RESUMEN

OBJECTIVE: Immunosuppressive agents have become the standard of therapy for proliferative lupus nephritis, but some patients may relapse after discontinuing treatment. We reviewed the cases of renal flares in a cohort of patients who participated in 2 randomized controlled clinical trials at the National Institutes of Health and explored the prevalence, outcome, and predictive factors of renal flares. METHODS: Data were obtained on 145 patients treated with pulse cyclophosphamide, pulse methylprednisolone, or the combination of both. Patients had not received immunosuppressive therapy for at least 6 months and had experienced complete or partial response according to defined criteria. Renal flares were classified as either proteinuric or nephritic based on changes in urinary protein and sediment. Most patients who experienced a flare received additional immunosuppressive therapy. RESULTS: Seventy-three patients had a complete response, and 19 had partial response/stabilization. Forty-one of these patients (45%) experienced renal flares (nephritic in 33, proteinuric in 8) after a mean followup of 117 months; 31 of them received additional immunosuppressive therapy. The median time to renal flare was 36 months in the complete responders and 18 months in the partial responders. Eleven of the 41 patients (27%) progressed to end-stage renal disease (ESRD); 9 had nephritic flares (all severe except for 1) and 2 had proteinuric flares (1 in each responder group). Compared with patients who had a complete response, those with a partial response were more likely to experience a flare, to have a severe nephritic flare, or to progress to ESRD. Low C4 at the time of response and African American ethnicity were significant independent risk factors for renal flare, by multivariate Cox proportional hazards analysis. CONCLUSION: Nephritic flares are common in patients with proliferative lupus nephritis, even in those with a complete response to therapy, but they do not necessarily result in loss of renal function if treated with additional immunosuppressive agents. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials.

Asunto(s)

Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/mortalidad , Adulto , Antiinflamatorios/administración & dosificación , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Fallo Renal Crónico/mortalidad , Masculino , Metilprednisolona/administración & dosificación , Valor Predictivo de las Pruebas , Prevalencia , Quimioterapia por Pulso , Recurrencia , Resultado del Tratamiento

RESUMEN

BACKGROUND: Controlled trials in lupus nephritis have demonstrated that cyclophosphamide therapy is superior to corticosteroid therapy alone. The long-term effectiveness and side-effect profiles of pulse immunosuppressive regimens warrant further study. OBJECTIVE: To define the long-term risk and benefit of monthly treatment with boluses of methylprednisolone, cyclophosphamide, or both. DESIGN: Extended follow-up (median, 11 years) of a randomized, controlled trial. SETTING: U.S. government research hospital. PATIENTS: 82 patients with proliferative lupus nephritis. MEASUREMENTS: Rates of treatment failure (defined as need for supplemental immunosuppressive therapy or doubling of serum creatinine concentration, or death) and adverse events. RESULTS: In an intention-to-treat survival analysis, the likelihood of treatment failure was significantly lower in the cyclophosphamide (P = 0.04) and combination therapy (P = 0.002) groups than in the methylprednisolone group. Combination therapy and cyclophosphamide therapy alone did not differ statistically in terms of effectiveness or adverse events. Of patients who completed the protocol (n = 65), the proportion of patients who had doubling of serum creatinine concentration was significantly lower in the combination group than in the cyclophosphamide group (relative risk, 0.095 [95% CI, 0.01 to 0.842]). CONCLUSION: With extended follow-up, pulse cyclophosphamide continued to show superior efficacy over pulse methylprednisolone alone for treatment of lupus nephritis. The combination of pulse cyclophosphamide and methylprednisolone appears to provide additional benefit over pulse cyclophosphamide alone and does not confer additional risk for adverse events.

Asunto(s)

Antiinflamatorios/administración & dosificación , Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Metilprednisolona/administración & dosificación , Adulto , Antiinflamatorios/efectos adversos , Creatinina/sangre , Ciclofosfamida/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/efectos adversos , Infusiones Intravenosas , Nefritis Lúpica/sangre , Nefritis Lúpica/mortalidad , Masculino , Metilprednisolona/efectos adversos , Prednisona/uso terapéutico , Inducción de Remisión , Análisis de Supervivencia , Insuficiencia del Tratamiento

