COMPLEMENT POLYMORPHISM IN RENAL DISEASE

肾脏疾病中的补体多态性

• 批准号: 3230420
• 负责人: ROBERT H MCLEAN
• 金额: $ 17.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-03-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3230420
• 关键词: alleles; antiidiotype antibody; antireceptor antibody; autoantibody; autoimmune disorder; biological polymorphism; chromosome disorders; complement; complement deficiency; complement receptor; complementary DNA; enzyme linked immunosorbent assay; gel electrophoresis; gene conversion; gene deletion mutation; genetic manipulation; glomerulonephritis; human subject; immunodiffusion; immunoglobulin A; major histocompatibility complex; molecular pathology; monoclonal antibody; nephrotic syndrome; nucleic acid probes; purpura; radioimmunoassay; radiotracer; systemic lupus erythematosus; tissue /cell culture

The overall goal of this research proposal is the exploration of functional consequences of specific immunogenetic and molecular DNA markers of disease which may be related to the pathogenesis of certain glomerulonephritides. Humoral factors such as complement (C) participate in many forms of immune mediated diseases; previous studies from this laboratory and other have identified specific alleles of the highly polymorphic C4A, C4B, BF and HLA loci of the 6th human chromosome which are statistically more common in certain glomerulonephritides - such as lupus erythematosus, Henoch-Schonlein purpura, IgA nephropathy and the nephrotic syndrome of childhood. Our specific aims are to further study the isolated DNA from selected patients with these diseases using available complement (C4 and C3) cDNA probes and endonuclease digestions followed by Southern transfer to nitrocellulose and hybridization with labelled (32P) probes. Gene deletions, restriction fragment polymorphism (RFLP) and other molecular abberations (such as gene conversion) will be sought using standard methods. Functional studies of specific alleles (which may be related to pathogenesis of disease) will be studied. Specifically, the activity of different C4 and C3 alleles to mediate attachment to the C3b/C4b (CR1) red cell receptor will be evaluated; circulating antibody which may interfere with the normal CR1 activity and which may be related to specific DNA abnormalities or to specific C alleles will be sought. The C3 nephritic factor - an autoantibody to activated C3 and factor B may be such an antibody. The recognition that the C4A allele is deleted from the "immune related" haplotype HLA-A1, B8, DR3, C4AQO, C4B1, BFS has lead us to investigate diseases associated with C4A and C4B null alleles but not necessarily with this entire "extended haplotype". Preliminary studies support the conclusion that deletions of C4 genes may be associated with certain glomerulonephritides. Clarification of the association between C gene abberations and glomerulonephritis may reveal important pathogenic mechanisms which may permit more specific therapy.

该研究建议的总体目标是探索 特定免疫遗传学和功能后果 疾病的分子DNA标记，可能与 某些肾小球酮的发病机理。 体液因素 例如补充（c）参与多种形式的免疫 介导的疾病；该实验室的先前研究和 其他已经确定了高度多态性的特定等位基因 第六人染色体的C4A，C4B，BF和HLA基因座 从统计学上讲，在某些肾小球酮中更常见 - 例如狼疮红斑，Henoch-Schonlein Purpura，Iga 肾病和儿童期肾病综合征。 我们的 具体目的是进一步研究来自 选择这些疾病的患者使用可用的补充 （C4和C3）cDNA探针和核酸内切酶消化随后 通过南部转移到硝酸纤维素和杂交 标记（32p）探针。 基因缺失，限制片段 多态性（RFLP）和其他分子差（例如 基因转化）将使用标准方法寻求。 特定等位基因的功能研究（可能与 将研究疾病的发病机理）。 具体来说， 不同的C4和C3等位基因的活动以介导附着 将评估C3B/C4B（CR1）红细胞受体； 可能干扰正常CR1的循环抗体 活性，可能与特定的DNA异常有关 或将寻求特定的C等位基因。 C3肾素因子 - 激活的C3和因子B的自身抗体可能是这样的 抗体。 认识到C4A等位基因被从“免疫”中删除 相关的“单倍型HLA-A1，B8，DR3，C4AQO，C4B1，BFS 引导我们研究与C4A和C4B无效的疾病 等位基因，但不一定是整个“扩展单倍型”。 初步研究支持删除C4的结论 基因可能与某些肾小球苯二酚有关。 澄清C基因差和 肾小球肾炎可能揭示了重要的致病机制 这可能允许更具体的疗法。