RESUMEN
Membrane cofactor protein (CD46) is a member of a family of glycoproteins that are regulators of complement and prevent activation of complement on autologous cells. Recently, CD46 has been identified as the cellular receptor for human herpesvirus Type 6 (HHV-6). Elevated levels of soluble CD46 have been described in several autoimmune disorders, and may be implicated in the pathogenesis of these diseases. As several reports have supported an association of HHV-6 and multiple sclerosis, it was of interest to compare levels of soluble CD46 in the sera of multiple sclerosis patients to that of healthy controls, other neurological disease controls, and other inflammatory disease controls. Using an immunoaffinity column comprised of immobilized monoclonal antibodies to CD46, serum levels of soluble CD46 were found to be significantly elevated in multiple sclerosis patients compared with healthy and other neurological disease controls. Moreover, multiple sclerosis patients who tested positive for HHV-6 DNA in serum had significantly elevated levels of soluble CD46 in their serum compared with those who were negative for HHV-6 DNA. A significant increase in soluble CD46 was also found in the serum of other inflammatory disease controls tested compared to healthy controls. Additionally, a significant correlation was demonstrated between levels of soluble CD46 in the serum and cerebrospinal fluid of multiple sclerosis patients. Collectively, these data suggest that elevated levels of soluble CD46 may contribute to the pathogenesis of inflammatory diseases, including multiple sclerosis.
Asunto(s)
Antígenos CD/sangre , Antígenos CD/líquido cefalorraquídeo , Infecciones por Herpesviridae/diagnóstico , Herpesvirus Humano 6/aislamiento & purificación , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/líquido cefalorraquídeo , Esclerosis Múltiple/virología , Estudios de Cohortes , ADN Viral/análisis , Femenino , Herpesvirus Humano 6/genética , Humanos , Masculino , Proteína Cofactora de Membrana , Esclerosis Múltiple/sangre , Esclerosis Múltiple/líquido cefalorraquídeo , SolubilidadRESUMEN
TGF-beta 1 null (TGF-beta1-/-) mice die at 3-4 wk of age and show an autoimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules. To determine the role of MHC class I Ags in the autoimmune manifestations and the inflammation observed in TGF-beta 1-/- mice, we generated TGF-beta 1-/- mice in the genetic background of beta 2-microglobulin deficiency (beta 2M-/-). TGF-beta 1-/-;beta 2M-/- mice had improved survival compared with TGF-beta 1-/- mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-beta 1-/- mice. In vivo depletion of CD8+ T cells in TGF-beta 1-/- mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-beta 1-/-;beta 2M-/- mice was also lower than that in TGF-beta 1-/- mice, suggesting reduced systemic inflammation. Autoimmune response as judged by serum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidney was reduced in TGF-beta 1-/-;beta 2M-/- mice, when compared with that in TGF-beta 1-/- mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-beta 1-/- mice and CD8+ T cells may have a contribution to the inflammation in TGF-beta 1-/- mice.
Asunto(s)
Genes Letales/inmunología , Factor de Crecimiento Transformador beta/deficiencia , Factor de Crecimiento Transformador beta/genética , Microglobulina beta-2/deficiencia , Microglobulina beta-2/genética , Animales , Complejo Antígeno-Anticuerpo/metabolismo , Autoanticuerpos/biosíntesis , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Cruzamientos Genéticos , Desarrollo Embrionario y Fetal/genética , Desarrollo Embrionario y Fetal/inmunología , Citometría de Flujo , Genotipo , Antígenos de Histocompatibilidad Clase II/biosíntesis , Antígenos de Histocompatibilidad Clase II/genética , Inflamación/genética , Inflamación/inmunología , Inflamación/prevención & control , Riñón/inmunología , Riñón/metabolismo , Leucopoyesis/genética , Leucopoyesis/inmunología , Depleción Linfocítica , Linfopenia/genética , Linfopenia/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Fenotipo , ARN Mensajero/biosíntesis , Análisis de SupervivenciaAsunto(s)
Enfermedades Autoinmunes/epidemiología , Trastorno Obsesivo Compulsivo/epidemiología , Infecciones Estreptocócicas/epidemiología , Enfermedades Autoinmunes/tratamiento farmacológico , Preescolar , Comorbilidad , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Terminología como Asunto , Síndrome de Tourette/tratamiento farmacológico , Síndrome de Tourette/epidemiologíaRESUMEN
Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.
