RESUMEN

The study of systemic lupus erythematosus (SLE) is a challenging undertaking. It is difficult to assess outcomes in SLE randomized controlled trials (RCTs), and this is illustrated by the lack of new therapies approved for use in lupus. In a disease that is waxing and waning, and requires constantly changing medications, identifying treatment effects of new therapies may be difficult, and the use of potentially toxic therapies requires a rigorous understanding of the benefit to risk ratio. Some issues that need to be considered by the investigator in designing these studies include: 1) should the trial focus on patients with active or inactive disease; 2) which of the measures of disease activity should be used or should prevention of flares be examined; 3) should the study focus on defined organ specific endpoints or utilize one of the available disease activity indices to identify changes in disease activity; 4) should the trial be a superiority trial or an equivalence trial. This review summarizes the critical issues involving the design of studies in lupus and provides the reader with suggestions and recommendations for consideration before embarking on trials in this area.

Asunto(s)

Lupus Eritematoso Sistémico/terapia , Proyectos de Investigación/tendencias , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento

RESUMEN

Dysregulation of interleukin-2 (IL-2), the prototypical T cell growth factor and immunoregulatory cytokine, may modify self-tolerance and predisposition to autoimmunity. The available literature suggested that IL-2 could be hypothesized to either propagate or inhibit the development autoimmune demyelinating disorders of the central nervous system such as multiple sclerosis. Thus, the present study sought to test these competing hypotheses by examining whether disrupting one or both IL-2 gene alleles would render mice more or less vulnerable to experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein was used to induce EAE in C57BL/6-IL-2(-/-) knockout, C57BL/6-IL-2(+/-) heterozygote and C57BL/6-IL-2(+/+) wild-type mice. All of the wild-type and heterozygote mice developed signs of EAE compared with only 23% of the IL-2 knockout mice. Histopathological examination of lumbar spinal cord sections confirmed that subpial perivascular inflammatory infiltrates found in wild-type and heterozygote mice were absent in the unaffected IL-2 knockout mice. These data demonstrate that vulnerability to EAE is markedly reduced in C57BL/6 mice lacking IL-2, and suggest that this cytokine may play a critical role in autoimmune processes of the central nervous system.

Asunto(s)

Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/prevención & control , Eliminación de Gen , Predisposición Genética a la Enfermedad/prevención & control , Interleucina-2/genética , Animales , Femenino , Tamización de Portadores Genéticos , Homocigoto , Interleucina-2/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados

RESUMEN

Experimental autoimmune encephalomyelitis develops in mice immunized with CNS antigens. To elucidate the role that specific proinflammatory cytokines play in the induction of this process we examined the development of EAE in mice with targeted disruptions of the TNF p55 or p75 or the IL-1 p80 receptors. EAE developed in mice with either one or both TNF receptors deleted although the onset of disease in mice with the p55 receptor deleted was delayed. However, mice with a deletion of the IL-1 p80 receptor failed to develop any inflammatory lesions in the CNS or evidence of clinical EAE. Thus we conclude that TNF or its receptors contribute to, but are not necessary for, the induction of EAE while the IL-1 p80 receptor is absolutely required. The p55 TNF receptor plays a role in determining the onset of disease and its severity.

Asunto(s)

Encefalomielitis Autoinmune Experimental/etiología , Receptores de Interleucina-1/fisiología , Receptores del Factor de Necrosis Tumoral/fisiología , Animales , Ratones , Ratones Endogámicos C57BL , Índice de Severidad de la Enfermedad , Transducción de Señal

RESUMEN

In viable motheaten mice, a mutation in the gene encoding the phosphatase, SHP1, causes severe immunodeficiency and autoimmunity. A defective phosphatase may result in modified phosphorylation of proteins involved in gene regulation. Since the NFkappaB/IkappaB proteins are regulated through phosphorylation, we wished to understand if the expression of these proteins was altered by the SHP1 defect. Splenic B cells from viable motheaten mice were isolated and assessed for purity by flow cytometry. Levels of each protein in isolated B cells were examined by Western blot analyses. Measurement of RNA levels for each protein was assessed by semi-quantitative RT-PCR. Western blots revealed that, in me(v) whole cell lysates, there were reduced levels of RelA and RelB proteins and increased levels of p50 and c-Rel. Furthermore, we analyzed the protein levels of IkappaBalpha and found that, in me(v), this inhibitor was significantly reduced, while the level of another member of the IkappaB family, IkappaBbeta, was not. To determine if these findings in me(v) were secondary to the autoimmune process, we evaluated NF-kappaB/IkappaB expression in the BXSB murine model of autoimmunity. Unlike me(v), B cells from BXSB/Yaa mice had NF-kappaB complexes composed of the RelA submit, and IkappaBalpha was readily detected. In addition, RNA for the RelA and IkappaBalpha proteins in me(v) and control littermates was detected by RT-PCR, indicating that the reduced amounts of these proteins was not exclusively due to transcriptional defects. We conclude that the differences in NF-kappaB/IkappaB proteins that we have described in me(v) are likely a consequences of the SHP1 defect and could contribute to the clinical disorder that characterizes me(v) mice.

