MOLECULAR STRUCTURE OF AUTOANTIGENS

抗Sm抗体与风湿性心脏病有内在联系 系统性红斑狼疮(SLE)。这是一种慢性 影响女性比例较大的炎症性疾病 这个国家的人口。拟议的研究旨在模拟 将Sm多肽定义为自身抗体的分子特性 系统性红斑狼疮的靶点。这一信息是必要的前奏 下一代临床检测方法的发展。这样的化验将会 被设计成具有广度和敏感度， 检测任何在病理上有意义的抗Sm抗体 个人的血清。在描绘离散的Sm免疫反应域时， 最初的重点将是两个主要的Sm抗原，Sm-D(D1)。 和Sm-B‘/(B3)。这些自身抗原的特征是既有 连续表位和不连续表位。提出了一种新的方法来 将单个Sm抗原作为一个整体来看待，使用 针对单个氨基酸残基的随机聚合酶链式反应突变-和 最终生成残留物地形图，当 改变，导致抗原性丧失。根据初步的情况 表明Sm-D1表位占优势的证据是 将实施构象、结构研究，以可视化 褶皱结构。具体的实验方法(核磁共振位移 相关谱研究)的选择既是因为它的简单性，也是为了 它适用于抗原-抗体接触部位的研究。全 这些实验将产生信息来指导表达 紧密模拟真实抗原的重组多肽。 这些重组蛋白将作为开发的基础。 新的、选择性的抗Sm抗体检测方法 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的图谱 多肽。最后，Sm多肽的性质是交叉的- 探讨反应性时将特别注意内部 基团关系(在蛋白质D家族内)和基团间 (B与D的)关系。Sm多肽，凭借其 数量和多样性，以及它们与一种显著风湿病的关联 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结论 这个主要自身抗原家族的多维复合体，它 信息是理解系统性红斑狼疮及其病因学的基础 伴随着自身抗体的产生。

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.