Mechanisms of the suppression of autoimmunity

抑制自身免疫的机制

• 批准号: 7628045
• 负责人: Anne B Satterthwaite
• 金额: $ 24.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628045
• 关键词: Affect; Alleles; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bone Marrow; Cell Count; Cell Lineage; Cell Survival; Cell physiology; Cells; Chimera organism; Defect; Dendritic Cells; Deposition; Disease; Equilibrium; Face; Gene Activation; Gene Expression; Gene Expression Profile; Hypersensitivity; In Vitro; Individual; Inflammation; Lead; Longevity; Lupus; Measures; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Mus; Myelogenous; Myeloid Cells; Nuclear Antigens; Organ; Pathway interactions; Phenotype; Plasma Cells; Population; Predisposition; Process; Production; Signal Transduction; Stimulus; System; Systemic Lupus Erythematosus; cell motility; crosslink; dosage; in vivo; novel therapeutics; plasma cell differentiation; prevent; response; therapeutic target

Systemic lupus erythematosis (SLE) is an autoimmune disease characterized by loss of tolerance to nuclear antigens. Mice deficient in Lyn, a negative regulator of B and myeloid cell function, develop SLE-like disease. Reduced dosage of Btk in B cells and lack of Btk expression in myeloid cells prevents plasma cell accumulation and autoantibodies in lyn-/- mice while maintaining B cell hypersensitivity to BCR crosslinking. This suggeststhat 1) control of plasma cell numbers by the balance of Lyn and Btk signals is a checkpoint that normally prevents autoimmunity and 2) myeloid defects may contribute to autoimmunity in lyn-/- mice. The mechanism for the Btk-dependent increase in splenic plasma cells in lyn-/- mice will be defined in Specific Aim 1. Plasma cell lifespan will be measured in vivo to determine whether increased production or increased survival of plasma cells occurs in lyn-/- mice. In vitro culture systems will be used to compare the ability of wild type, lyn-/-, and Iyn-/-Btklo plasma cells to differentiate and survive alone, in response to various stimuli, and in the presence of wild type, lyn-/-, and Iyn-/-Btklo myeloid lineage cells. In Specific Aim 2, mixed bone marrow chimeras and mice with conditional deletion of lyn in either the B or myeloid lineage will be used to determine whether autoimmunity requires Lyn deficiency in B cells, myeloid cells, or both. Specific Aim 3 will determine whether reduced Btk dosage and the Slesl suppressor allele (characterized in detail in Project 1) suppress autoimmunity via similar or different mechanisms. Iyn-/-Sles1 mice will be generated and compared to lyn-/- and Iyn-/-Btklo mice in terms of autoimmune phenotypes, splenic cell populations, sensitivity of B and myeloid lineage cells to activation, and gene expression profiles. In addition, the effect of Btk and Slesl on tolerance checkpoints in immature B cells will be compared. These studies will identify potential new therapeutic targets for SLE at the level of cell populations, pathways,and individual molecules.

系统性狼疮性肾炎（SLE）是一种自身免疫性疾病，其特征是对核毒性的耐受性丧失。 抗原缺乏林恩（一种B和骨髓细胞功能的负调节因子）的小鼠， 疾病B细胞中Btk剂量的减少和骨髓细胞中Btk表达的缺乏阻止了浆细胞 在林恩-/-小鼠中的自身抗体的积累，同时维持B细胞对BCR交联的超敏性。 这表明：1）通过平衡林恩和Btk信号来控制浆细胞数量是一个检查点 2）髓样缺陷可能导致林恩-/-小鼠的自身免疫。 林恩-/-小鼠中脾浆细胞的Btk依赖性增加的机制将在下文中定义。 具体目标1.将在体内测量浆细胞寿命，以确定是否增加的产量或增加的细胞周期。 在林恩-/-小鼠中出现浆细胞存活增加。体外培养系统将用于比较 野生型、林恩-/-和Iyn-/-Btklo浆细胞响应于 各种刺激，并且在野生型、林恩-/-和Iyn-/-Btklo骨髓谱系细胞存在下。具体目标 2，混合骨髓嵌合体和在B或髓系中具有条件性林恩缺失的小鼠 将用于确定自身免疫是否需要B细胞、骨髓细胞或两者中的林恩缺陷。 具体目标3将确定减少的Btk剂量和Slesl抑制等位基因（特征在于， 项目1中的细节）通过相似或不同的机制抑制自身免疫。Iyn-/-Sles 1小鼠将 产生并与林恩-/-和Iyn-/-Btklo小鼠在自身免疫表型、脾细胞 群体、B和髓系细胞对活化的敏感性以及基因表达谱。在 此外，将比较Btk和Slesl对未成熟B细胞中耐受性检查点的影响。这些 这些研究将在细胞群、通路和免疫学水平上确定SLE潜在的新治疗靶点。 单个分子。