Nucleoprotein Immune Complexes and Interferon in Diffuse Neuropsychiatric SLE

弥漫性神经精神 SLE 中的核蛋白免疫复合物和干扰素

• 批准号: 7238549
• 负责人: Keith B. Elkon
• 金额: $ 20.11万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238549
• 关键词: Accounting; Addendum; Affect; Antibodies; Antigen-Antibody Complex; Antigens; Apoptotic; Autoantibodies; Autoantigens; Behavior; Brain; Cell Death; Cell Death Induction; Cells; Complex; Coupled; Diffuse; Frequencies; Human; Immune system; Inflammatory; Injury; Interferons; Lead; Link; Lupus; Mass Spectrum Analysis; Microglia; NIH Program Announcements; Nature; Necrosis; Neuraxis; Neuropsychiatric Systemic Lupus Erythematosus; Nucleic Acids; Nucleoproteins; Numbers; Oligonucleotides; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Process; Proteins; Publishing; Reporting; Role; Sensitivity and Specificity; Serum; Small Interfering RNA; Source; Specificity; Symptoms; Systemic Lupus Erythematosus; Techniques; Testing; Tissues; Toll-like receptors; Writing; cytokine; cytotoxic; neuron loss; neuropsychiatry; response

DESCRIPTION (provided by applicant): The cause(s) of neuropsychiatric systemic lupus erythematosus (NPSLE) remains an enigma. Although numerous reports of associations between specific autoantibodies and CNS manifestations have been published, serum levels of none of these autoantibodies has consistently shown a high degree of sensitivity and specificity for NPSLE. Recently it has been demonstrated that immune complexes containing nucleoproteins become internalized and stimulate Toll Like Receptors (TLRs) to produce type 1 interferon (IFN). IFN has previously been implicated in NPSLE and high concentrations of IFN are known to cause neuropsychiatric symptoms similar to NPSLE. We therefore hypothesize that cell death coupled with the release of nucleoproteins results in the formation of immune complexes that stimulate TLRs to produce high local concentrations of type 1 IFN (and perhaps other cytokines) in the central nervous system (CNS) thereby causing NPSLE. The specific aims of the proposal are: To compare the frequency and activity of interferogenic (IFG) complexes in the serum (and CSF) of patients with and without NPSLE. The ability of serum from NPSLE and non NPSLE, matched for activity and other parameters to stimulate IFN and other inflammatory cytokines from mixed peripheral blood mononuclear cells as well as from cultured human microglia will be compared. A requirement for apoptotic or necrotic cells as a source of antigens will be tested and the ability of NPSLE serum to induce both cell death of neuronal targets followed by IFG immune complex formation will be examined. To determine the autoantibody specificities, nature of the antigens and TLR pathway responsible for the IFG activity. The autoantigens, their nucleic acid composition will be defined by immunochemical techniques and mass spectrometry as required. The cellular origin of cytokines will be determined by positive and negative selection. Identification of specific TLRs will be achieved by selective inhibition of endosomal TLR using oligonucleotides or siRNA. These studies are expected to lead to a new understanding of the pathogenesis of NPSLE that accounts for both autoantibodies with 'cytotoxic' function as well as autoantibodies that form nucleoprotein complexes that are now known to stimulate IFN and other pro-inflammatory and neuromodulatory cytokines. The cause of most cases of lupus affecting the brain is unknown, but there is good evidence to suggest that certain types of antibodies may play a role. Here, we test the idea that the sequential action of different antibodies that cause tissue injury followed by antibodies that capture antigens and enter the cell, causes the release of proteins called cytokines that alter brain function.

描述（由申请人提供）：神经精神系统性红斑狼疮（NPSLE）的病因仍然是一个谜。尽管已经发表了许多关于特异性自身抗体与CNS表现之间的相关性的报道，但这些自身抗体的血清水平均未一致地显示出NPSLE的高度敏感性和特异性。最近已经证明，含有核蛋白的免疫复合物被内化并刺激Toll样受体（TLR）产生1型干扰素（IFN）。干扰素先前已被牵连在NPSLE和高浓度的干扰素是已知的，导致类似于NPSLE的神经精神症状。因此，我们假设，细胞死亡加上释放的核蛋白导致免疫复合物的形成，刺激TLR产生高浓度的1型IFN（和其他细胞因子）在中枢神经系统（CNS），从而导致NPSLE。该提案的具体目的是：比较有和没有NPSLE患者血清（和CSF）中干扰素（IFG）复合物的频率和活性。将比较来自NPSLE和非NPSLE的血清在活性和其它参数上匹配的刺激来自混合的外周血单核细胞以及来自培养的人小胶质细胞的IFN和其它炎性细胞因子的能力。将测试对凋亡或坏死细胞作为抗原来源的需求，并将检查NPSLE血清诱导神经元靶细胞死亡以及随后IFG免疫复合物形成的能力。确定自身抗体特异性、抗原性质和负责IFG活性的TLR途径。根据需要，将通过免疫化学技术和质谱法确定自身抗原及其核酸组成。细胞因子的细胞来源将通过阳性和阴性选择来确定。特异性TLR的鉴定将通过使用寡核苷酸或siRNA选择性抑制内体TLR来实现。这些研究预计将导致对NPSLE发病机制的新理解，其解释了具有“细胞毒性”功能的自身抗体以及形成核蛋白复合物的自身抗体，所述核蛋白复合物现在已知刺激IFN和其他促炎性和神经调节性细胞因子。大多数狼疮影响大脑的原因尚不清楚，但有很好的证据表明某些类型的抗体可能起作用。在这里，我们测试的想法，不同的抗体，导致组织损伤，其次是抗体，捕获抗原和进入细胞的顺序行动，导致释放的蛋白质称为细胞因子，改变大脑功能。