THE ROLE OF INTERFERON REGULATORY FACTOR 5 IN THE PATHOGENESIS OF SLE

干扰素调节因子5在SLE发病中的作用

• 批准号: 8120845
• 负责人: IAN R RIFKIN
• 金额: $ 0.16万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120845
• 关键词: Address; Adverse effects; Animal Model; Antigen-Antibody Complex; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Bacterial Artificial Chromosomes; Biological; Biological Assay; Bone Marrow; Cells; Chimera organism; Complex; DNA; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease Progression; Etiology; Exhibits; Gene Dosage; Generations; Genetic; Genetic Polymorphism; Genetic Recombination; Goals; Heterozygote; Human Genetics; Immune response; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunosuppression; Instruction; Interferon Type I; Interferons; Lupus; Mediating; Modeling; Molecular Abnormality; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Principal Investigator; Process; Production; Proteins; Residual Tumors; Risk; Role; Stimulus; Systemic Lupus Erythematosus; TLR7 gene; Tamoxifen; Therapeutic; Time; Transgenic Mice; active method; autoreactive B cell; cell type; cytokine; functional outcomes; human TLR7 protein; in vitro Assay; in vivo; medical attention; mortality; mouse model; overexpression; prevent; response; systemic autoimmune disease; therapeutic target; type I interferon receptor

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with appreciable morbidity and mortality. Current treatment comprises non-specific immunosuppression with many serious side-effects. Furthermore, response to therapy is often incomplete. More specific, and less toxic therapies are thus required. Interferon regulatory factor 5 (IRFS) polymorphisms are strongly associated in human genetic studies with an increased risk of developing SLE although the biological role of IRFS in lupus pathogenesis, if any, is not known. We have found that IRFS is absolutely required for disease development in a mouse model of SLE. In addition, a critical level of IRFS is required as IRFS heterozygous mice develop minimal disease manifestations. This suggests that IRFS might be a key therapeutic target in SLE. The application's objectives are to obtain a detailed understanding of the mechanisms whereby IRFS contributes to disease pathogenesis in SLE. The goal of specific aim 1 is to determine the role of IRFS in lupus-relevant immune responses by comparing the functional effects of homozygous and heterozygous IRFS deficiency on the response of dendritic cells and B cells to TLR stimuli including DNA- and RNA-containing immune complexes. Specific aim 2a will determine the generalizability of the IRFS role in SLE by evaluating the effect of IRFS-deficiency in additional lupus models. Specific aim 2b will determine to what extent the beneficial effect of IRFS-deficiency in lupus is TLR7- and/or TLR9-dependent or independent. Specific aim 2c will determine whether IRFS overexpression is able to induce disease in wildtype or autoimmune-prone mice. Specific aim 3 will determine which IRFS-expressing cells are required for disease pathogenesis by using bone-marrow chimeras, and by deleting IRFS in specific cell types using a Cre-loxP approach with cell- specific Cre. Specific aim 4 will determine whether deleting IRFS (in all cell types) after disease is established can reverse disease or prevent disease progression. This will be done also using a Cre-loxP approach but using an inducible Cre. It is anticipated that these studies will enhance the understanding of the role of IRFS in SLE pathogenesis and contribute to the development of new effective, safer and more specific therapies. RELEVANCE (See instructions): Genetic abnormalities in a protein called interferon regulatory factor S (IRFS) are found in many patients with the autoimmune disease systemic lupus erythematosus (SLE). We have found in an animal model of SLE that deficiency of IRFS prevents the development of disease. This suggests that IRFS might be a key therapeutic target in SLE

系统性红斑狼疮（SLE）是一种系统性自身免疫性疾病，具有明显的发病率和发病率