RESUMEN

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by diverse cellular and biochemical aberrations, including decreased production of IL-2. Here we show that nuclear extracts from unstimulated SLE T cells, unlike extracts from normal T cells, express increased amounts of phosphorylated cAMP-responsive element modulator (p-CREM) that binds the -180 site of the IL-2 promoter. Nuclear extracts from stimulated normal T cells display increased binding of phosphorylated cAMP-responsive element binding protein (p-CREB) to the -180 site of the IL-2 promoter, whereas nuclear extracts from stimulated SLE T cells display primarily p-CREM and decreased p-CREB binding. In SLE T cells, p-CREM bound to the transcriptional coactivators, CREB binding protein and p300. Increased expression of p-CREM correlated with decreased production of IL-2. The transcription of a reporter gene driven by the -180 site was enhanced in normal T cells, but was suppressed in SLE T cells. These experiments demonstrate that transcriptional repression is responsible for the decreased production of IL-2 by SLE T cells.

Asunto(s)

Interleucina-2/biosíntesis , Interleucina-2/deficiencia , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Regiones no Traducidas 5'/metabolismo , Adulto , Anciano , Proteína de Unión a CREB , Modulador del Elemento de Respuesta al AMP Cíclico , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/fisiología , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Femenino , Estudios de Seguimiento , Humanos , Interleucina-2/genética , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/metabolismo , Sustancias Macromoleculares , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas/inmunología , Unión Proteica/genética , Unión Proteica/inmunología , Proteínas Represoras/biosíntesis , Proteínas Represoras/metabolismo , Proteínas Represoras/fisiología , Transactivadores/metabolismo

RESUMEN

Laser technology has advanced dramatically and is an integral part of the healthcare delivery systems of today. Lasers are used in laboratory analyses of human blood samples and serve as surgical tools that kill, burn or cut tissue. Recent semiconductor microtechnology has reduced the laser size to the size of a biological cell or even a virus particle. The integration of these ultra-small lasers with biological systems makes it possible to create microelectrical mechanical systems that might revolutionize healthcare delivery.

Asunto(s)

Terapia por Láser , Rayos Láser , Astrocitos/citología , Astrocitos/metabolismo , Biotecnología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Ciclo Celular , División Celular , Diseño de Equipo , Eritrocitos/química , Hemoglobinas/análisis , Humanos , Neoplasias/diagnóstico , Neoplasias/patología , Proteínas/análisis

RESUMEN

OBJECTIVE: To determine if clinically asymptomatic knee joints in patients with recent onset arthritis reveal histological evidence of synovitis. METHODS: As part of a prospective study of patients with synovitis of less than one year duration, we performed blind needle biopsies on the knees of 20 patients who had synovitis elsewhere but no symptoms or detectable swelling or tenderness of the biopsied joint. RESULTS: Histologic evidence of synovitis was observed in 11 knees (55%). All patients with synovitis had evidence of synovial lining cell hyperplasia, increased vascularity, and lymphocytic infiltrates. Five of 6 patients with rheumatoid arthritis (RA) and 5 of 8 with undifferentiated arthritis had histological evidence of synovitis, but none of the 5 with reactive arthritis (ReA) had synovitis in the asymptomatic joints. Histologic evidence of synovitis persisted in some after clinical resolution of previous pain and swelling, while it occurred in others with no history of previous involvement of that knee. CONCLUSION: Even asymptomatic joints in patients with RA and undifferentiated arthritis of recent onset reveal histologic signs of synovitis. The earliest changes may occur before symptoms. Histologic changes also persist after resolution of previous early symptoms. Evidence of inflammation was not present in asymptomatic joints in our 5 patients diagnosed with ReA.

Asunto(s)

Artritis Reactiva/complicaciones , Artritis Reumatoide/complicaciones , Articulación de la Rodilla/patología , Sinovitis/etiología , Adulto , Artritis Reactiva/patología , Artritis Reumatoide/patología , Biopsia con Aguja , Vasos Sanguíneos/patología , Femenino , Humanos , Hiperplasia/patología , Linfocitos/patología , Masculino , Monocitos/patología , Neovascularización Patológica/patología , Neutrófilos/patología , Células Plasmáticas/patología , Prohibitinas , Estudios Prospectivos , Membrana Sinovial/irrigación sanguínea , Membrana Sinovial/patología , Sinovitis/patología

