RESUMEN
Macrophages (MФ) and microglia (MG) are critical in the pathogenesis of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Glucocorticoids (GCs) and interferon ß (IFN-ß) are frontline treatments for MS, and disrupting each pathway in mice aggravates EAE. Glucocorticoid receptor-interacting protein 1 (GRIP1) facilitates both GR and type I IFN transcriptional actions; hence, we evaluated the role of GRIP1 in neuroinflammation. Surprisingly, myeloid cell-specific loss of GRIP1 dramatically reduced EAE severity, immune cell infiltration of the CNS, and MG activation and demyelination specifically during the neuroinflammatory phase of the disease, yet also blunted therapeutic properties of IFN-ß. MФ/MG transcriptome analyses at the bulk and single-cell levels revealed that GRIP1 deletion attenuated nuclear receptor, inflammatory and, interestingly, type I IFN pathways and promoted the persistence of a homeostatic MG signature. Together, these results uncover the multifaceted function of type I IFN in MS/EAE pathogenesis and therapy, and an unexpectedly permissive role of myeloid cell GRIP1 in neuroinflammation.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Interferón beta/farmacología , Macrófagos/inmunología , Esclerosis Múltiple , Coactivador 2 del Receptor Nuclear/inmunología , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Macrófagos/patología , Ratones , Ratones Noqueados , Microglía/inmunología , Microglía/patología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Coactivador 2 del Receptor Nuclear/genéticaRESUMEN
RATIONALE: There is a need to further characterize the antibody repertoire in relation to sarcoidosis and potentially related autoantigens. OBJECTIVES: We investigated bronchoalveolar lavage (BAL) and serum samples from patients with sarcoidosis and healthy and diseased control subjects to discover sarcoidosis-associated autoantigens. METHODS: Antigen microarrays built on 3,072 protein fragments were used to screen for IgG reactivity in 73 BAL samples from subjects with sarcoidosis, subjects with asthma, and healthy subjects. A set of 131 targets were selected for subsequent verification on suspension bead arrays using 272 additional BAL samples and 141 paired sera. Reactivity to four antigens was furthermore analyzed in 22 unprocessed BAL samples from patients with fibrosis and 269 plasma samples from patients diagnosed with myositis. MEASUREMENTS AND MAIN RESULTS: Reactivity toward zinc finger protein 688 and mitochondrial ribosomal protein L43 were discovered with higher frequencies in patients with sarcoidosis, for mitochondrial ribosomal protein L43 especially in patients with non-Löfgren syndrome. Increased reactivity toward nuclear receptor coactivator 2 was also observed in patients with non-Löfgren syndrome as compared with patients with Löfgren syndrome. The antigen representing adenosine diphosphate-ribosylation factor GTPase activating protein 1 revealed high reactivity frequency in all sample groups but with significantly higher level of IgG reactivities in patients with sarcoidosis. CONCLUSIONS: Autoantigen reactivity was present in most BAL and serum samples analyzed, and the results revealed high interindividual heterogeneity, with most of the reactivities observed in single individuals only. Four proteins are here proposed as sarcoidosis-associated autoimmune targets and of interest for further validation in independent cohorts.
Asunto(s)
Autoantígenos/análisis , Sarcoidosis Pulmonar/diagnóstico , Sarcoidosis Pulmonar/inmunología , Adolescente , Adulto , Anciano , Biomarcadores/análisis , Líquido del Lavado Bronquioalveolar/química , Proteínas Portadoras/análisis , Proteínas Portadoras/sangre , Proteínas Portadoras/inmunología , Femenino , Proteínas Activadoras de GTPasa/análisis , Proteínas Activadoras de GTPasa/inmunología , Ensayos Analíticos de Alto Rendimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/análisis , Proteínas Mitocondriales/sangre , Proteínas Mitocondriales/inmunología , Coactivador 2 del Receptor Nuclear/análisis , Coactivador 2 del Receptor Nuclear/inmunología , Análisis por Matrices de Proteínas , Proteómica , Proteínas Ribosómicas/análisis , Proteínas Ribosómicas/sangre , Proteínas Ribosómicas/inmunología , Sarcoidosis Pulmonar/sangre , Adulto Joven , Dedos de Zinc/inmunologíaRESUMEN
A majority of the developing T cells are eliminated by apoptosis because they do not meet the positive and negative selection criteria. Developing T cells are thus susceptible to apoptotic signals. On the other hand, there are mechanisms to prevent developing T cells from premature apoptosis. Maintenance of a fine balance between life and death is thus critical for successful completion of T-cell development. Our recent studies demonstrated an essential role of transcriptional coactivators in maintaining such a balance for developing T cells. Transcriptional coactivators are recruited by transcriptional factors to quantitatively regulate gene expression via modifying chromatin structure. Two transcriptional factors, TCF-1 and ROR gamma t, are required to upregulate the levels of Bcl-xL, a critical survival factor for CD4+CD8+ double-positive thymocytes. However, TCF-1 and ROR gamma t by themselves are not sufficient to stimulate Bcl-xL expression. Transcriptional coactivator beta-catenin recruited by TCF-1, and steroid receptor coactivators (SRCs) recruited by ROR gamma t, are also required for optimal stimulation of Bcl-xL expression. Thus, transcriptional coactivators are a substantial component of the transcriptional machinery to regulate thymocye survival, ensuring the completion of T-cell development.