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 numéricosRESUMEN
The human leukocyte antigen (HLA) Class II antigen presentation alleles DR and DQ are associated with susceptibility to systemic lupus erythematosus (SLE) and the production of lupus-related autoantibodies. Here, we explore the effect of different combinations of Class II risk haplotypes in a large, multi-center collection of 780 SLE families. Haplotypes bearing the DRB1*1501/DQB1*0602 (DR2) and DRB1*0301/DQB1*0201 (DR3) alleles were present in nearly two-thirds of SLE cases and were significantly associated with disease susceptibility in both family-based and case-control study designs. DR3-containing haplotypes conferred higher risk for disease than DR2, and individual homozygous for DR3 or compound heterozygous for DR3 and DR2 showed the highest risk profile. DR2 haplotypes were also found to be associated with antibodies to the nuclear antigen Sm, and, as previously observed, DR3 genotypes were associated with Ro and La autoantibodies. Interestingly, SLE cases and unaffected family members who were DR2/DR3 compound heterozygotes showed particularly strong risk of developing antibodies to Ro, and were enriched for La and Sm. These data provide convincing evidence that particular combinations of HLA Class II DR2 and DR3 haplotypes are key determinants of autoantibody production and disease susceptibility in human SLE.
Asunto(s)
Autoanticuerpos/biosíntesis , Predisposición Genética a la Enfermedad , Antígeno HLA-DR2/genética , Antígeno HLA-DR3/genética , Haplotipos/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Medición de RiesgoRESUMEN
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/métodosRESUMEN
Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
Asunto(s)
Regulación de la Expresión Génica , Interferones/metabolismo , Leucocitos Mononucleares/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Vulgar/inmunología , Regulación hacia Abajo , Citometría de Flujo , Humanos , Interferones/farmacología , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/genética , Lupus Vulgar/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Regulación hacia ArribaRESUMEN
Human leukocyte antigen (HLA) class I and class II alleles are implicated as genetic risk factors for many autoimmune diseases. However, the role of the HLA loci in human systemic lupus erythematosus (SLE) remains unclear. Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, we identified three distinct haplotypes that encompassed the class II region and exhibited transmission distortion. DRB1 and DQB1 typing of founders showed that the three haplotypes contained DRB1*1501/ DQB1*0602, DRB1*0801/ DQB1*0402, and DRB1*0301/DQB1*0201 alleles, respectively. By visualizing ancestral recombinants, we narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to an approximately 500-kb region. We conclude that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.