RESUMEN

The presence of the D (deletion) allele at the angiotensin converting enzyme (ACE) gene has been associated with a) adverse vascular events contributing to early mortality and b) progressive deterioration of renal function in a variety of chronic glomerular diseases. We investigated the potential role of ACE polymorphisms in patients with systemic lupus erythematosus (SLE). Two hundred and sixteen (216) SLE patients (121 Caucasians; 78 African Americans; and 17 other) and 200 normal controls were studied; 134 patients had evidence of renal disease. ACE genotypes were determined by a polymerase chain reaction based assay. The frequency of genotype DD was increased in African American normal controls compared to Caucasians (55% vs. 37%, p = 0.017) and in African American normal controls vs. African American lupus patients (55% vs. 30%, p = 0.008). Trend analysis of the genotype distribution across the three African American groups (renal, non-renal, controls) revealed a trend of increased frequency of I and decreased frequency of D as likelihood of renal disease increases (p = 0.008). No association between any ACE genotype with parameters of renal disease and/or response to therapy was identified. African American patients with lupus have a lower frequency of DD genotype as compared to African American normal controls. Further studies will be necessary to address whether this is due to decreased survival of these patients, a protective effect of DD genotype from developing the disease or a chance sample effect.

Asunto(s)

Alelos , Población Negra/genética , Eliminación de Gen , Lupus Eritematoso Sistémico/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/genética , Adulto , Análisis de Varianza , Distribución de Chi-Cuadrado , Femenino , Genotipo , Humanos , Lupus Eritematoso Sistémico/epidemiología , Masculino , Prevalencia , Población Blanca/genética

RESUMEN

OBJECTIVE: To assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis. METHODS: Thirty patients with refractory myositis, of whom 25 had an inadequate or no response to previous cytotoxic therapy, were randomized to begin either a combination of weekly oral methotrexate and daily azathioprine (MTX/AZA) or intravenous methotrexate with leucovorin rescue (I.V. MTX) every 2 weeks for 6 months. Crossover to the alternate therapy occurred according to defined rules; evaluations of muscle strength and functional abilities were performed at the beginning, and after 3 and 6 months, of each treatment. RESULTS: Of the 15 patients initially randomized to oral MTX/AZA, 8 improved with oral therapy and 1 improved with I.V. MTX during the crossover period. Of the 15 patients initially randomized to I.V. MTX therapy, 3 improved with the I.V. therapy and 4 with the oral combination during the crossover period. Although the study lacked the power to directly compare both treatments, intention-to-treat analysis showed a trend in favor of those patients who first received oral combination therapy (P = 0.025). There were 0.09 adverse events per patient-month with oral combination therapy and 0.16 per patient-month with I.V. therapy (P = 0.09). CONCLUSION: Combination oral MTX/AZA may benefit patients with treatment-resistant myositis, including those who previously had inadequate responses to either MTX or AZA alone. I.V. MTX with leucovorin rescue may also benefit some patients with refractory myositis.

Asunto(s)

Antimetabolitos Antineoplásicos/uso terapéutico , Antirreumáticos/uso terapéutico , Azatioprina/uso terapéutico , Leucovorina/uso terapéutico , Metotrexato/uso terapéutico , Miositis/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Azatioprina/efectos adversos , Estudios Cruzados , Quimioterapia Combinada , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Terapia Recuperativa

RESUMEN

Autoantibodies to the collagen-like region of the first complement component (C1qAB) are found in patients with systemic lupus erythematosus (SLE), particularly those with renal disease. In a cohort of 46 SLE patients with diffuse proliferative glomerulonephritis, we found declining C1qAB titers in 77% of treatment responders and in only 38% of treatment non-responders (P < 0.03). To further characterize this autoantibody, we tested 240 SLE patients for the presence of C1qAB. Positive titers were found in 44% of patients with renal disease and 18% of patients without renal disease (chi2 P < 0.0003). Analysis of IgG subclass revealed IgG2 C1qAB alone in 34%, IgG1 C1qAB alone in 20%, and both IgG1 and IgG2 in 46% of patients. Fewer than 10% of patients had measurable titers of IgG3 or IgG4 C1qAB. The pathogenic role of these IgG2-skewed C1qAB may relate to impaired immune complex clearance by the mononuclear phagocyte system: IgG2 antibodies are efficiently recognized by only one IgG receptor, the H131 allele of Fc gamma RIIa (Fc gamma RIIa-H131). In contrast, Fc gamma RIIa-R131, which is characterized by minimal IgG2 binding, has recently been associated with lupus nephritis. In our C1qAB positive patients, the presence of Fc gamma RIIA-R131 was associated with an increased risk for renal disease. Autoantibodies to C1q may have pathogenic significance in SLE patients with genetic defects in the ability to clear IgG2 containing immune complexes.

