• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Molecular and structural characterization of autoreactive epitopes in human glutamic acid decarboxylase (GAD 65).
【24h】

Molecular and structural characterization of autoreactive epitopes in human glutamic acid decarboxylase (GAD 65).

机译：人谷氨酸脱羧酶（GAD 65）中自身反应性表位的分子和结构表征。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The goal of this thesis is to gain a molecular understanding of the autoreactivity to glutamic acid decarboxylase 65 (GAD65), which plays a major role in two human diseases, type I diabetes and stiff-man syndrome. Homolog scanning mutagenesis was used to fine map distinct conformational and linear epitopes recognized by a panel of sixteen human monoclonal antibodies derived from patients and eight murine monoclonal antibodies derived from immunized Balb/c mice. The high resolution epitope mapping together with two- and three-dimensional structure prediction resulted in a model of the GAD65 dimer which has structural similarities to ornithine decarboxylase in the co-enzyme binding middle domain and to dialkylglycine decarboxylase in the C-terminal domain. A comparative study of GAD65 antibodies in prediabetic children, newly diagnosed individuals, and long-term diabetics revealed multiple epitopes are recognized throughout all disease stages and that waves of autoimmunity target different regions of the molecule during chronic inflammation. Amongst children who had recently developed GAD65 antibodies, multiple epitopes are recognized suggesting that epitope spreading is a very rapid event and/or that there are multiple co-dominant epitope regions in GAD65. The identified epitopes localize to multiple hydrophilic patches and reveal a spectrum of human autoreactivity to GAD65, which is not confined to one dominant region, but rather involves most of the surface of the folded protein, suggesting that GAD65 is mainly presented to B cells as a native rather than degraded antigen. Together, these findings establish a useful paradigm for the study of autoreactivity in other human autoimmune diseases.
机译：本文的目的是获得对谷氨酸脱羧酶65（GAD65）自身反应性的分子理解，谷氨酸脱羧酶65在两种人类疾病，I型糖尿病和僵硬综合症中起主要作用。同源扫描诱变用于精细定位由一组来自患者的十六种人单克隆抗体和来自免疫Balb / c小鼠的八种鼠类单克隆抗体识别的独特构象和线性表位。高分辨率表位作图以及二维和三维结构预测产生了GAD65二聚体模型，该模型与辅酶结合中间结构域中的鸟氨酸脱羧酶和C末端结构域中的二烷基甘氨酸脱羧酶具有结构相似性。对糖尿病前期儿童，新诊断的个体和长期糖尿病患者中GAD65抗体的比较研究表明，在所有疾病阶段均识别出多个表位，并且在慢性炎症过程中，自身免疫波针对分子的不同区域。在最近发展出GAD65抗体的儿童中，认识到多个表位表明表位扩散是一个非常迅速的事件，并且/或者GAD65中存在多个共同的表位区域。鉴定出的表位位于多个亲水性斑块上，揭示了人类对GAD65的自身反应谱，该谱不限于一个显性区域，而是涉及折叠蛋白的大部分表面，这表明GAD65主要以B形式呈递给B细胞。天然而不是降解的抗原。这些发现共同为研究其他人类自身免疫性疾病的自身反应性建立了有用的范例。

著录项

  • 作者

    Schwartz, Heather Lauren.;

  • 作者单位

    University of California, San Francisco.;

  • 授予单位 University of California, San Francisco.;
  • 学科 Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 1998
  • 页码 199 p.
  • 总页数 199
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号