Asunto(s)
Antígenos HLA/inmunología , Esquizofrenia Infantil/inmunología , Adolescente , Adulto , Niño , Femenino , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Antígenos HLA-D/inmunología , Humanos , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS). METHOD: The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities. RESULTS: The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure. CONCLUSIONS: The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Trastorno Obsesivo Compulsivo/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Streptococcus pyogenes/inmunología , Trastornos de Tic/diagnóstico , Enfermedad Aguda , Edad de Inicio , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/epidemiología , Enfermedades del Sistema Nervioso Central/inmunología , Niño , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/epidemiología , Preescolar , Comorbilidad , Femenino , Humanos , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiología , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/inmunología , Faringitis/diagnóstico , Faringitis/etiología , Faringitis/inmunología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/inmunología , Índice de Severidad de la Enfermedad , Infecciones Estreptocócicas/complicaciones , Infecciones Estreptocócicas/inmunología , Trastornos de Tic/etiologíaRESUMEN
This study examines cerebrospinal fluid from patients with three neuropsychiatric diseases of childhood for the presence and levels of several cytokines relevant to cell-mediated (type 1) and humoral (type 2) immunity. The patient groups include childhood-onset schizophrenia (n = 22), obsessive-compulsive disorder (OCD) (n = 24), and attention deficit hyperactivity disorder (n = 42). The cytokines examined include IL-2, IFN-gamma, TNF-beta/LT, IL-4, IL-5, IL-10, and TNF-alpha. Patients with OCD had a preponderance of type 1 cytokines. IL-4 was detectable only in samples from patients with schizophrenia. IL-10 was rarely detected and never in patients with OCD. Few patients with schizophrenia had detectable amounts of IFN-gamma in CSFL. We conclude that there is a relative skewing of CSFL profiles toward type 1 cytokines in patients with OCD, whereas in schizophrenia the relative preponderance is toward type 2 mediators. Patients with attention deficit hyperactivity disorder exhibited profiles intermediate between OCD and schizophrenia. We infer that cell-mediated immunity may be involved in the etiopathogenesis of OCD, whereas a relative lack of cell-mediated immunity and involvement of humoral immunity may be present in schizophrenia. These data provide a rationale for immune-based strategies of study and therapeutics in childhood neuropsychiatric disease.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/líquido cefalorraquídeo , Citocinas/líquido cefalorraquídeo , Trastorno Obsesivo Compulsivo/líquido cefalorraquídeo , Esquizofrenia Infantil/líquido cefalorraquídeo , Trastorno por Déficit de Atención con Hiperactividad/inmunología , Niño , Humanos , Inmunidad , Masculino , Trastorno Obsesivo Compulsivo/inmunología , Esquizofrenia Infantil/inmunologíaRESUMEN
OBJECTIVE: The authors' goal was to determine whether a trait marker of rheumatic fever susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychiatric disorders (obsessive-compulsive disorder and tic disorders) associated with streptococcal infections (PANDAS). METHOD: Blood samples obtained from 27 children with PANDAS, nine children with Sydenham's chorea, and 24 healthy children were evaluated for D8/17 reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells. RESULTS: The frequency of D8/17-positive individuals was significantly higher in both patient groups than it was among the healthy volunteers: 85% of the children with PANDAS and 89% of the children with Sydenham's chorea, compared with 17% of the healthy children, were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient groups and was significantly higher in these groups than in the group of healthy children. CONCLUSIONS: These results suggest that there may be a subgroup of D8/17-positive children who present with clinical symptoms of obsessive-compulsive disorder and Tourette's syndrome, rather than Sydenham's chorea, but who have similar poststreptococcal autoimmunity.