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: 7393201
• 负责人: Keith B. Elkon
• 金额: $ 16.43万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393201
• 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。尽管已有大量关于特定自身抗体与 CNS 表现之间关联的报告，但这些自身抗体的血清水平均未始终表现出对 NPSLE 的高度敏感性和特异性。最近已证明，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)。 IFN 先前已被证实与 NPSLE 有关，并且已知高浓度的 IFN 会引起与 NPSLE 类似的神经精神症状。因此，我们假设细胞死亡与核蛋白的释放相结合，导致免疫复合物的形成，刺激 TLR 在中枢神经系统 (CNS) 中产生高局部浓度的 1 型 IFN（可能还有其他细胞因子），从而导致 NPSLE。该提案的具体目的是： 比较患有和不患有 NPSLE 的患者血清（和 CSF）中干扰原（IFG）复合物的频率和活性。将比较来自 NPSLE 和非 NPSLE 的血清与活性和其他参数相匹配的混合外周血单核细胞以及培养的人小胶质细胞刺激 IFN 和其他炎症细胞因子的能力。将测试对凋亡或坏死细胞作为抗原来源的需求，并检查 NPSLE 血清诱导神经元靶标细胞死亡和 IFG 免疫复合物形成的能力。确定自身抗体特异性、抗原性质以及负责 IFG 活性的 TLR 通路。自身抗原及其核酸组成将根据需要通过免疫化学技术和质谱法来确定。细胞因子的细胞起源将通过正选择和负选择来确定。通过使用寡核苷酸或 siRNA 选择性抑制内体 TLR，可以实现特异性 TLR 的鉴定。这些研究预计将导致对 NPSLE 发病机制的新认识，该机制解释了具有“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，目前已知核蛋白复合物可以刺激 IFN 和其他促炎和神经调节细胞因子。大多数影响大脑的狼疮病例的原因尚不清楚，但有充分的证据表明某些类型的抗体可能发挥作用。在这里，我们测试了这样的想法：引起组织损伤的不同抗体的连续作用，然后是捕获抗原并进入细胞的抗体，导致释放称为细胞因子的蛋白质，从而改变大脑功能。

项目成果

Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus.

• DOI: 10.4049/jimmunol.182.2.1192
• 发表时间: 2009-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Santer DM;Yoshio T;Minota S;Möller T;Elkon KB
• 通讯作者: Elkon KB

Nature and functions of autoantibodies.

• DOI: 10.1038/ncprheum0895
• 发表时间: 2008-09
• 期刊: NATURE CLINICAL PRACTICE RHEUMATOLOGY
• 作者: Elkon, Keith;Casali, Paolo
• 通讯作者: Casali, Paolo