Asunto(s)

Alelos , Autoanticuerpos/sangre , Complemento C1q/inmunología , Lupus Eritematoso Sistémico/inmunología , Receptores de IgG/genética , Adulto , Anciano , Autoanticuerpos/clasificación , Estudios Transversales , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad

RESUMEN

It has been reported that the mRNA of the type 1 cytokine, interferon-gamma (IFN-gamma)--but not the type 2 cytokine interleukin-4 (IL-4)--is detected in synovial tissues of rheumatoid arthritis (RA) patients, whereas both IFN-gamma and IL-4 mRNA are detected in reactive arthritis (ReA). To evaluate such data more extensively, we obtained 208 synovial specimens in a prospective study of 52 early synovitis patients (13 RA, 11 ReA, 28 undifferentiated oligoarthropathy) and analyzed type 1 and type 2 cytokine mRNA expression in specimens containing sufficient mRNA. Using a nested reverse transcriptase polymerase chain reaction technique, we measured the relative mRNA levels of 10 cytokines and CD3 delta chain. We detected IL-10, IL-15, and CD3 delta chain mRNA in all RA and ReA patients and frequently detected tumor necrosis factor-alpha, IL-1 beta, and IFN-gamma mRNA. IL-6 and IL-12 p40 mRNA were detected in approximately one-half of the patients. We also detected greater amounts of IL-2 and IFN-gamma mRNA in ReA than were detected in RA. However, we rarely detected IL-4 or IL-13 mRNA. Similar cytokine profiles were observed in undifferentiated oligoarthropathy. The amounts of cytokine mRNAs, except for IL-10, in specimens from the patients taking prednisone or second-line antirheumatic drugs tended to be less than in specimens from the patients taking neither prednisone nor second-line antirheumatic drugs. These results suggest that cytokine mRNA profiles in patients with RA, ReA, and undifferentiated arthritis in their early stages are skewed toward proinflammatory macrophage-derived and type 1 cytokines. IL-10--not IL-4 or IL-13--mRNA appears to be the major antiinflammatory cytokine mRNA. Drug therapy is associated with depressed proinflammatory and type 1 cytokine mRNA production. The differences in the expression of IL-2 and IFN-gamma mRNA between RA and ReA may reflect unique etiological or host factors associated with the early stages of these diseases.

Asunto(s)

Artritis Reumatoide/inmunología , Citocinas/genética , Expresión Génica , Membrana Sinovial/inmunología , Adulto , Anciano , Artritis Reumatoide/genética , Citocinas/inmunología , ADN Complementario/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prohibitinas , ARN Mensajero/análisis

RESUMEN

BACKGROUND: Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis. OBJECTIVE: To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone. DESIGN: Randomized, controlled trial with at least 5 years of follow-up. SETTING: Government referral-based research hospital. PATIENTS: 82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (> 1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis. INTERVENTIONS: Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or bolus therapy with both methylprednisolone and cyclophosphamide. MEASUREMENTS: 1) Renal remission (defined as < 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of < 1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis. RESULTS: Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41% of the cyclophosphamide group, 43% of the combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11% of the cyclophosphamide group. 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in 15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group. 32% of the combination therapy group, and 7.4% of the methylprednisolone group). CONCLUSIONS: Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen.

Asunto(s)

Antiinflamatorios/uso terapéutico , Ciclofosfamida/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Metilprednisolona/uso terapéutico , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Tablas de Vida , Masculino , Metilprednisolona/administración & dosificación , Metilprednisolona/efectos adversos , Persona de Mediana Edad , Inducción de Remisión

RESUMEN

OBJECTIVE: To compare the phenotype and frequency of cells that actively secrete type 1 and type 2 cytokines in systemic lupus erythematosus (SLE) patients (n = 46), versus normal controls (n = 60). METHODS: ELISPOT analysis of freshly isolated peripheral blood mononuclear cells (PBMC). RESULTS: T cells were the major source of interleukin-2 (IL-2), IL-4, and interferon gamma (IFN gamma), whereas monocytes were the primary source of IL-6 and IL-10 in the PB of lupus patients. Significantly fewer PBMC spontaneously secreted IFN gamma and IL-2 (P > or = 0.03), while significantly more PBMC produced IL-6 and IL-10 (P < 0.001), in lupus patients versus controls. Disease severity in lupus patients correlated with an elevated ratio of IL-1O:IFN gamma-secreting cells (P < 0.001). CONCLUSION: SLE is characterized by an imbalance in the ratio of type 1:type 2 cytokine-secreting PBMC.

