Agonists and Antagonists of Neuropsychiatric Lupus

神经精神狼疮的激动剂和拮抗剂

• 批准号: 8278629
• 负责人: Keith B. Elkon
• 金额: $ 33.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278629
• 关键词: Address; Adult; Affect; Agonist; Antibodies; Antigen-Antibody Complex; Aseptic Meningitis; Attenuated; Autoantibodies; Binding; Biological Markers; Brain; Brain Injuries; Cell Death; Cells; Cerebrospinal Fluid; Childhood; Clinical; Collection; Complement; Complement 1q; Coupled; Data; Defect; Diffuse; Dinoprostone; Disease; Employee Strikes; Functional disorder; Funding; Future; Goals; Health; Immunoglobulin G; Individual; Inflammation; Inflammatory; Interferon Type II; Interferons; Intravenous Immunoglobulins; Link; Liquid substance; Lupus; Magnetic Resonance Imaging; Molecular; Neurocognitive; Neuropsychiatric Systemic Lupus Erythematosus; Non-Steroidal Anti-Inflammatory Agents; Nucleoproteins; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Play; Population; Process; Production; Property; Proteins; Proteomics; Publications; Receptor Signaling; Relative (related person); Role; Serum; Signal Transduction; Specificity; Subgroup; Systemic Lupus Erythematosus; Testing; Therapeutic Uses; Toll-like receptors; brain cell; cell injury; cell type; central nervous system injury; cytokine; follow-up; inhibitor/antagonist; monocyte; nervous system disorder; neuropsychiatry; receptor; response; sialylation; uptake

DESCRIPTION (provided by applicant): Agonists and Antagonists of Neuropsychiatric Lupus Project Summary Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common and potentially lethal form of lupus. Two abnormalities have consistently been linked to NPSLE: the presence of autoantibodies and the presence of pro-inflammatory cytokines. However, the role of individual autoantibodies as well as specific cytokines remains controversial and the relationship between these two abnormalities is relatively unexplored. In our previously funded R21 proposal, we hypothesized that cell death coupled with the release of nucleoproteins resulted in the formation of immune complexes that stimulate Toll like receptors (TLRs) to produce high local concentrations of type 1 IFN (and perhaps other cytokines). In preliminary data, we have indeed observed that cerebrospinal fluid (CSF) from NPSLE patients have significantly higher interferon (IFN)-a inducing potential compared to controls and that, normalized for IgG concentrations, the IFN inducing activity was 800-fold higher than serum. The high IFN inducing activity of autoantibodies in CSF relative to serum was explained by the low concentration of certain protein inhibitors in CSF. In the current proposal, we will ask the following questions: 1) Does the IFN-a or other cytokine inducing activity of immune complexes correlate with autoantibody specificity, disease subsets or CNS injury in patients with NPSLE? Cytokine inducing capacity of serum and CSF from well characterized NPSLE patients will be compared between the 19 case definitions of NPSLE, between different autoantibody specificities as determined by a proteomic array and correlations determined with markers of brain cell injury. In the pediatric population, we will examine whether IFN-a inducing activity is associated with neurocognitive defects or MRI changes. 2) In the second Aim, we ask what are the mechanisms whereby two identified serum factors inhibit IFG activity? At least two serum factors have been identified that suppress IFN-a inducing activity by autoantibodies in CSF. We will identify the cell type and receptors that the inhibitors act on and then investigate the mechanism of inhibition. Relevance: Even when the most common (but least specific) subtypes of NPSLE are excluded, NPSLE occurs in about half of pediatric cases of SLE and a high proportion of cases with adult SLE. We have documented the potent inflammatory potential of autoantibodies in the CSF of NPSLE patients and have identified protein inhibitors. The ready availability of these inhibitors will allow us to consider therapeutic uses in the future. PUBLIC HEALTH RELEVANCE: Agonists and Antagonists of Neuropsychiatric Lupus Project Narrative The cause(s) of most cases of lupus affecting the brain are unknown, but there is good evidence to suggest that certain types of antibodies may play a role. We have documented that these antibodies in brain fluid can cause the production of certain inflammatory proteins. Here, we determine which types of neurological disease are associated with specific inflammatory proteins and we determine how certain protein inhibitors can be used to dampen the inflammation.

描述（由申请人提供）：神经精神性狼疮的激动剂和拮抗剂 项目摘要 神经精神性系统性红斑狼疮 (NPSLE) 是一种常见且可能致命的狼疮形式。两种异常一直与 NPSLE 有关：自身抗体的存在和促炎细胞因子的存在。然而，个体自身抗体以及特定细胞因子的作用仍然存在争议，并且这两种异常之间的关系相对尚未被探索。在我们之前资助的 R21 提案中，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 Toll 样受体 (TLR) 产生局部高浓度的 1 型干扰素（可能还有其他细胞因子）。在初步数据中，我们确实观察到，与对照组相比，NPSLE 患者的脑脊液 (CSF) 具有显着更高的干扰素 (IFN) 诱导潜力，并且对 IgG 浓度进行标准化后，IFN 诱导活性比血清高 800 倍。脑脊液中自身抗体相对于血清的高干扰素诱导活性可以通过脑脊液中某些蛋白质抑制剂的低浓度来解释。在当前的提案中，我们将提出以下问题：1）免疫复合物的 IFN-a 或其他细胞因子诱导活性是否与 NPSLE 患者的自身抗体特异性、疾病亚型或 CNS 损伤相关？将在 19 个 NPSLE 病例定义之间、通过蛋白质组阵列确定的不同自身抗体特异性以及与脑细胞损伤标志物确定的相关性之间比较来自明确表征的 NPSLE 患者的血清和脑脊液的细胞因子诱导能力。在儿科人群中，我们将检查 IFN-a 诱导活性是否与神经认知缺陷或 MRI 变化相关。 2) 在第二个目标中，我们询问两种确定的血清因子抑制 IFG 活性的机制是什么？已鉴定出至少两种血清因子可抑制脑脊液中自身抗体诱导 IFN-α 的活性。我们将确定抑制剂作用的细胞类型和受体，然后研究抑制机制。相关性：即使排除最常见（但最不具体）的 NPSLE 亚型，大约一半的儿童 SLE 病例和很高比例的成人 SLE 病例中也会发生 NPSLE。我们已经记录了 NPSLE 患者脑脊液中自身抗体的潜在炎症潜力，并确定了蛋白质抑制剂。这些抑制剂的现成可用性将使我们能够考虑未来的治疗用途。公共卫生相关性：神经精神狼疮项目的激动剂和拮抗剂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。我们已经证明，脑液中的这些抗体可以导致某些炎症蛋白的产生。在这里，我们确定哪些类型的神经系统疾病与特定的炎症蛋白相关，并确定如何使用某些蛋白质抑制剂来抑制炎症。

项目成果

C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes.

• DOI: 10.4049/jimmunol.1001731
• 发表时间: 2010-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Santer DM;Hall BE;George TC;Tangsombatvisit S;Liu CL;Arkwright PD;Elkon KB
• 通讯作者: Elkon KB

Plasmacytoid dendritic cells and C1q differentially regulate inflammatory gene induction by lupus immune complexes.

• DOI: 10.4049/jimmunol.1102797
• 发表时间: 2012-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Santer DM;Wiedeman AE;Teal TH;Ghosh P;Elkon KB
• 通讯作者: Elkon KB

Beyond apoptosis in lupus.

• DOI: 10.1097/bor.0000000000000083
• 发表时间: 2014-09
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: Colonna L;Lood C;Elkon KB
• 通讯作者: Elkon KB