HUMORAL IMMUNITY IN MULTIPLE SCLEROSIS

在最初三年的工作中，我们的研究重点是 多发性硬化症（MS）中体液免疫应答。 我们发现 鞘内游离κ轻链的合成表明 通过显著增加游离κ链的浓度， 脑脊液（CSF）是一致的，早期的，稳定的 MS患者的异常。 相比之下，我们还没有观察到 在非感染性疾病患者中， 神经系统;培养确定的CNS感染患者 特征性地表现出IgG-λ鞘内体液免疫 免疫反应 因此，我们迄今为止的工作表明， 鞘内游离κ链的过度合成不仅 在MS中的一致异常，但也是非常具体的 与其他IgG的相对非特异性相比，MS 异常 为随后三年的支助提出的研究将 从逻辑上讲，从最初的研究。 我们谨慎地建议- 设计的前瞻性临床研究，旨在确定 在女士体液免疫异常的相关性。首先，我们将 进行前瞻性研究，以确定如何使用CSF 预测疾病进展速率和严重程度的参数 这项研究很重要，因为我们完全无法 早期预测个别MS患者可能的疾病严重程度 这种变异性极大的疾病的病程 除了 这给所有相关人员带来了痛苦， 治疗试验中组内异质性，混杂 治疗效果的解释。 第二，我们将确定 脑脊液IgG异常在预测预后中价值 在患有以下疾病的个体中进展为播散性疾病 单一症状疾病 第三，我们将确定最佳的 特别是用于诊断MS的测试或测试组合 临床环境。 我们将使用接收器操作特性 和决策分析，以提出临床上有用的算法 生成的数据。 这些研究提供了这样的承诺： 阐明体液免疫异常的临床相关性 在疾病中。

During the initial three years of work our studies focused on the humoral immune response in Multiple Sclerosis (MS). We found that the intrathecal synthesis of free kappa light chains manifest by markedly increased concentrations of free kappa chains in cerebrospinal fluid (CSF) was a consistent, early, and stable abnormality in MS patients. In contrast, we have not yet observed this abnormality in patients with noninfectious diseases of the nervous system; patients with culture-established CNS infections characteristically exhibited an IgG-lambda intrathecal humoral immune response. Thus, our work to date suggests that exaggerated intrathecal synthesis of free kappa chains is not only a consistent abnormality in MS, but is also remarkably specific for MS compared with the relative nonspecificity of other IgG abnormalities. Studies proposed for the subsequent three years of support will logically follow from the initial studies. We propose carefully- designed prospective clinical studies designed to determine the relevance of humoral immune abnormalities in Ms. First, we will conduct a prospective study to determine how to use CSF parameters to predict the rate and severity of disease progression in MS. This study is important because of our total inability to predict the likely disease severity in individual MS patient early in the course of this extremtly variable disease. In addition to causing distress for all concerned, this results in marked heterogeneity within groups in therapeutic trials, confounding interpretation of treatment efficacy. Second, we will determine the prognostic value of CSF IgG abnormalities in predicting progression to disseminated disease in individuals with monosymptomatic disease. Third, we will determine the optimal test or combination of tests for the diagnosis of MS in particular clinical settings. We will use receiver operating characteristics and decision analysis to propose clinically useful algorithms based on the generated data. These studies offer the promise of clarifying the clinical relevance of humoral immune abnormalities in the disease.