Asunto(s)

Enfermedades Autoinmunes/genética , Linfocitos B/metabolismo , Proteínas de Unión al ADN/biosíntesis , Regulación de la Expresión Génica/genética , Proteínas I-kappa B , Síndromes de Inmunodeficiencia/genética , FN-kappa B/biosíntesis , Proteínas Tirosina Fosfatasas/genética , Animales , Enfermedades Autoinmunes/enzimología , Enfermedades Autoinmunes/inmunología , Proteínas de Unión al ADN/genética , Células Madre Hematopoyéticas/enzimología , Células Madre Hematopoyéticas/patología , Síndromes de Inmunodeficiencia/enzimología , Síndromes de Inmunodeficiencia/inmunología , Péptidos y Proteínas de Señalización Intracelular , Ligasas/análisis , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Modelos Biológicos , Inhibidor NF-kappaB alfa , FN-kappa B/análisis , FN-kappa B/genética , Subunidad p50 de NF-kappa B , Fosforilación , Procesamiento Proteico-Postraduccional , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Proteínas Tirosina Fosfatasas/deficiencia , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas c-rel , ARN Mensajero/análisis , Bazo/inmunología , Factor de Transcripción ReIB , Factores de Transcripción/análisis , Transcripción Genética

RESUMEN

Sle1 is a potent autoimmune susceptibility locus on chromosome 1 originally identified in a genome scan of testcross progeny between the systemic lupus erythematosus-prone NZM2410 strain and C57BL/6. We subsequently produced B6.NZMc1, a congenic strain carrying the NZM2410-derived Sle1 genomic interval on the B6 background and demonstrated that Sle1 mediated the loss of tolerance to chromatin in both the B and T cell compartments. In this communication, we show by adoptive transfer experiments that the autoimmune phenotypes of Sle1 are completely reconstituted in B6 radiation chimeras receiving B6.NZMc1 bone marrow but not by the reciprocal reconstitution, demonstrating that Sle1 is functionally expressed in B cells. In additional experiments, cotransfer of mixtures of bone marrow derived from B6.NZMc1 and nonautoimmune congenic B6 mice carrying allelic T and B cell markers showed that only B cells derived from B6.NZMc1 bone marrow produced anti-chromatin autoantibodies. In contrast, increased expression of CD69 was equivalent in CD4+ T cells derived from either B6.NZMc1 or congenic B6 bone marrow, suggesting that either T cell population could be activated subsequent to loss of tolerance in the B cell compartment. These findings indicate that the expression of Sle1 in B cells is essential for the development of autoimmunity.

Asunto(s)

Traslado Adoptivo , Subgrupos de Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Tolerancia Inmunológica/genética , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/genética , Animales , Antígenos CD/biosíntesis , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Autoanticuerpos/biosíntesis , Autoantígenos/biosíntesis , Autoantígenos/inmunología , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/trasplante , Antígeno B7-2 , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea/inmunología , Linfocitos T CD4-Positivos/trasplante , Regulación de la Expresión Génica/inmunología , Marcadores Genéticos/inmunología , Inmunoglobulina G/biosíntesis , Inmunofenotipificación , Lectinas Tipo C , Lupus Eritematoso Sistémico/inmunología , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos NZB , Nucleosomas/inmunología , Nucleosomas/metabolismo , Subgrupos de Linfocitos T/metabolismo , Quimera por Trasplante/genética , Quimera por Trasplante/inmunología

