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）：神经精神狼疮项目的激动剂和拮抗剂摘要神经精神上的全身性狼疮红斑（NPSLE）是狼疮的常见且潜在的致命形式。两种异常一直与NPSLE有关：自身抗体的存在和促炎性细胞因子的存在。但是，个体自身抗体以及特定的细胞因子的作用仍然存在争议，这两个异常之间的关系是相对尚未探索的。在我们先前资助的R21提案中，我们假设细胞死亡与核蛋白的释放相结合，导致形成免疫复合物，这些复合物会刺激像受体（TLR）产生高局部局部IFN的高局部浓度（以及其他细胞因子）。在初步数据中，我们确实观察到，来自NPSLE患者的脑脊液（CSF）的干扰素（IFN） - 与对照相比，诱导潜力的干扰素明显更高，并且IGG浓度归一化，IFN诱导活性的诱导活性比血清高800倍。 CSF相对于血清中自身抗体的高IFN诱导活性由CSF中某些蛋白质抑制剂的低浓度解释。在当前建议中，我们将提出以下问题：1）IFN-A或其他细胞因子诱导免疫复合物的活性是否与NPSLE患者的自身抗体特异性，疾病亚群或中枢神经系统损伤相关？将在NPSL的19例定义之间比较来自良好表征的NPSL患者的血清和CSF的细胞因子能力，这是由蛋白质组学阵列确定的不同自身抗体特异性和由脑细胞损伤标记确定的相关性。在小儿人群中，我们将检查IFN-A诱导活性是否与神经认知缺陷或MRI变化有关。 2）在第二个目标中，我们问哪种机制是什么机制鉴定出血清因子抑制IFG活性？至少已经确定了两个血清因子抑制CSF中自身抗体诱导活性的IFN-A。我们将确定抑制剂作用的细胞类型和受体，然后研究抑制作用的机理。相关性：即使排除了最常见（但最少特异性）的NPSE亚型，NPSLE也会发生在大约一半的SLE小儿病例中，而成人SLE的比例很高。我们已经记录了NPSLE患者CSF自身抗体的有效炎症潜力，并鉴定了蛋白质抑制剂。这些抑制剂的现成可用性将使我们将来考虑治疗用途。公共卫生相关性：神经精神狼疮项目叙事的激动剂和对手的大多数影响大脑的狼疮病例的原因是未知的，但是有充分的证据表明某些类型的抗体可能起作用。我们已经证明，这些脑液中的这些抗体会导致某些炎症蛋白的产生。在这里，我们确定哪种类型的神经系统疾病与特定的炎症蛋白有关，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