Regulation of the anti-phospholipid response in SLE

SLE 抗磷脂反应的调节

• 批准号: 7867726
• 负责人: Anne Davidson
• 金额: $ 42.48万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867726
• 关键词: Address; Affinity; Alleles; Antibodies; Antibody Formation; Anticoagulation; Antigen-Antibody Complex; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Apoptosis; Apoptotic; Autoantibodies; Autoimmune Process; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Blood Clot; Blood coagulation; Bone Marrow; Cardiolipins; Cell Death; Cell Maturation; Cell Survival; Cells; Ceramides; Chimera organism; Clinical; Clinical Trials; Coagulation Process; Complement; Data; Dendritic Cells; Development; Disease; Endosomes; Endothelial Cells; Endothelium; Event; Fc Receptor; Female; Fostering; General Population; Genes; Genetic; Goals; Human; IRAK1 gene; Immune response; Immune system; Immunoglobulin Class Switching; Immunoglobulin G; Individual; Inflammation; Inflammation Mediators; Interferon-alpha; Interferons; Lupus; Maps; Mediating; Mus; Nephritis; Nucleic Acids; Outcome; Pathogenicity; Pathway interactions; Patients; Phospholipids; Plasma Cells; Production; Proliferative Glomerulonephritis; Recurrence; Regulation; Risk; Role; STAT4 gene; Second Messenger Systems; Serum; Signal Transduction; Staging; Stress; Syndrome; Systemic Lupus Erythematosus; T-Cell Depletion; T-Lymphocyte; TALL-1 protein; TLR7 gene; Testing; Therapeutic immunosuppression; Thrombocytopenia; Thrombophilia; Thrombosis; Thrombus; Tissues; To autoantigen; Transgenic Organisms; Up-Regulation; acid sphingomyelinase; anti-IgG; base; cytokine; effective therapy; fetal; genome wide association study; genome-wide analysis; human disease; immune function; in vivo; male; mouse model; novel therapeutics; overexpression; particle; research study; response; second messenger

The goal of this proposal is to determine the mechanisms for loss of B cell tolerance to phospholipids and mechanisms for tissue damage by anti-phospholipid antibodies in NZW/BXSB F1 (W/B) mice that develop both proliferative glomerulonephritis and anti-phospholipid syndrome. Disease is accelerated in male W/B mice that carry the Yaa locus containing a reduplication of the TLR7 gene. We have shown that T cell help is required for initial activation of anti-phospholipid B cells and induction of high affinity IgG autoantibodies. We hypothesize that immune complex formation and opsonization of apoptotic particles by IgG anti-phospholipid antibodies results in delivery of nucleic acids to TLR containing endosomes. Engagement of TLRs induces both IFNα that fosters plasma cell maturation and BAFF that decreases the stringency for B cell negative selection and enhances B cell survival and class switching. Although disease is initiated by T cells, we hypothesize that after class switched antibodies with high enough affinity to generate immune complexes accumulate, disease can then be propagated by T cell independent mechanisms that are prominent in males bearing excess TLR7. Because excess IFNα production is a feature of SLE and IFNα induces upregulation of TLR7, particularly in females, similar mechanisms may pertain in individuals with the IFN signature even though genetic TLR7 overexpression has not been found in humans with SLE. To address this hypothesis, we will use mice with an autoreactive transgenic heavy chain and examine B cell selection at sequential stages of the B cell developmental pathway. This strategy will allow us to examine the role of intrinsic alterations in B cell signaling, exogenous signals from the innate immune system and T cell help in the initial loss of tolerance to autoantigens and in the perpetuation of the anti-phospholipid response. Our data will also help determine why anti-phospholipid syndrome fails to respond to conventional immunosuppressive therapies and help suggest new strategies for treating this devastating syndrome. The second hypothesis that we wish to address is that pathogenic autoantibodies alone can cause the manifestations of the anti-phospholipid syndrome that are mediated by Fc receptor or complement dependent mechanisms but that the formation of thromboses requires other inflammatory mediators to activate the endothelium. We will test the hypothesis that one mechanism for this ¿second hit¿ is endothelial cell death mediated via the ceramide pathway. Our long term goal is to define the interactions of the crucial pathways that contribute to induction and propagation of the anti-phospholipid syndrome so as to best devise individualized therapies for patients with SLE.

本提案的目的是确定B细胞对磷脂耐受性丧失的机制 NZW/BXSB F1（W/B）小鼠中抗磷脂抗体引起的组织损伤的机制 增生性肾小球肾炎和抗磷脂综合征。在雄性W/B小鼠中疾病加速 其携带含有TLR 7基因的重复的Yaa基因座。我们已经证明，T细胞的帮助是 抗磷脂B细胞的初始活化和高亲和力IgG自身抗体的诱导所需。我们 假设免疫复合物形成和抗磷脂抗体对凋亡颗粒的调理作用 抗体导致核酸递送到含有TLR的内体。TLR的参与诱导 促进浆细胞成熟的IFN和降低B细胞阴性严格性的BAFF 选择并增强B细胞存活和类别转换。虽然疾病是由T细胞引发的，但我们 假设在具有足够高亲和力以产生免疫复合物的类别转换抗体之后 积累，疾病可以通过T细胞独立机制传播，这在男性中很突出。 携带过量的TLR 7。由于IFN的过量产生是SLE的一个特征，而IFN可诱导SLE的细胞因子表达上调， TLR 7，特别是在女性中，类似的机制可能涉及具有IFN特征的个体， 尽管在SLE患者中尚未发现TLR 7基因过表达。 为了解决这一假设，我们将使用具有自身反应性转基因重链的小鼠， 在B细胞发育途径的连续阶段的B细胞选择。这一战略将使我们能够 检查B细胞信号传导中内在改变的作用，来自先天免疫系统的外源信号 和T细胞帮助对自身抗原的耐受性的最初丧失和抗磷脂抗体的永久存在。 反应我们的数据还将有助于确定为什么抗磷脂综合症对常规治疗没有反应 免疫抑制疗法，并帮助提出治疗这种毁灭性综合征的新策略。 我们希望解决的第二个假设是，致病性自身抗体本身就可以引起 由Fc受体或补体依赖性介导的抗磷脂综合征的表现 但是血栓形成需要其他炎症介质来激活 内皮细胞我们将检验这一假设，即第二次打击的一种机制是内皮细胞死亡 通过神经酰胺途径介导。 我们的长期目标是确定有助于诱导的关键途径的相互作用， 抗磷脂综合征的传播，以便为患有 SLE。