Protein targets of ovarian and oocyte autoantibodies

描述(由申请人提供)：有令人信服的证据表明卵巢的自身免疫性疾病。在美国，卵巢自身免疫可能会影响100-200万女性。为了识别患有卵巢自身免疫的女性，我们开发了检测卵巢特异性自身抗体的原型免疫分析方法，并利用它们开发了关于卵巢自身免疫与过早绝经(卵巢早衰或POF)和不明原因不孕症之间关系的表型信息。进一步的人类研究和临床应用取决于相关蛋白质抗原的鉴定。该研究的目的是确定与卵巢自身免疫相关表型相关的主要自身抗原。以前的研究表明，卵巢特异性自身抗体与几种卵巢抗原发生反应。此外，在一维免疫印迹中，自身免疫血清与卵巢蛋白的四个主要条带发生反应。这与其他自身免疫性疾病是一致的，在这些疾病中，针对多种抗原的抗体对疾病具有最显著的预测价值。我们将检验阳性血清与不止一种主要卵巢抗原反应的假设(目标1)。蛋白质组学方法结合使用一组系统地选择的自身免疫血清将被用来识别主要的蛋白质抗原。鉴定出的人类蛋白质的重组形式将被生产出来。将评估每一种识别出的蛋白质与自身免疫血清测试小组的反应，以验证识别出的蛋白质的真实性。在目标2中，将检验自身免疫性POF和不明原因不孕症共享相同抗原的假设，以支持它们代表同一自身免疫性疾病的不同阶段的概念。来自POF和不明原因不孕症妇女的血清的反应将通过使用AIM 1中已识别的蛋白质的免疫分析进行比较。此外，先前的研究表明，卵巢抗体与不孕症治疗后怀孕的可能性较低有关。在目标3中，将测试对已识别蛋白质的自身抗体也可以预测体外受精后不明原因不孕不育妇女怀孕可能性的假设。我们将确定抗一种抗原或一种抗原组合的自身抗体是否对怀孕有预测价值。这项拟议的研究有望提高检测卵巢自身免疫的精确度。这将有助于研究疾病的发病机制、与卵巢自身免疫相关的健康风险、与疾病易感性相关的遗传因素，并改善临床诊断。这也将有助于更好地了解一种影响女性健康的自身免疫性疾病。

DESCRIPTION (provided by applicant): There is compelling evidence for an autoimmune disease of the ovary. Ovarian autoimmunity may affect 1-2 million women in the US. In order to identify women with ovarian autoimmunity we developed prototype immunoassays to detect ovary specific autoantibodies, and used them to develop phenotypic information on the association of ovarian autoimmunity with premature menopause (premature ovarian failure or POF) and unexplained infertility. Further human research and clinical use depends on identification of the relevant protein antigens. The objective of the proposed study is to identify major autoantigens relevant to the phenotypes associated with ovarian autoimmunity. Previous studies suggest that ovary specific autoantibodies react with several ovarian antigens. In addition, autoimmune sera react with four predominant bands of ovarian protein in one-dimensional Western blots. This is consistent with other autoimmune diseases in which antibodies to multiple antigens have the most significant predictive value for disease. We will test the hypothesis that positive sera react with more than one major ovarian antigen (Aim 1). Proteomics methodology combined with the use of a systematically selected panel of autoimmune sera will be used to identify major protein antigens. Recombinant forms of the identified human proteins will be produced. The reaction of each identified protein with the autoimmune sera test panel will be evaluated to verify the authenticity of identified proteins. In Aim 2 the hypothesis that autoimmune POF and unexplained infertility share the same antigens will be tested in order to support the concept that they represent different stages of the same autoimmune disorder. The reaction of sera from women with POF and unexplained infertility will be compared by immunoassay using the identified proteins produced in Aim 1. Furthermore, previous studies showed that ovarian antibodies are associated with a low likelihood of pregnancy after infertility treatment. In Aim 3, the hypothesis that autoantibodies to identified proteins also predict a low likelihood of pregnancy in women with unexplained infertility after in-vitro fertilization will be tested. We will determine if autoantibodies to one antigen or a combination of antigens has predictive value for pregnancy. The proposed study is expected to improve the precision with which ovarian autoimmunity is detected. This will permit studies of disease pathogenesis, health risks associated with ovarian autoimmunity, genetic factors associated with disease susceptibility and improve clinical diagnosis. It will also contribute to a better understanding of an autoimmune disease that affects women's health.