Asunto(s)

Interferón gamma/sangre , Interleucina-10/metabolismo , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/metabolismo , Adulto , Citocinas/biosíntesis , Citocinas/metabolismo , Citocinas/farmacología , Femenino , Humanos , Técnicas para Inmunoenzimas , Inmunofenotipificación , Interleucina-10/sangre , Interleucina-2/sangre , Interleucina-2/metabolismo , Interleucina-6/sangre , Interleucina-6/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Fitohemaglutininas/farmacología , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Linfocitos T/efectos de los fármacos

RESUMEN

Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.

Asunto(s)

Población Negra/genética , Nefritis Lúpica/etiología , Receptores de IgG/genética , Alelos , Humanos , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Proyectos Piloto , Receptores de IgG/fisiología , Factores de Riesgo

RESUMEN

Skin involvement is common in patients with SLE, and in some cases is related to the menstrual period. We describe the clinical course of 3 patients with menstrual related rashes who experienced a significant improvement from their skin disease after the initiation of oral contraceptives. The potential role of hormones in the manifestations of SLE is discussed.

Asunto(s)

Anticonceptivos Orales/uso terapéutico , Dermatitis/tratamiento farmacológico , Dermatitis/etiología , Congéneres del Estradiol/uso terapéutico , Etinilestradiol/uso terapéutico , Lupus Eritematoso Sistémico/complicaciones , Adolescente , Niño , Dermatitis/patología , Combinación de Medicamentos , Femenino , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Ciclo Menstrual , Norgestrel/uso terapéutico

RESUMEN

Retroviruses have been implicated in the pathogenesis of murine and human lupus; however, many positive findings have been followed by alternative explanations. Initial findings implicating xenotropic retroviruses were subsequently invalidated. The first solid demonstration that endogenous retroviruses mediate disease was the study of SL/Ni mice. Here budding ecotropic retroviral particles from arterial smooth muscle cells caused an antibody response to the particles with subsequent complement deposition. Our laboratory has focused on derangements in endogenous MCF retroviral expression. We found that lupus-prone NZB, BXSB and MRL strains have a marked increase in expression of Mpmv RNA in their thymuses while bone marrow expression did not differ from normal strains. Sequence analysis demonstrated mutations in the NZB endogenous retroviruses which could alter expression. A phosphorothioate antisense oligonucleotide to the initiation sequence of Mpmv caused lymphocyte activation in vivo in normal mice, providing further evidence for in vivo effects of Mpmv and potential for pathological abnormalities in lupus-prone strains.

Asunto(s)

Enfermedades Autoinmunes/virología , Retroviridae/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Humanos , Lupus Eritematoso Sistémico/virología , Ratones , Oligonucleótidos Antisentido , Retroviridae/genética

Asunto(s)

Lupus Eritematoso Sistémico/terapia , Humanos , Lupus Eritematoso Sistémico/inmunología , Educación del Paciente como Asunto , Factores de Riesgo

RESUMEN

Previous in vitro studies had suggested that a product of the env gene of murine MCF (polytropic)-related sequences plays a role in regulating lymphocyte activation. To determine whether such an effect occurs in vivo, we have studied mice injected with phosphorothioate oligonucleotides antisense to such sequences. Injection of mice with antisense to the initiation region of the env gene resulted in (i) increased spleen cell numbers, primarily due to an increase in splenic B cells, (ii) increased class II MHC expression on B cells, (iii) increased RNA and DNA synthesis, and (iv) increased numbers of Ig producing cells. These results obtained with the antisense to MCF-related env did not occur with two scrambled phosphorothioate oligonucleotides or with antisense oligonucleotides to the initiation region of the env gene of xenotropic or ecotropic retroviral sequences. These data suggest that products of certain endogenous retroviral sequences regulate lymphocyte activation in vivo.

