Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
J Immunol ; 192(3): 906-18, 2014 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-24379124

RESUMEN

Inappropriate activation of type I IFN plays a key role in the pathogenesis of autoimmune disease, including systemic lupus erythematosus (SLE). In this study, we report the presence of IFN activation in SLE bone marrow (BM), as measured by an IFN gene signature, increased IFN regulated chemokines, and direct production of IFN by BM-resident cells, associated with profound changes in B cell development. The majority of SLE patients had an IFN signature in the BM that was more pronounced than the paired peripheral blood and correlated with both higher autoantibodies and disease activity. Pronounced alterations in B cell development were noted in SLE in the presence of an IFN signature with a reduction in the fraction of pro/pre-B cells, suggesting an inhibition in early B cell development and an expansion of B cells at the transitional stage. These B cell changes strongly correlated with an increase in BAFF and APRIL expression in the IFN-high BM. Furthermore, we found that BM neutrophils in SLE were prime producers of IFN-α and B cell factors. In NZM lupus-prone mice, similar changes in B cell development were observed and mediated by IFN, given abrogation in NZM mice lacking type-I IFNR. BM neutrophils were abundant, responsive to, and producers of IFN, in close proximity to B cells. These results indicate that the BM is an important but previously unrecognized target organ in SLE with neutrophil-mediated IFN activation and alterations in B cell ontogeny and selection.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Médula Ósea/inmunología , Interferón Tipo I/fisiología , Lupus Eritematoso Sistémico/inmunología , Linfopoyesis/inmunología , Neutrófilos/inmunología , Adulto , Animales , Factor Activador de Células B/biosíntesis , Factor Activador de Células B/genética , Subgrupos de Linfocitos B/patología , Médula Ósea/metabolismo , Quimiocinas/biosíntesis , Quimiocinas/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Humanos , Interferón Tipo I/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , Persona de Mediana Edad , Neutrófilos/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Regulación hacia Arriba/inmunología
2.
Nat Genet ; 38(5): 550-5, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16642019

RESUMEN

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.


Asunto(s)
Factores Reguladores del Interferón/fisiología , Lupus Eritematoso Sistémico/genética , Empalme del ARN/fisiología , Estudios de Casos y Controles , Estudios de Cohortes , Genotipo , Haplotipos , Humanos , Factores Reguladores del Interferón/genética , Datos de Secuencia Molecular , Polimorfismo Genético
3.
PLoS Med ; 3(12): e491, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17177599

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a role for type I interferon (IFN) in SLE pathogenesis; however, the downstream effects of IFN pathway activation are not well understood. Here we test the hypothesis that type I IFN-regulated proteins are present in the serum of SLE patients and correlate with disease activity. METHODS AND FINDINGS: We performed a comprehensive survey of the serologic proteome in human SLE and identified dysregulated levels of 30 cytokines, chemokines, growth factors, and soluble receptors. Particularly striking was the highly coordinated up-regulation of 12 inflammatory and/or homeostatic chemokines, molecules that direct the movement of leukocytes in the body. Most of the identified chemokines were inducible by type I IFN, and their levels correlated strongly with clinical and laboratory measures of disease activity. CONCLUSIONS: These data suggest that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed in human SLE. Furthermore, the levels of serum chemokines may serve as convenient biomarkers for disease activity in lupus.


Asunto(s)
Biomarcadores/sangre , Quimiocinas/sangre , Interferón Tipo I/farmacología , Lupus Eritematoso Sistémico/sangre , Adulto , Estudios de Casos y Controles , Quimiocinas/metabolismo , Femenino , Humanos , Inmunoensayo , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Masculino , Proteoma/análisis , Proteómica/métodos
4.
Nat Rev Rheumatol ; 5(5): 257-65, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19412192