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Biomarcadores , Corea/inmunología , Antígenos HLA-DR/inmunología , Subgrupos Linfocitarios/inmunología , Trastorno Obsesivo Compulsivo/diagnóstico , Fiebre Reumática/inmunología , Infecciones Estreptocócicas/inmunología , Adolescente , Anticuerpos Monoclonales/inmunología , Enfermedades Autoinmunes/inmunología , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Fiebre Reumática/genéticaAsunto(s)
Enfermedades Autoinmunes/etiología , Corea/etiología , Citocinas/fisiología , Trastorno Obsesivo Compulsivo/etiología , Infecciones Estreptocócicas/complicaciones , Streptococcus pyogenes , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Niño , Corea/inmunología , Citocinas/clasificación , Humanos , Trastorno Obsesivo Compulsivo/inmunología , Infecciones Estreptocócicas/inmunología , Streptococcus pyogenes/inmunología , Streptococcus pyogenes/patogenicidadRESUMEN
Experimental SLE can be induced in susceptible 129/J mice by immunization with a human anti-DNA antibody bearing a common idiotype designated 16/6 Id. Immunized mice develop autoantibodies, leukopenia, proteinuria, and immune complex deposits in renal glomeruli. Case reports have described clinical improvement in SLE in individuals becoming infected with HIV-1. Because 129/J mice are susceptible to experimental SLE and to infection with the BM5def murine leukemia virus (MuLV) mixture but do not develop the lymphoproliferative/ immunodeficiency disorder known as murine AIDS (MAIDS), we superimposed this infection on immunization with the 16/6 Id. Multiple effects were observed. First, we noted an amelioration in the course of experimental SLE. Second, both in experimental SLE and in BM5def MuLV infection, immunoreactivity to HIV-1 gp120 was demonstrated, although gp120 is not present in the BM5def MuLV viruses. Third, production of autoantibodies characteristically found in SLE, e.g., anti-DNA, anti-RNP, and anti-SSA, was seen in BM5def MuLV-infected mice, demonstrating that an immune response as a consequence of infection had occurred despite the absence of MAIDS induction. We conclude that (1) retrovirus inoculation may ameliorate the course of experimental SLE; and (2) retrovirus inoculation, even in the absence of MAIDS induction, induces an immunologic response which promotes the production of potentially pathogenic autoantibodies.
Asunto(s)
Lupus Eritematoso Sistémico/complicaciones , Infecciones por Retroviridae/complicaciones , Animales , Complejo Antígeno-Anticuerpo/análisis , Autoanticuerpos/biosíntesis , Autoanticuerpos/efectos de los fármacos , Femenino , Proteína gp120 de Envoltorio del VIH/sangre , Inmunohistoquímica , Riñón/inmunología , Leucopenia/etiología , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Endogámicos , Síndrome de Inmunodeficiencia Adquirida del Murino/complicaciones , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Infecciones por Retroviridae/inmunologíaRESUMEN
Targeted disruption of the transforming growth factor-beta 1 (TGF-beta 1) gene in mice results in the development of a massive multifocal inflammatory disease in many tissues. Because no detectable pathogen was identified, we examined whether autoimmune mechanisms played a role in initiating or maintaining the inflammatory disease. The serum of TGF-beta 1 knockout mice contained elevated titers of antibodies to nuclear antigens (ssDNA, dsDNA, Sm, and RNP) as well as reactivity against the 16/6 idiotype (16/6 Id). In addition, Ig deposits were detected in renal glomeruli of TGF- beta 1 knockout mice. Transplantation of TGF-beta 1 knockout hematopoietic cells into normal irradiated recipients resulted in a similar profile of autoantibody production as well as in the induction of inflammatory lesions. Our results describe autoimmune activity that ensues when the TGF-beta 1 cytokine is absent.