RESUMEN

We analyzed the linkage of GN and a wide spectrum of serological phenotypes associated with systemic lupus erythematosus in a (NZM2410 x C57BL/6)F2 cross. Some phenotypes, such as glomerulonephritis (GN) and anti-chromatin IgG antibody production, were more penetrant in females, but others, such as anti-dsDNA antibody production, did not show a gender bias. These results suggest that gender bias affects only a subset of SLE-component phenotypes, and that NZM2410 can be used to dissect the genetic basis of this phenomenon. Genome scanning linked six chromosomal intervals with the expression of one or more component phenotypes. These loci included two Sle loci previously identified in an (NZM2410 x B6)F1 x NZM2410 backcross, loci identified by others in the NZB/W model. Our analysis also suggested two new intervals on chromosomes (Chrs.) 10 and 11. Detailed analysis of the segregation of different phenotypes within these intervals suggests that they encompass more than one susceptibility locus. This clustering has been a common finding in several murine polygenic traits. Each of NZM2410 susceptibility loci can be aligned with a specific genetic pathways contributing to SLE pathogenesis on the basis of the spectrum of component phenotypes expressed.

Asunto(s)

Lupus Eritematoso Sistémico/genética , Animales , Anticuerpos/análisis , Anticuerpos/genética , Cromatina/inmunología , Mapeo Cromosómico , Cromosomas/genética , ADN/inmunología , ADN de Cadena Simple/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Genes/genética , Glomerulonefritis/genética , Histonas/inmunología , Inmunoglobulina G/análisis , Inmunoglobulina G/genética , Inmunoglobulina M/análisis , Inmunoglobulina M/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NZB , Peroxidasa/inmunología , Fenotipo , Factores Sexuales , Tiroglobulina/inmunología

RESUMEN

The ability of superantigens to activate large numbers of T cells suggests that they may play a role in the course of autoimmune disorders. Data from several animal models of autoimmune disorders including experimental allergic encephalomyelitis and collagen induced arthritis supports this hypothesis. Administration of bacterial superantigens can induce an exacerbation of the autoimmune process in these models, or induce disease de novo in the appropriately immunized animal. Studies of several human disorders including rheumatoid arthritis, Kawasaki disease, insulin-dependent diabetes, and psoriasis lend credence to the concept that bacterial superantigens may play a role in the pathogenesis of these diseases. Nevertheless, in some cases, depending on the timing of administration and the model, superantigens may lead to an amelioration of the autoimmune process. Based on these results in seems logical to conclude that superantigens can have a significant impact on the course of the immune and autoimmune mediated disorders.

Asunto(s)

Enfermedades Autoinmunes/etiología , Superantígenos/fisiología , Animales , Artritis Reumatoide/etiología , Diabetes Mellitus Tipo 1/etiología , Humanos , Activación de Linfocitos , Síndrome Mucocutáneo Linfonodular/etiología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Linfocitos T/inmunología

RESUMEN

Exposure to low doses of mercury chloride induces autoantibodies to the nucleolar protein fibrillarin in H-2s, but not in H-2b, mice. Surprisingly, F1 crosses between resistant and sensitive haplotypes are resistant. Previously, we have shown that the resistance in these F1 mice was due to coexpression of the resistant class II allele. Using adoptive transfer techniques we have examined several mechanisms by which the resistant haplotype could be down-regulating the antifibrillarin response in F1 (s/b) mice. Similar to other autoimmune models, mercury-induced autoimmunity requires cognate MHC-restricted T cell help. The absence of autoantibody production in F1 mice was not due to a difference in thymic education or to the absence of antifibrillarin-specific T cell help. These results suggest that the resistance is due to an intrinsic property of the haplotype-heterozygous B cells.

Asunto(s)

Enfermedades Autoinmunes/genética , Subgrupos de Linfocitos B/inmunología , Heterocigoto , Cloruro de Mercurio/inmunología , Animales , Anticuerpos Antinucleares/biosíntesis , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Subgrupos de Linfocitos B/metabolismo , Nucléolo Celular/inmunología , Proteínas Cromosómicas no Histona/inmunología , Cruzamientos Genéticos , Haplotipos , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Cooperación Linfocítica/genética , Cloruro de Mercurio/farmacología , Ratones , Ratones Endogámicos C57BL , Quimera por Radiación/genética , Quimera por Radiación/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Timo/inmunología , Timo/patología