RESUMEN

Gene-expression profiling is a powerful tool for the discovery of molecular fingerprints that underlie human disease. Microarray technologies allow the analysis of messenger RNA transcript levels for every gene in the genome. However, gene-expression profiling is best viewed as part of a pipeline that extends from sample collection through clinical application. Key genes and pathways identified by microarray profiling should be validated in independent sample sets and with alternative technologies. Analysis of relevant signaling pathways at the protein level is an important step towards understanding the functional consequences of aberrant gene expression. Peripheral blood is a convenient and rich source of potential biomarkers, but surveying purified cell populations and target tissues can also enhance our understanding of disease states. In rheumatic disease, probing the transcriptome of circulating immune cells has shed light on mechanisms underlying the pathogenesis of complex diseases, such as systemic lupus erythematosus. As these discoveries advance through the pipeline, a variety of clinical applications are on the horizon, including the use of molecular fingerprints to aid in diagnosis and prognosis, improved use of existing therapies, and the development of drugs that target relevant genes and pathways.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Expresión Génica , Enfermedades Reumáticas/genética , Biomarcadores/sangre , Dermatoglifia del ADN , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Enfermedades Reumáticas/diagnóstico , Enfermedades Reumáticas/terapia
5.
Arthritis Rheum ; 60(10): 3098-107, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19790071

RESUMEN

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by unpredictable flares of disease activity and irreversible damage to multiple organ systems. An earlier study showed that SLE patients carrying an interferon (IFN) gene expression signature in blood have elevated serum levels of IFN-regulated chemokines. These chemokines were associated with more-severe and active disease and showed promise as SLE disease activity biomarkers. This study was designed to validate IFN-regulated chemokines as biomarkers of SLE disease activity in 267 SLE patients followed up longitudinally. METHODS: To validate the potential utility of serum chemokine levels as biomarkers of disease activity, we measured serum levels of CXCL10 (IFNgamma-inducible 10-kd protein), CCL2 (monocyte chemotactic protein 1), and CCL19 (macrophage inflammatory protein 3beta) in an independent cohort of 267 SLE patients followed up longitudinally over 1 year (1,166 total clinic visits). RESULTS: Serum chemokine levels correlated with lupus activity at the current visit (P = 2 x 10(-10)), rising at the time of SLE flare (P = 2 x 10(-3)) and decreasing as disease remitted (P = 1 x 10(-3)); they also performed better than the currently available laboratory tests. Chemokine levels measured at a single baseline visit in patients with a Systemic Lupus Erythematosus Disease Activity Index of < or =4 were predictive of lupus flare over the ensuing year (P = 1 x 10(-4)). CONCLUSION: Monitoring serum chemokine levels in SLE may improve the assessment of current disease activity, the prediction of future disease flares, and the overall clinical decision-making.


Asunto(s)
Quimiocina CCL19/sangre , Quimiocina CCL2/sangre , Quimiocina CXCL10/sangre , Interferones/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Interferones/genética , Estudios Longitudinales , Masculino , Análisis Multivariante , Estudios Prospectivos , Transducción de Señal
6.
Arthritis Rheum ; 60(11): 3436-46, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19877033

RESUMEN

OBJECTIVE: Up-regulation of whole blood type I interferon (IFN)-driven transcripts and chemokines has been described in a number of autoimmune diseases. An IFN gene expression "signature" is a candidate biomarker in patients with dermatomyositis (DM). This study was performed to evaluate the capacity of IFN-dependent peripheral blood gene and chemokine signatures and levels of proinflammatory cytokines to serve as biomarkers for disease activity in adult and juvenile DM. METHODS: Peripheral blood samples and clinical data were obtained from 56 patients with adult or juvenile DM. The type I IFN gene signature in the whole blood of patients with DM was defined by determining the expression levels of 3 IFN-regulated genes (IFIT1, G1P2, and IRF7) using quantitative real-time reverse transcription-polymerase chain reaction. Multiplexed immunoassays were used to quantify the serum levels of 4 type I IFN-regulated chemokines (IFN-inducible T cell alpha chemoattractant, IFNgamma-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], and MCP-2) and the serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). RESULTS: DM disease activity correlated significantly with the type I IFN gene signature (r = 0.41, P = 0.007) and with the type I IFN chemokine signature (r = 0.61, P < 0.0001). Furthermore, the serum levels of IL-6 were significantly correlated with disease activity (r = 0.45, P = 0.001). In addition, correlations between the serum levels of IL-6 and both the type I IFN gene signature (r = 0.47, P < 0.01) and the type I IFN chemokine signature (r = 0.71, P < 0.0001) were detected in patients with DM. CONCLUSION: These results suggest that serum IL-6 production and the type I IFN gene signature are candidate biomarkers for disease activity in adult and juvenile DM. Coregulation of the expression of IFN-driven chemokines and IL-6 suggests a novel pathogenic linkage in DM.


