Mechanisms of the suppression of autoimmunity

系统性红斑狼疮(SLE)是一种自身免疫性疾病，其特征是对核的耐受性丧失。 抗原。B和髓系细胞功能的负调节因子Lyn缺乏的小鼠会发展成SLE样 疾病。B细胞BTK剂量减少和髓系细胞缺乏BTK表达可阻止浆细胞 在LYN-/-小鼠体内积累自身抗体，同时维持B细胞对BCR交联物的超敏反应。 这表明1)通过Lyn和Btk信号的平衡来控制浆细胞的数量是一个检查点 这通常会阻止自身免疫，2)髓系缺陷可能会导致LYN-/-小鼠的自身免疫。 依赖BTK的Lyn-/-小鼠脾浆细胞增加的机制将在 具体目标1.将在体内测量浆细胞寿命，以确定增加的产量或 在Lyn-/-小鼠中，浆细胞的存活率增加。体外培养系统将被用来比较 野生型、Lyn-/-和iyn-/-Btklo浆细胞单独分化和存活的能力 各种刺激，在野生型存在时，Lyn-/-和iyn-/-Btklo髓系细胞。以特定的目标 2，混合骨髓嵌合体和B或髓系LYN有条件缺失的小鼠 将用于确定自身免疫是否需要B细胞、髓系细胞或两者都有LYN缺陷。 具体目标3将确定减少的BTK剂量和SLEL抑制等位基因(特征为 项目1)通过相似或不同的机制抑制自身免疫。Iyn-/-sles1小鼠将成为 产生并与Lyn-/-和iyn-/-Btklo小鼠在自身免疫表型、脾细胞 人群，B细胞和髓系细胞对激活的敏感性，以及基因表达谱。在……里面 此外，还将比较BTK和Slesl对未成熟B细胞耐受检查点的影响。这些 研究将确定SLE潜在的新治疗靶点，从细胞群体、途径和 单个分子。

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.