RESUMEN

To define the functional consequences of the src-homology domain-1 protein (SHP-1) defect, we examined cytokine production and NF-kappa B activity in motheaten viable (Mev) mice. We found elevated levels of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor (TNF), and interferon-gamma (IFN-gamma) in Mev mice sera and cultured B and T cells compared to littermate control adult mice. The levels of interleukin-2 (IL-2) detected in Mev sera and activated Mev T cells were decreased, but IL-2 receptor expression was increased. We then evaluated the activity of NF-kappa B and found that this protein is highly expressed in Mev B and T cells. To determine if NF-kappa B had a role in causing the elevated levels of cytokines in Mev mice, we treated activated Mev T cells with an NF-kappa B decoy and found that cell culture treatment with the decoy resulted in significant reduction of the secretion of IL-6, GM-CSF, and TNF, but not IFN-gamma. Therefore, our data show that Mev mice secrete elevated levels of inflammatory cytokines, which can be mediators in the development of the Mev clinical disorder, and that NF-kappa B has an important role in this process, impacting upon the regulation of the immune response.

Asunto(s)

FN-kappa B/fisiología , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/fisiología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos B/efectos de los fármacos , Subgrupos de Linfocitos B/metabolismo , Unión Competitiva , Células Cultivadas , Citocinas/sangre , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Inflamación/sangre , Inflamación/inmunología , Péptidos y Proteínas de Señalización Intracelular , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Proteínas Tirosina Fosfatasas/deficiencia , Proteínas Tirosina Fosfatasas con Dominio SH2 , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismo , Dominios Homologos src/genética , Dominios Homologos src/inmunología

RESUMEN

lpr, a murine mutation of the Fas apoptosis receptor, causes lymphadenopathy and autoantibody production, with lymphadenopathy primarily due to a population of CD4-CD8-B220+ T cells. Previous in vivo experiments, in which lpr and normal bone marrow cells were coinfused into lpr hosts, have demonstrated that only T cells of lpr origin accumulated abnormally and only B cells of lpr origin produced autoantibodies. Moreover, in these chimeras, B cells of normal origin were unable to respond to conventional, T cell-dependent exogenous Ag. To address the role of lpr B cells in regulation of lpr autoimmunity, we have prepared lpr-+ mixed chimeras and selectively eliminated lpr B cells using allele-specific, mAb treatment, thus allowing normal B cells to develop in an environment with lpr T cells. From these data, we arrived at four major conclusions: 1) Compared with control-treated chimeric mice, lpr B cell-depleted mice had greatly reduced total lymph node cell counts; 2) the T cells were derived equally from normal and lpr donors, and the percentage of lpr-derived CD4-CD8- T cells was greatly reduced; 3) despite the presence of the remaining lpr T cells, no autoantibodies were produced by the normal derived B cells; and 4) lpr T cells without lpr B cells were unable to prevent a normal B cell response to conventional Ag. These data demonstrate that B cells can play a critical and expansive regulatory role, not only for T cells, but for other B cells as well.

Asunto(s)

Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Quimera por Radiación/inmunología , Animales , Formación de Anticuerpos/genética , Autoanticuerpos/biosíntesis , Subgrupos de Linfocitos B/metabolismo , Antígenos CD4 , Antígenos CD8 , Movimiento Celular/genética , Movimiento Celular/inmunología , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Humanos , Alotipos de Inmunoglobulinas/genética , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Enfermedades Linfáticas/genética , Enfermedades Linfáticas/inmunología , Enfermedades Linfáticas/patología , Cooperación Linfocítica/genética , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Quimera por Radiación/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , gammaglobulinas/inmunología

RESUMEN

The ability of superantigens (SAgs) to activate the immune system suggests that they may play a role in the course of autoimmune disorders. Here, Joel Schiffenbauer and colleagues review evidence from animal models of autoimmunity, as well as human data that support this hypothesis, and propose a model for SAg involvement in autoimmune disorders.

Asunto(s)

Antígenos Bacterianos/inmunología , Enfermedades Autoinmunes/etiología , Superantígenos/inmunología , Animales , Humanos , Modelos Inmunológicos

RESUMEN

NF-kappaB is a potential target for immunosuppressive therapy. Two methods were evaluated to inhibit NF-kappaB: the antisense (AS) approach in which single-stranded oligodeoxynucleotides (ODNs) bind the mRNA for the RelA subunit of NF-kappaB and the transcription factor decoy (TFD) approach in which double-stranded ODNs bind the NF-kappaB protein. AS and TFD inhibited NF-kappaB binding and decreased total IgG and anti-dsDNA antibody production in splenocytes from the BXSB/Yaa autoimmune mouse strain. TNF-alpha expression was reduced by AS and TFD, as were the levels of IL-2. But AS effects did not last beyond 24 h, whereas TFD inhibited cytokine production after 72 h. AS had no effect upon IL-6, while the TFD reduced the secretion of IL-6. Therefore, the suppression of immune response mediators by AS or TFD, through inhibition of NF-kappaB, is substantial. These inhibitors can serve as novel choices for therapy in the treatment of autoimmune disorders.

