RESUMEN
The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/ß-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the FcÉ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the diagnoses and understanding of autoimmunity and/or specific autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Leucocitos Mononucleares/inmunología , Mapas de Interacción de Proteínas , Receptores de IgE/inmunología , Transcriptoma , Apoptosis , Artritis Juvenil/inmunología , Artritis Juvenil/metabolismo , Enfermedades Autoinmunes/metabolismo , Proteínas del Linfoma 3 de Células B , Proliferación Celular , Quimiocina CXCL1/biosíntesis , Quimiocina CXCL5/biosíntesis , Quimiocina CXCL6/biosíntesis , Quimiocinas CXC/biosíntesis , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Expresión Génica , Humanos , Inflamación , Interferón gamma/metabolismo , Interleucina-8/biosíntesis , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores de Calcitriol/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
Laquinimod (LAQ) is a new immunomodulatory drug shown to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS); however, its molecular target pathways are not well recognized. In this study we characterized in-vitro the molecular effects of LAQ in peripheral blood mononuclear cells (PBMC) of healthy subjects and RRMS patients by gene expression microarrays. We demonstrated that LAQ induced suppression of genes related to antigen presentation and corresponding inflammatory pathways. These findings were demonstrated mainly via the NFkB pathway. Analysis of PBMC subpopulations identified activation of Th2 response in CD14+ and CD4+ cells and suppression of proliferation in CD8+ cells.