemagglutinin, which also determines in vivo the affinity of reovirus type 1 for ependyma. Mumps virus, measles virus, parainfluenza type 3, and herpes simplex virus type 1 bind to murine ependyma cells, whereas reovirus type 3, herpes simplex virus type 2, and poliovirus type 2 do not.
Asunto(s)
Epéndimo/metabolismo , Receptores Virales/metabolismo , Reoviridae/metabolismo , Animales , Células Cultivadas , Epéndimo/microbiología , Hemaglutininas Virales/metabolismo , Humanos , Hidrocefalia/microbiología , Virus del Sarampión/metabolismo , Ratones , Virus de la Parotiditis/metabolismo , Virus de la Parainfluenza 3 Humana/metabolismo , Simplexvirus/metabolismoRESUMEN
Rat pups that are separated early from their mothers, at postnatal day 15, become hypothermic when subjected to physical restraint on postnatal day 30. Restraint of separated pups also elicits an unusually high incidence of gastric erosions, as well as insomnia and an increase in quiet wakefulness. If hypothermia during restraint is prevented, neither the erosions nor the behavioral responses occur. Rat pups separated at the customary age (postnatal day 22) do not become hypothermic during restraint, and the restraint of such pups is not associated with either gastric erosion or insomnia.
Asunto(s)
Regulación de la Temperatura Corporal , Privación Materna , Úlcera Gástrica/etiología , Estrés Psicológico , Animales , Animales Recién Nacidos/fisiología , Nivel de Alerta/fisiología , Conducta Animal/fisiología , Privación de Alimentos , Humanos , Ratas , Restricción Física , Sueño/fisiología , Estrés Psicológico/fisiología , Vigilia/fisiologíaRESUMEN
New blood vessel growth occurs during normal fetal development and in diseases such as cancer and diabetes. The polypeptide angiogenin induces new blood vessel growth in two biological assays and may play a role in the vascular development of the fetus and in the neovascularization that accompanies diseases and wound healing. A complementary DNA probe for human angiogenin was used to examine the tissue distribution of angiogenin messenger RNA (mRNA) in the developing rat and in selected transformed cell lines. Angiogenin mRNA was detected predominantly in adult liver but was also detectable at low levels in other tissues. The expression of the angiogenin gene in rat liver was found to be developmentally regulated; mRNA levels were low in the developing fetus, increased in the neonate, and maximal in the adult. The amount of angiogenin mRNA in human HT-29 colon carcinoma and SK-HEP hepatoma cells was not greater than that in normal rat liver. These results demonstrate that angiogenin is predominantly expressed in adult liver, that the pattern of angiogenin gene expression is not temporally related to vascular development in the rat, and that the transformed cells studied do not contain more angiogenin mRNA than does normal liver. If angiogenin activity is controlled at the transcriptional level, the results of this study suggest that the primary function of angiogenin in vivo may be in processes other than the regulation of vascular growth.
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Proteínas de Neoplasias/genética , Ribonucleasa Pancreática , Factores de Edad , Animales , Línea Celular , Regulación de la Expresión Génica , Humanos , Hígado/fisiología , Neovascularización Patológica , ARN Mensajero/genética , Ratas , Distribución TisularRESUMEN
Premature separation of rat pups from their dams greatly increases their susceptibility to restraint-induced gastric erosions. When prematurely separated female rats grow to adulthood and mate with stock males, their normally reared F 1 progeny also have increased susceptibility to restraint-induced erosions. Cross-fostering studies show that prenatal rather than postnatal factors transmit this susceptibility to the F 1 progeny.
Asunto(s)
Úlcera Gástrica/genética , Estrés Psicológico/complicaciones , Animales , Animales Lactantes/fisiología , Femenino , Humanos , Conducta Materna , Embarazo , Ratas , Restricción Física , Úlcera Gástrica/embriología , Úlcera Gástrica/etiologíaRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease that serves as an animal model for multiple sclerosis. Oral administration of myelin basic protein (MBP) suppresses EAE by inducing peripheral tolerance. T cell clones were isolated from the mesenteric lymph nodes of SJL mice that had been orally tolerized to MBP. These clones were CD4+ and were structurally identical to T helper cell type 1 (TH1) encephalitogenic CD4+ clones in T cell receptor usage, major histocompatibility complex restriction, and epitope recognition. However, they produced transforming growth factor-beta with various amounts of interleukin-4 and interleukin-10 and suppressed EAE induced with either MBP or proteolipid protein. Thus, mucosally derived TH2-like clones induced by oral antigen can actively regulate immune responses in vivo and may represent a different subset of T cells.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica , Proteína Básica de Mielina/inmunología , Administración Oral , Secuencia de Aminoácidos , Animales , Células Clonales , Epítopos/inmunología , Interleucina-10/biosíntesis , Interleucina-4/biosíntesis , Ganglios Linfáticos/inmunología , Complejo Mayor de Histocompatibilidad , Mesenterio/inmunología , Ratones , Datos de Secuencia Molecular , Proteína Básica de Mielina/administración & dosificación , Proteínas de la Mielina/inmunología , Proteína Proteolipídica de la Mielina , Receptores de Antígenos de Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Multiple sclerosis (MS) is thought to be an autoimmune disease mediated by T lymphocytes that recognize myelin components of the central nervous system. In a 1-year double-blind study, 30 individuals with relapsing-remitting MS received daily capsules of bovine myelin or a control protein to determine the effect of oral tolerization to myelin antigens on the disease. Six of 15 individuals in the myelin-treated group had at least one major exacerbation; 12 or 15 had an attack in the control group. T cells reactive with myelin basic protein were reduced in the myelin-treated group. No toxicity or side effects were noted. Although conclusions about efficacy cannot be drawn from these data, they open an area of investigation for MS and other autoimmune diseases.