Asunto(s)

Inmunosupresores/farmacología , FN-kappa B/antagonistas & inhibidores , Oligonucleótidos Antisentido/farmacología , Tionucleótidos/farmacología , Animales , Células Cultivadas , Citocinas/biosíntesis , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoglobulina G/metabolismo , Interleucina-2/metabolismo , Ratones , FN-kappa B/biosíntesis , FN-kappa B/genética , Bazo/citología , Bazo/inmunología , Factor de Transcripción ReIA

RESUMEN

CD45 is involved in the regulation of lymphocyte activation, and it has been demonstrated that ligation of CD45 induces apoptosis of T and B lymphocytes. Recently anti-CD45RB antibody therapy was shown to block acute allograft rejection in a mouse model of transplantation. Therefore, we wanted to examine the effects of anti-CD45RB antibody treatment on the course of an autoimmune disorder, experimental allergic encephalomyelitis (EAE), a Th1-mediated process. Mice immunized with myelin basic protein and treated with anti-CD45RB antibody did not develop EAE. Histologically, there was no evidence of lymphocytic infiltrates in the central nervous system. T cell proliferation and TNF-alpha production were significantly decreased in anti-CD45RB-treated mice. Furthermore, there was a significant reduction in the production of other Th1 cytokines including interferon-gamma and IL-2, but not IL-4 or IL-6. However, levels of a number of adhesion markers or markers of activation such as VLA-4 and LFA-1 on T cells were no different in treated versus control animals. Thus, anti-CD45RB can prevent EAE and appears to do so by altering T cell proliferation and cytokine production.

Asunto(s)

Anticuerpos Monoclonales/uso terapéutico , Encefalomielitis Autoinmune Experimental/prevención & control , Antígenos Comunes de Leucocito/inmunología , Animales , División Celular , Citocinas/biosíntesis , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/terapia , Integrina alfa4beta1 , Integrinas/biosíntesis , Antígeno-1 Asociado a Función de Linfocito/biosíntesis , Ratones , Ratas , Receptores Mensajeros de Linfocitos/biosíntesis , Linfocitos T/inmunología

RESUMEN

One of the most striking features of exposure to low doses of mercury in mice is the high-titer haplotype-linked anti-nucleolar (ANoA) autoantibody response. Mice of H-2(s) haplotype have been high responders, while H-2(b) mice have been low. This pattern has been attributed to the class II molecule itself, but the poor response of F1 crosses between high and low responders raised the possibility that the anti-fibrillarin specificity was actually due to a closely linked dominant negative gene. To test the role of class II explicitly, F1 crosses between congenic B6.SJL (H-2(s)) and C57BL/6 (H-2(b)) mice with a targeted deletion of I-AbAbeta were generated, creating mice heterozygous for all MHC loci, but expressing only I-As. In comparison with B6.SJL, no diminution of ANoA titers was found, proving that I-As itself was responsible for susceptibility and I-Ab for downregulation. Unlike I-A, expression of the I-E class II molecule could not downregulate the response in an otherwise susceptible mouse. These results suggest a complicated role for class II in the regulation of a novel, environmentally induced autoimmune response.

Asunto(s)

Enfermedades Autoinmunes/inducido químicamente , Antígenos de Histocompatibilidad Clase II/genética , Cloruro de Mercurio/toxicidad , Animales , Formación de Anticuerpos , Autoanticuerpos/inmunología , Autoinmunidad/efectos de los fármacos , Autoinmunidad/genética , Femenino , Haplotipos , Inmunidad Innata/genética , Masculino , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , Esclerodermia Sistémica/genética

RESUMEN

NF-kappaB is a regulatory protein of immune response genes and a candidate for targeting in immunosuppressive therapy. NF-kappaB proteins are formed from components of which p50 (NFkappaB1) is a subunit. By targeting p50 gene expression with specific antisense 3' phosphorothioate-oligodeoxynucleotides (3' PS-ODNs), an effect upon NF-kappaB regulation and immunoglobulin synthesis in murine B cells was achieved. A 49% decrease in p50 protein was induced by treatment of WEHI 231 B cells with p50 antisense 3' PS-ODNs and not by control 3' PS-ODNs. p50 antisense specifically reduced the expression of NF-kappaB by 51%, but not the transcription factor, Oct-1. In the BXSB murine model of autoimmunity, p50 antisense inhibited NF-kappaB expression and total IgM and IgG synthesis, but, more importantly, dsDNA antibodies were reduced 90%. These results validate the use of p50 antisense to reduce NF-kappaB expression and, by downregulating the immune response, has application in the treatment of autoimmune disorders.