Asunto(s)
Quimiocinas/sangre , Dermatomiositis/sangre , Interferón Tipo I/genética , Interleucina-6/sangre , Índice de Severidad de la Enfermedad , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Proteínas Portadoras/sangre , Estudios de Casos y Controles , Quimiocina CCL2/sangre , Quimiocina CCL8/sangre , Quimiocina CXCL10/sangre , Quimiocina CXCL11/sangre , Niño , Citocinas/sangre , Dermatomiositis/diagnóstico , Femenino , Humanos , Factor 7 Regulador del Interferón/sangre , Masculino , Persona de Mediana Edad , Proteínas de Unión al ARN , Ubiquitinas/sangre , Adulto Joven
7.
Mol Med ; 13(1-2): 59-68, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17515957

RESUMEN

Recent studies have shown increased expression of interferon (IFN)-regulated genes in the peripheral blood cells of patients with systemic lupus erythematosus. A similar interferon signature has been observed in affected muscle tissue from patients with dermatomyositis (DM), but it has not yet been determined if this signature extends to the peripheral blood in DM. We performed global gene expression profiling of peripheral blood cells from adult and juvenile DM patients and healthy controls. Several interesting groups of genes were differentially expressed in DM, including genes with immune function, and others that function in muscle or are involved in mitochondrial/oxidative phosphorylation. Investigation of type I IFN-regulated transcripts revealed a striking interferon signature present in most DM patients studied. Levels of type I IFN-regulated proteins were also elevated in DM serum samples. Furthermore, both the transcript and serum protein IFN signatures were associated with disease activity. These data suggest that the IFN signature may be a useful marker for DM disease activity, and that sampling peripheral blood may be a more practical alternative to muscle biopsy for measuring this signature.


Asunto(s)
Dermatomiositis/sangre , Dermatomiositis/patología , Interferón Tipo I/sangre , Interferón Tipo I/genética , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Proteínas Sanguíneas/genética , Estudios de Casos y Controles , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Población Blanca/estadística & datos numéricos
8.
J Immunol ; 179(11): 7397-405, 2007 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-18025183

RESUMEN

We have previously shown that rheumatoid factors produced by Fas-deficient autoimmune-prone mice typically bind autologous IgG2a with remarkably low affinity. Nevertheless, B cells representative of this rheumatoid factor population proliferate vigorously in response to IgG2a/chromatin immune complexes through a mechanism dependent on the sequential engagement of the BCR and TLR9. To more precisely address the role of both receptors in this response, we analyzed the signaling pathways activated in AM14 B cells stimulated with these complexes. We found that the BCR not only serves to direct the chromatin complex to an internal compartment where it can engage TLR9 but also transmits a suboptimal signal that in combination with the signals emanating from TLR9 leads to NF-kappaB activation and proliferation. Importantly, engagement of both receptors leads to the up-regulation of a group of gene products, not induced by the BCR or TLR9 alone, that include IL-2. These data indicate that autoreactive B cells, stimulated by a combination of BCR and TLR9 ligands, acquire functional properties that may contribute to the activation of additional cells involved in the autoimmune disease process.


Asunto(s)
Linfocitos B/inmunología , Cromatina/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Receptor Toll-Like 9/metabolismo , Animales , Calcio/metabolismo , Inmunoglobulina G/inmunología , Interleucina-2/biosíntesis , Ligandos , Ratones , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/inmunología , Fosforilación , Transducción de Señal/inmunología , Tirosina/metabolismo
9.
Proc Natl Acad Sci U S A ; 104(16): 6758-63, 2007 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-17412832

RESUMEN

Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.


Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Estudios de Casos y Controles , Línea Celular Transformada , Regulación de la Expresión Génica/fisiología , Humanos , Factores Reguladores del Interferón/biosíntesis , Factores Reguladores del Interferón/fisiología , Lupus Eritematoso Sistémico/etiología , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Factores de Riesgo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA