MOLECULAR STRUCTURE OF AUTOANTIGENS

抗Sm抗体与风湿性关节炎有内在联系， 系统性红斑狼疮（SLE） 这是一种慢性 炎症性疾病影响了很大一部分女性 这个国家的人口。 拟议的研究旨在模拟 确定Sm多肽为自身抗体的分子特性 SLE中的靶点。 这一信息是必要的前奏， 开发下一代临床检测方法。 这种测定将 设计的广度和敏感度应 检测任何病理显著的抗Sm抗体存在于 个体的血清。 在描绘离散Sm免疫反应域， 最初的重点是两种主要的Sm抗原，Sm-D（D1） 和Sm-B ′/（B3）。 这些自身抗原将被表征为 连续和不连续表位。 提出了一种新的方法， 将单个Sm抗原作为一个整体，使用以下技术： 随机PCR诱变以靶向单个氨基酸残基-和 最终生成残留物的地形图，当 改变，导致抗原性丧失。 根据初步 有证据表明Sm-D1表位的优势是 构象，结构研究将实施可视化 折叠结构 具体的实验方法（NMR位移 相关光谱研究）的选择，因为它的简单性和 其对抗原抗体接触位点研究的适用性。 所有 这些实验将产生信息， 重组多肽，其紧密模拟真实抗原。 这些重组蛋白将作为开发的基础 抗Sm抗体的新的选择性检测， SLE的诊断/预后。 类似的研究将包括新的 描述了Sm-D2和Sm-D3抗原，以扩展主要Sm 多肽。 最后，Sm多肽的性质交叉- 反应性将进行探讨，特别注意内部， 组间关系（D蛋白家族内）和组间关系 关系（B对D）。 Sm多肽，凭借其 数量和多样性，以及它们与突出的风湿性关节炎的关系， 疾病，提供了一个独特的模式系统。 所有这些研究都应该得出 这种主要自身抗原家族的多维复合物， 这些信息是了解SLE病因及其 伴随自身抗体的产生。

Anti-Sm antibodies are intrinsically associated with the rheumatic disease systemic lupus erythematosus (SLE). This is a chronic inflammatory disease affecting a significant proportion of the female population in this country. The proposed studies were intended to model the molecular properties that define the Sm polypeptides as autoantibody targets in SLE. This information is a necessary prelude to the development of the next generation of clinical assays. Such assays will be designed to have a breadth and a level of sensitivity that should detect any pathologically significant anti-Sm antibodies present in an individual's serum. In delineating discrete Sm immunoreactive domains, the initial emphasis will be on two of the major Sm antigens, Sm-D (D1) and Sm-B'/(B3). These autoantigens will be characterized as to both continuous and discontinuous epitopes. A new approach is proposed to look at the individual Sm antigens as a whole, using the technique of random PCR mutagenesis to target individual amino acid residues - and ultimately to generate a topographical map of residues which, when changed, result in a loss of antigenicity. In light of preliminary evidence that suggests the preponderance of Sm-D1 epitopes are conformational, structural studies will be implemented to visualize the folded structure. The specific experimental approach (NMR shift correlation spectra studies) was chosen both for its simplicity and for its applicability to the study of antigen-antibody contact sites. All these experiments will generate information to direct the expression of recombinant polypeptides that closely mimic the bona fide antigens. These recombinant proteins will serve as the basis for the development of new, selective assays for the anti-Sm antibodies that are diagnostic/prognostic for SLE. Similar studies will encompass the newly described Sm-D2 and Sm-D3 antigens to extend the profile of the major Sm polypeptides. Finally, the nature of the Sm polypeptides cross- reactivities will be explored with particular attention to the intra- group relationships (within the D family of proteins) and the inter-group relationships (of B versus D). The Sm polypeptides, by virtue of their number and diversity, and their association with a prominent rheumatic disease, provide a unique model system. All of these studies should draw a multi-dimensional composite of this major autoantigen family, which information is basic to any understanding of the etiology of SLE and its attendant autoantibody production.