Asunto(s)

Linfocitos B/inmunología , Genes env , Activación de Linfocitos , Virus Inductores de Focos en Células del Visón/genética , Oligonucleótidos Antisentido/farmacología , Tionucleótidos/farmacología , Animales , Secuencia de Bases , Células Cultivadas , ADN/biosíntesis , Antígenos de Histocompatibilidad Clase II/análisis , Inmunoglobulinas/biosíntesis , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , ARN/biosíntesis , Bazo/inmunología

RESUMEN

This study examines the expression of human endogenous retroviral or retroviral-like (ERV) sequences in peripheral blood mononuclear cells (PBMC). Probes to 12 human ERV were used in Northern analyses of 38 patients with autoimmune muscle diseases and 31 blood donor controls. All patients and controls expressed multiple classes of ERV RNA. This expression was quite heterogenous: for each of the nine ERV classes for which expression was detected, some individuals showed high RNA levels whereas others showed low levels. ERV expression was independent of disease and autoantibody production. Statistical analysis of densitometric data indicated that expression of several classes of ERV was coordinately regulated. ERV expression in individual patients showed coordinate fluctuations with time. These studies demonstrate the heterogeneity and coordinate regulation of human ERV expression. To evaluate whether ERV expression might be affected by lymphocyte activation, PBMC were cultured with or without lymphocyte mitogens before RNA extraction. These studies demonstrated complex changes in ERV expression after lymphocyte activation. Murine ERV have several immunoregulatory activities. If human ERV have analogous effects, their heterogeneous expression and association with lymphocyte activation may have important biologic consequences.

Asunto(s)

Leucocitos Mononucleares/microbiología , Retroviridae/genética , Enfermedades Autoinmunes/microbiología , Regulación Viral de la Expresión Génica , Humanos , Técnicas In Vitro , Leucocitos Mononucleares/inmunología , Activación de Linfocitos , Sondas Moleculares , ARN Viral/genética , Retroviridae/aislamiento & purificación

RESUMEN

The genomes of all organisms, from yeast to humans, contain thousands of endogenous retroviruses (ERV). In most species all or almost all ERV are noninfectious, but some ERV retain open reading frames capable of encoding proteins. RNA and proteins derived from ERV are expressed in humans and other species. Until recently, there was little evidence that this ERV expression resulted in any immunologic effects. Recent studies make it increasingly clear that some ERV have important immunologic effects. The immune effects of ERV expression raise the question of a possible pathogenic role in idiopathic autoimmune diseases. Interest in this question has been heightened by the observation that some infectious retroviruses cause manifestations of autoimmunity. Nonetheless, attempts to isolate infectious retroviruses from patients with idiopathic autoimmune diseases have generally failed. The possible role of ERV in idiopathic autoimmune diseases has not yet been fully explored. This review focuses on the known and the potential immune effects of ERV, especially as they may relate to autoimmune diseases.

Asunto(s)

Autoinmunidad , Retroviridae/inmunología , Animales , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Mapeo Cromosómico , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Ratones , Biosíntesis de Proteínas , Retroviridae/genética , Síndrome de Sjögren/genética , Síndrome de Sjögren/inmunología , Transcripción Genética

RESUMEN

We have insufficient data to guide us to the optimal timing of immunosuppression in the natural history of any autoimmune disease. Moreover, there are differences among the many autoimmune diseases and the many drugs available for use. Nevertheless, certain principles have emerged. Prophylactic non-specific immunosuppression prior to the onset of the immune-mediated process often is of minimal benefit. Vigorous immunosuppression shortly after the onset of the immune-mediated process is most effective; many agents are of benefit at such times. If the disease has progressed to substantial clinical involvement, certain drugs previously useful may no longer be effective. At such a time of moderately advanced clinical involvement, only selected agents may suppress the disease. With substantial loss of function of irreplaceable organs, or parts thereof, immunosuppression becomes progressively less effective. Such drugs can interfere with inflammatory processes, but are of little benefit after deletion of cells or scarring of an organ. Therefore, to have any benefit, immunosuppression must be instituted prior to the time of irreversible loss of critical organs or parts thereof.

Asunto(s)

Enfermedades Autoinmunes/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Animales , Esquema de Medicación , Femenino , Humanos , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Ratones , Ratones Endogámicos

RESUMEN

Systemic lupus erythematosus is an immune-mediated disease in which the etiology is unknown. Full-length (8.4 kb), type C, modified polytropic (Mpmv) retroviral transcripts from the thymus are characteristic of murine lupus. Reciprocal bone marrow transplantation studies determined that this thymic expression maps to the pre-T bone marrow stem cell. In vitro and in vivo oligonucleotide antisense work suggest that type C retroviruses play a role in immune activation. This paper summarizes our studies of endogenous retroviruses in murine lupus.

Asunto(s)

Lupus Eritematoso Sistémico/microbiología , Retroviridae/fisiología , Animales , Elementos sin Sentido (Genética) , Trasplante de Médula Ósea , Ratones , Retroviridae/genética , Retroviridae/metabolismo , Timo/microbiología , Transcripción Genética