Asunto(s)

Linfocitos B/metabolismo , Inmunoglobulinas/biosíntesis , FN-kappa B/antagonistas & inhibidores , FN-kappa B/biosíntesis , Oligonucleótidos Antisentido/farmacología , Tionucleótidos/farmacología , Animales , Anticuerpos Antinucleares/biosíntesis , Autoanticuerpos/análisis , Enfermedades Autoinmunes/diagnóstico , Autoinmunidad/fisiología , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , ADN/inmunología , Modelos Animales de Enfermedad , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Subunidad p50 de NF-kappa B , Bazo/citología , Células Tumorales Cultivadas

RESUMEN

Virulence factors are microbial products that are known to be harmful to the host and may assist in the pathogenesis of the micro-organism. Superantigens, including those produced by bacteria and viruses, clearly act as virulence factors. The clinical effects of superantigens can be not only acute but also chronic and complex. Recent evidence suggests that superantigens may play a central role in the pathogenesis of autoimmune and immunodeficiency disorders. It is our contention that superantigens, as environmental factors, can change a controllable disease into one that becomes relentless for susceptible individuals. To illustrate the detrimental effects of superantigens on disease outcome, modulation of experimental allergic encephalomyelitis by superantigen, as well as the potential role of superantigens in human immunodeficiency virus pathogenesis will be discussed. The information presented may provide valuable insight into the role of superantigens in autoimmunity and human immunodeficiency virus infection.

Asunto(s)

Enfermedades Autoinmunes/inmunología , Síndromes de Inmunodeficiencia/inmunología , Superantígenos , Animales , Antígenos Bacterianos , Antígenos Virales , Enfermedades Autoinmunes/etiología , Susceptibilidad a Enfermedades , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Síndromes de Inmunodeficiencia/etiología , Ratones , Modelos Inmunológicos , Virulencia

RESUMEN

Systemic lupus erythematosus is characterized by polyclonal B cell activation, the production of autoantibodies, and often by renal disease. Previous studies demonstrated that unfractionated B cells from several strains of mice with lupus hyperproliferate in culture when stimulated with lipopolysaccharide (LPS) or anti-IgM. We wished to further examine proliferation of resting B cells from the BXSB mouse model of lupus and mice with the Yaa allele, when activated with a number of stimuli. Our work demonstrates that: (1) resting B cells from mice containing the Yaa allele hyperproliferated compared to that seen with B cells from mice lacking the Yaa allele, (2) this hyperproliferation occurred whether cells were stimulated with phorbol myristate acetate/ionomycin, LPS, anti-IgM, or CD40L cross-linking, (3) this hyperproliferation is specific to B and not T cells. Taken together these data suggest that one mechanism by which the Yaa allele contributes to the accelerated onset of lupus in BXSB male mice is through its influence on B cell activation.

Asunto(s)

Linfocitos B/inmunología , Alelos , Animales , Anticuerpos Antiidiotipos/farmacología , Modelos Animales de Enfermedad , Ligamiento Genético , Inmunoglobulina M/inmunología , Ionomicina/farmacología , Lipopolisacáridos/farmacología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Activación de Linfocitos/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Bazo/citología , Acetato de Tetradecanoilforbol/farmacología , Factores de Tiempo

