USING IDIOTYPES TO ASSESS SLE IN MINORITY WOMEN

使用独特型评估少数民族女性的系统性红斑狼疮

• 批准号: 3162802
• 负责人: Anne Davidson
• 金额: $ 23.08万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3162802
• 关键词: B lymphocyte; DNA binding protein; affinity chromatography; antiantibody; antibody receptor; antibody specificity; antigen antibody reaction; antiidiotype antibody; antinuclear autoantibody; biomarker; electron microscopy; enzyme linked immunosorbent assay; female; histochemistry /cytochemistry; human subject; immune complex; immunopathology; kidney disorder; kidney disorder diagnosis; laboratory mouse; laboratory rat; medical complication; protein sequence; systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disorder primarily affecting women of childbearing age. IgG antibodies to double stranded DNA (antidsDNAb) appear to be a critical pathogenetic factor in the renal disease of SLE. These antibodies are deposited in the kidneys of patients with SLE nephropathy and their levels correlate with severity of renal disease. However, not all antibodies that bind dsDNA are pathogenic. Despite intense study, the factors that contribute to renal pathogenicity have not been clearly elucidated. We are interested in studying the features of anti-dsDNAb that may be responsible for causing renal disease in SLE patients. Our approach will be to analyze anti-dsdnab reactive with three monoclonal anti-idiotypes: F4, that recognizes a heavy chain determinant on IgG anti-dsdnab; 8.12, that recognizes a lambda light chain determinant; and 3I that recognizes a kappa light chain determinant. F4 reactive heavy chains are often associated with 3I reactive light chains and these antibodies are preferentially DNA binding. F4 rarely associates with 8.12 but F4 and 8.12 both recognize positively charged (cationic) anti-dsdnab. Cationic anti-dsdnab are preferentially deposited in the kidneys of both mice and humans with SLE, and in fact, all three of our anti-idiotypes bind to Ig deposited in lupus kidneys. We propose to study a large cohort of SLE patients to correlate clinical disease activity with serum levels of 3I, F4 and 8.12 reactivity. In addition we will test polyclonal anti-dsdnab from serum and monoclonal anti-dsdnab derived from transformed B cell lines from SLE patients for renal sequestration in a rat perfusion model. We will perform immunolocalization studies on perfused rat kidneys and on kidneys from SLE patients undergoing renal biopsy to determine specific sites of deposition of pathogenic antibodies. We will further analyze the structural features of 3I, F4 and 8.12 reactive antibodies using immunochemical and molecular biology techniques and develop new antidiotypic reagents that preferentially recognize nephritogenic anti- dsdnab. These experiments will define the features of anti-dsdnab that make them likely to deposit in lupus kidneys and may help establish diagnostic tests that will allow us predict onset and follow the course of patients with lupus nephropathy.

全身性红斑狼疮（SLE）是多系统炎症障碍 主要影响育龄的妇女。 IgG抗体加倍 滞留的DNA（抗AntidsDNAB）似乎是关键的致病因素 SLE的肾脏疾病。 这些抗体沉积在肾脏中 SLE肾病及其水平与严重程度相关的患者 肾脏疾病。 但是，并非所有结合dsDNA的抗体都是 致病性。 尽管进行了深入研究，但导致肾脏的因素 致病性尚未清楚地阐明。 我们有兴趣研究抗DSDNAB的特征 负责在SLE患者中引起肾脏疾病。 我们的做法意愿 要用三种单克隆抗IDiotypes分析抗DSDNAB反应性： F4，它识别IgG抗DSDNAB上的重链决定因素； 8.12， 这识别出Lambda轻链决定因素； 3i认识到 Kappa轻链决定因素。 F4反应性重链通常是 与3i反应光链和这些抗体有关 优先使用DNA结合。 F4很少与8.12相关，但是F4和 8.12都识别带正电的（阳离子）抗DSDNAB。 阳离子 抗DSDNAB优先沉积在小鼠的肾脏和 具有SLE的人，实际上，我们所有三种抗IDiotypes都与Ig结合 存放在狼疮肾脏中。 我们建议研究大量的SLE患者，以相关临床 血清水平为3i，F4和8.12反应性的疾病活性。 在 此外，我们将测试血清和单克隆的多克隆抗DSDNAB 抗DSDNAB来自SLE患者转化的B细胞系的抗DSDNAB 大鼠灌注模型中的肾隔离。 我们将表演 对灌注大鼠肾脏和肾脏的免疫定位研究 SLE患者正在进行肾脏活检以确定 致病抗体的沉积。 我们将进一步分析 3i，F4和8.12的结构特征使用使用 免疫化学和分子生物学技术并开发新的 抗原型试剂优先识别肾病 DSDNAB。 这些实验将定义抗DSDNAB的特征 使它们可能存入狼疮肾脏，并可能有助于建立 诊断测试将使我们预测发作并遵循课程 狼疮肾病的患者。