Asunto(s)
Enfermedades Autoinmunes/genética , Factor de Crecimiento Transformador beta/fisiología , Animales , Anticuerpos Antinucleares/inmunología , Autoanticuerpos/inmunología , Trasplante de Células Madre Hematopoyéticas , Enfermedades del Complejo Inmune/genética , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Patients with systemic lupus erythematosus (SLE) are known to have defects in both humoral and cellular immunity. The significance of defective T cell-mediated immunity and its relationship to disease activity have not been clearly established. We studied in vitro T helper cell (Th) function in 150 SLE outpatients and correlated Th function with validated measures of disease activity. Interleukin 2 (IL-2) production by peripheral blood mononuclear cells (PBMC) was measured after stimulation with the recall antigens influenza A virus (FLU) and tetanus toxoid (TET), irradiated allogeneic peripheral blood mononuclear cells (ALLO), and phytohemagglutinin (PHA). We observed three patterns of Th response: (1) 76 of 150 (50%) of patients responded to the recall antigens FLU and/or TET, ALLO, and PHA; (2) 62 of 150 (42%) of patients did not respond to recall antigens but responded to ALLO and PHA; and (3) 12 of 150 (8%) of patients did not respond to either recall antigens or ALLO antigens. This diminished T cell function was correlated with higher disease activity as measured by four scales of clinical activity, such that individuals who exhibited more in vitro immune dysfunction presented with significant increases in their clinical activity indices. The alterations in T cell function could not be accounted for by medication doses alone. Thus, SLE patients have multiple distinct defects at the level of the Th cell which are associated with clinical measures of disease activity.
Asunto(s)
Lupus Eritematoso Sistémico/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Antígenos Virales/inmunología , Relación CD4-CD8 , Femenino , Humanos , Virus de la Influenza A/inmunología , Interleucina-2/biosíntesis , Isoantígenos/inmunología , Lupus Eritematoso Sistémico/patología , Activación de Linfocitos/inmunología , Masculino , Fitohemaglutininas/inmunología , Linfocitos T Colaboradores-Inductores/patología , Toxoide Tetánico/inmunologíaRESUMEN
OBJECTIVE: To investigate the relationship between L-tryptophan (LT) ingestion and eosinophilic fasciitis (EF) occurring prior to the outbreak of eosinophilia-myalgia syndrome in 1989. METHODS: Interviews and record reviews of 45 EF case-patients and 126 polymyositis patients (controls) diagnosed prior to 1988. RESULTS: Nine case-patients (20%) and no controls recalled taking LT before onset of the disease (odds ratio = infinity, 95% confidence interval = 8.3-infinity). Among EF case-patients, LT ingestion was associated with dyspnea. CONCLUSION: LT ingestion was associated with EF prior to the 1989 outbreak of eosinophilia-myalgia syndrome. Lung abnormalities may be a distinguishing feature of LT-mediated illness.
Asunto(s)
Brotes de Enfermedades , Síndrome de Eosinofilia-Mialgia/epidemiología , Eosinofilia/inducido químicamente , Fascitis/inducido químicamente , Triptófano/efectos adversos , Estudios de Casos y Controles , Síndrome de Eosinofilia-Mialgia/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miositis/diagnóstico , Triptófano/administración & dosificaciónRESUMEN
5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole, an adenosine analogue, has been used previously as an inhibitor of heterogeneous nuclear and messenger RNA synthesis. In an in vitro transcriptional system, we have detected inhibition of synthesis of full-length runoff RNAs at concentrations at which in vivo mRNA synthesis is inhibited. By hybridization of RNA synthesized in vitro to single-stranded DNA and gel analysis, we were able to reduce the background of the transcription reaction, detect DRB-induced inhibition of full-length runoff RNAs and DRB-insensitive transcription of short RNAs. To establish further the effect of DRB on initiation of transcription, preincubation experiments with template, whole cell extract and two initial nucleotides of the transcript were performed. Elongation was then measured as discrete-sized RNAs transcribed from the truncated template after addition of the other triphosphates (one of them labeled), in the presence or absence of DRB. An effect on initiation but not on elongation or termination was detected. Fingerprint analysis of these runoff RNAs indicates that the labeling of U in the presence of DRB is uniform throughout the molecule. A model to explain a novel interpretation of the action of DRB is presented.
