Agonists and Antagonists of Neuropsychiatric Lupus

描述（由申请人提供）：神经精神狼疮的激动剂和拮抗剂项目摘要神经精神系统性红斑狼疮（NPSLE）是一种常见的和潜在的致命形式的狼疮。两种异常一直与NPSLE相关：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，这两种异常之间的关系相对未被探索。在我们之前资助的R21提案中，我们假设细胞死亡加上核蛋白的释放会导致免疫复合物的形成，这些复合物刺激Toll样受体（TLR）产生高局部浓度的1型IFN（也许还有其他细胞因子））。在初步数据中，我们确实观察到，与对照组相比，来自NPSLE患者的脑脊液（CSF）具有显著更高的干扰素（IFN）-α诱导潜力，并且对于IgG浓度进行标准化，IFN诱导活性比血清高800倍。CSF中的自身抗体相对于血清的高IFN诱导活性由CSF中某些蛋白抑制剂的低浓度解释。1）免疫复合物的IFN-α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、疾病亚群或CNS损伤相关？将在NPSLE的19个病例定义之间、在通过蛋白质组学阵列确定的不同自身抗体特异性之间以及与脑细胞损伤标志物确定的相关性之间比较来自充分表征的NPSLE患者的血清和CSF的细胞因子诱导能力。在儿科人群中，我们将研究IFN-α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，我们问什么是机制，两个确定的血清因子抑制IFG活性？已经鉴定了至少两种血清因子，其抑制CSF中自身抗体的IFN-α诱导活性。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：即使排除了最常见（但特异性最低）的NPSLE亚型，NPSLE也发生在约一半的SLE儿科病例中，并且在成人SLE病例中比例很高。我们已经证明了NPSLE患者CSF中自身抗体的潜在炎症作用，并鉴定了蛋白抑制剂。这些抑制剂的现成可用性将使我们能够考虑在未来的治疗用途。公共卫生相关性：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。我们已经证明，这些抗体在脑液中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，并确定某些蛋白质抑制剂如何用于抑制炎症。

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.