RESUMEN

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease if the central nervous system (CNS). Recently, the type I IFN, IFN-beta-1b was demonstrated to be a useful immunotherapy for MS. During treatment with IFN-beta-1b, toxicity at higher doses has been observed. IFN-tau, discovered for its role in the reproductive cycle, possesses all of the functions normally ascribed to the type I IFNs but lacks the toxicity normally associate with IFN treatment in vitro. We have examined the effects of IFN-tau treatment on experimental allergic encephalomyelitis (EAE), an animal model useful for the study of MS. EAE is a model of Ag-induced autoimmunity that can be modulated by bacterial superantigen to resemble the relapsing-remitting pattern of autoimmune disease observed in MS. IFN-tau was able to prevent development of EAE as effectively as IFN-beta but without associated toxicity such as lymphocyte suppression and weight loss. In addition, IFN-tau was able to prevent superantigen reactivation of EAE akin to the reduction in disease exacerbations observed in IFN-beta-1b treated MS patients. Mechanisms by which IFN-tau may prevent EAE include reduced proliferation in response to the autoantigen myelin basic protein and reduced TNF-alpha production. Thus, IFN-tau may prove to be a promising new IFN therapy for MS in light of its ability to prevent EAE and the lack of toxicity exhibited by this novel IFN.

Asunto(s)

Encefalomielitis Autoinmune Experimental/prevención & control , Interferón Tipo I/farmacología , Interferón Tipo I/toxicidad , Proteínas Gestacionales/farmacología , Proteínas Gestacionales/toxicidad , Superantígenos/efectos de los fármacos , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos , Proteína Básica de Mielina/efectos de los fármacos , Proteína Básica de Mielina/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Ovinos , Superantígenos/inmunología , Subgrupos de Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis

RESUMEN

Superantigens such as the staphylococcal enterotoxins can play an important role in exacerbation of autoimmune disorders such as experimental allergic encephalomyelitis (EAE) in mice. In fact, superantigens can reactivate EAE in PL/J mice that have been sensitized to rat myelin basic protein (MBP). The T-cell subset predominantly responsible for disease in PL/J mice bears the V beta 8+ T-cell antigen receptor (TCR). The question arises as to whether T cells bearing other V beta specificities are involved in induction or reactivation of EAE with superantigen. Thus, we have investigated the ability of a non-V beta 8-specific superantigen, staphylococcal enterotoxin A (SEA) (V beta specificities 1, 3, 10, 11, and 17), to induce EAE in PL/J mice that have been previously protected from disease by anergy and deletion of V beta 8+ T cells. PL/J mice were first pretreated with the V beta 8-specific superantigen staphylococcal enterotoxin B (SEB) and then immunized with MBP. These mice exhibited V beta 8-specific anergy and depletion and did not develop EAE, even when further treated with SEB. However, administration of SEA to these same mice induced an initial episode of EAE which was characterized by severe hindleg paralysis and accelerated onset of disease. In contrast to SEB pretreatment, PL/J mice pretreated with SEA did develop EAE when immunized with MBP, and after resolution of clinical signs of disease these mice were susceptible to relapse of EAE induced by SEB but not by SEA. Thus, superantigens can activate encephalitogenic MBP-specific non-V beta 8+ T cells to cause EAE in PL/J mice. These data suggest that superantigens can play a central role in autoimmune disorders and that they introduce a profound complexity to autoimmune diseases such as EAE, akin to the complexity seen in multiple sclerosis.

Asunto(s)

Encefalomielitis Autoinmune Experimental/fisiopatología , Enterotoxinas/inmunología , Superantígenos/inmunología , Linfocitos T/inmunología , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Citometría de Flujo , Activación de Linfocitos , Ratones , Ratones Endogámicos , Proteína Básica de Mielina/administración & dosificación , Proteína Básica de Mielina/inmunología , Ratas , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Bazo/inmunología , Staphylococcus aureus , Factores de Tiempo

RESUMEN

Development of rheumatoid arthritis is influenced by genetic and environmental factors. Over the years intense interest has been focused on analysis of genetic factors contributing to pathogenesis and it appears that the major histocompatibility complex class II genes make a major contribution. Utilizing epidemiological data as well as molecular techniques, an epitope located on a number of HLA-DR molecules (class II) seems to be associated with an increased susceptibility to development of the condition. Furthermore, the disease may be more severe among individuals homozygous for the disease-associated DR types. The specific immunological mechanisms accounting for these findings are not known but are likely related to the ability of class II molecules to bind autoantigens and stimulate the appropriate T cells which can lead to joint damage. A search for additional genetic factors contributing to disease development should be high on the list of objectives and would help to further elucidate the pathogenesis of this complex disorder.

Asunto(s)

Artritis Reumatoide/genética , Autoantígenos/genética , Epítopos/genética , Genes MHC Clase II/genética , Predisposición Genética a la Enfermedad , Antígenos HLA-DR/genética , Homocigoto , Humanos , Linfocitos T/inmunología