Asunto(s)
Diclororribofuranosil Benzoimidazol/farmacología , Ribonucleósidos/farmacología , Transcripción Genética/efectos de los fármacos , Adenoviridae/genética , Secuencia de Bases , ADN Viral/genética , Electroforesis en Gel de Poliacrilamida , Modelos Genéticos , Hibridación de Ácido Nucleico , Operón/efectos de los fármacos , Plásmidos , ARN Polimerasa II/genética , ARN Viral/biosíntesis , ARN Viral/genética , Moldes GenéticosRESUMEN
To determine the role of DRB in transcription, we isolated a resistant (DRBR) HeLa cell mutant. After mutagenesis with N-methyl-N'-nitro-nitrosoguanidine, cell colonies able to grow at 20 micrograms DRB/ml (63 microM) were selected. One of these colonies, DRBR-1, was stable and able to grow at concentrations of DRB three to five times higher than tolerated by normal HeLa cells. The DNA of DRBR-1 was able to confer resistance to DRB to other HeLa cells by transfection. Uridine uptake was reduced by DRB to a similar extent in both wild-type and mutant cells. In contrast, transcription in the mutant cells, as measured by [3H]uridine incorporation into RNA in short pulses, was resistant to DRB. Cell-free extracts prepared from DRBR-1 cells are able to transcribe the epsilon-globin or the adenovirus 2 major late promoter genes at DRB concentrations that eliminate the transcriptional activity of HeLa cell extracts. Thus the transcriptional machinery of the mutant is altered. The presence of both DRB-resistant and DRB-sensitive transcriptional activities in extracts from DRBR-1 cells, grown in the presence of the drug, suggests constitutive expression of this cellular component. Efficient somatic cell hybridization with an alpha-amanitin-resistant RNA polymerase II mouse mutant indicates cross-complementation in vivo. This DRBR mutant provides a useful tool for the biochemical analysis of the mechanism of action of DRB on transcription. It also serves as a genetic handle for selection of the gene responsible for DRB resistance.
Asunto(s)
Diclororribofuranosil Benzoimidazol/farmacología , Mutación , Ribonucleósidos/farmacología , Transcripción Genética/efectos de los fármacos , Adenovirus Humanos/genética , Clonación Molecular , Enzimas de Restricción del ADN , Resistencia a Medicamentos , Genes Virales , Células HeLa/citología , Células HeLa/efectos de los fármacos , Humanos , Microscopía de Contraste de Fase , Operón , ARN/biosíntesis , TransfecciónRESUMEN
The adenosine analog 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) and its mono- and triphosphate derivatives inhibit RNA polymerase II-specific transcription in an extract of whole HeLa cells. The analog does not inhibit RNA polymerase III-specific adenovirus VA RNA transcription in the whole cell extract. With purified RNA polymerase II under nonspecific transcription conditions, no effect on DRB could be detected. DRB is equally effective in inhibiting in vitro transcription from several of the adenovirus promoters and the human epsilon-globin gene. The inhibitory effects are in the order DRB greater than DRB monophosphate greater than DRB triphosphate. Thus DRB acts in vitro presumably on systems in which specific RNA polymerase II initiation of transcription occurs and with no detectable effect on premature termination. This will provide a suitable model for study of the molecular mechanism of action of DRB on transcription.