Asunto(s)
Anticuerpos Antinucleares/inmunología , Dermatomiositis/inmunología , Paniculitis/inmunología , Proteínas del Complejo de Iniciación de Transcripción Pol1/inmunología , Factores de Transcripción/inmunología , Proteína 28 que Contiene Motivos Tripartito/inmunología , Adulto , Anticuerpos Antinucleares/sangre , Biomarcadores/sangre , Biopsia , Dermatomiositis/complicaciones , Dermatomiositis/diagnóstico , Dermatomiositis/tratamiento farmacológico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Paniculitis/diagnóstico , Paniculitis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.
Asunto(s)
Autoanticuerpos/inmunología , Esclerodermia Sistémica/inmunología , Anciano , Antígenos Nucleares/inmunología , Australia , Autoantígenos/inmunología , Proteína A Centromérica , Proteína B del Centrómero/inmunología , Proteínas Cromosómicas no Histona/inmunología , Estudios de Cohortes , Contractura/etiología , Contractura/inmunología , ADN-Topoisomerasas de Tipo I/inmunología , Proteínas de Unión al ADN/inmunología , Trastornos de la Motilidad Esofágica/etiología , Trastornos de la Motilidad Esofágica/inmunología , Exorribonucleasas/inmunología , Complejo Multienzimático de Ribonucleasas del Exosoma/inmunología , Femenino , Ectasia Vascular Antral Gástrica/etiología , Ectasia Vascular Antral Gástrica/inmunología , Humanos , Immunoblotting , Autoantígeno Ku , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Proteínas del Complejo de Iniciación de Transcripción Pol1/inmunología , Análisis de Componente Principal , ARN Polimerasa III/inmunología , Proteínas de Unión al ARN/inmunología , Enfermedad de Raynaud/etiología , Enfermedad de Raynaud/inmunología , Receptores del Factor de Crecimiento Derivado de Plaquetas/inmunología , Ribonucleoproteínas/inmunología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/epidemiología , Factores Sexuales , Fumar/epidemiología , Telangiectasia/etiología , Telangiectasia/inmunologíaRESUMEN
OBJECTIVE: Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM. METHODS: To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102). RESULTS: A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1γ on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]). CONCLUSION: These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.
Asunto(s)
Adenosina Trifosfatasas/inmunología , Autoanticuerpos/sangre , Proteínas de Unión al ADN/inmunología , Dermatomiositis/epidemiología , Dermatomiositis/inmunología , Neoplasias/epidemiología , Neoplasias/inmunología , Proteínas del Complejo de Iniciación de Transcripción Pol1/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/análisis , Niño , Preescolar , Femenino , Estudios de Seguimiento , Células HeLa , Humanos , Masculino , Persona de Mediana Edad , Radioinmunoensayo/métodos , Factores de Riesgo , Estudios Seroepidemiológicos , Adulto JovenAsunto(s)
Anticuerpos Antinucleares/inmunología , Esclerodermia Sistémica/inmunología , Anticuerpos Antinucleares/sangre , Autoantígenos/inmunología , Nucléolo Celular/inmunología , Centrómero/inmunología , Proteínas Cromosómicas no Histona/inmunología , ADN-Topoisomerasas de Tipo I/inmunología , ARN Polimerasas Dirigidas por ADN/inmunología , Endotelio Vascular/patología , Exorribonucleasas/inmunología , Complejo Multienzimático de Ribonucleasas del Exosoma/inmunología , Fibroblastos/patología , Fibrosis , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Subgrupos Linfocitarios/inmunología , Estrés Oxidativo , Proteínas del Complejo de Iniciación de Transcripción Pol1/inmunología , Enfermedad de Raynaud/etiología , Ribonucleoproteína Nuclear Pequeña U1/inmunología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/fisiopatologíaRESUMEN
We describe the clinical and serological followup of a 9-year-old girl with anti-nucleolar organizing region 90/human upstream-binding factor (anti-NOR 90/hUBF) who had features of systemic sclerosis over a period of 17 years, from childhood into adulthood. We review the associations of anti-UBF autoantibodies, and provide evidence that anti-NOR 90/UBF immune response is antigen driven.