IMMUNOLOGIC MECHANISMS IN HUMAN FEMALE INFERTILITY

患者血清、卵泡液和/或血清中抗精子抗体的滴度 宫颈粘液已被证明与生育力下降的大鼠相关。 这项研究项目将开发一种免疫学的灵长类动物模型。 精子凝集抗原-1(SAGA-1)引起的不育症 糖蛋白已被确定为一种表面抗原，参与 抗体介导的人类不孕症。佐贺-1被鉴定为 凝集人的鼠源单抗(MAb)S19 精子，抑制精子带致盲，阻止精子穿透 宫颈粘液，并诱发抖动现象。佐贺-1也是 被H6-3C4识别的人精子凝集单抗 一名免疫不孕症妇女的淋巴细胞。人类H6-3C4病毒 识别碳水化合物的抗体和功能抑制单抗S19 SAGA-1糖蛋白上存在表位。微序列分析 证实sagA-1与CDw52相关，CDw52是一种首先与GPI锚定的蛋白 在淋巴细胞上识别并参与信号转导。S19和 CDw252糖蛋白上不存在H6-3C4碳水化合物表位。 因此，sagA-1和CDw52代表糖形式，即糖蛋白 具有相同的多肽序列但具有不同的异构体 低聚糖侧链。这项研究提案的具体目的 包括阐明SAGA-1的碳水化合物结构的研究 糖型。SAGA-1 S19碳水化合物的组织特异性表达 表位将通过免疫化学分析进行研究。推定的 SAGA-1在精子-卵泡/细胞-细胞外基质相互作用中的作用 使用人类半带试验进行检查。将SAGA-1作为 与免疫性不孕症有关的自身、异基因抗原，雌性猕猴 将用SAGA-1免疫。血清中抗SAGA-1抗体效价， 宫颈粘液、输卵管积液的监测及治疗效果(S) 这些对精子功能的抗体将在体外进行测定。这个 拟议的研究将有助于理解saga-1和saga-1的作用 精子-卵泡/细胞-细胞外基质相互作用中的精子糖基化 并将为抗体的研究提供非人类灵长类动物模型- 介入性不孕。

Titers of anti-sperm antibodies in patient sera, follicular fluid, and/or cervical mucus have been shown to correlate with reduced fertility rats. This research project will develop a primate model for immunologic infertility based on Sperm Agglutination Antigen-1 (SAGA-1), a sperm glycoprotein that has been identified as a surface antigen involved in antibody-mediated infertility in humans. SAGA-1 was identified with a murine monoclonal antibody (mAb), S19, that agglutinates human spermatozoa, inhibits sperm-zona blinding, blocks sperm penetration of cervical mucus, and induces the shaking phenomena. SAGA-1 is also recognized by H6-3C4, a human sperm-agglutinating mAb produced using lymphocytes from an immunologically infertile women. The human H6-3C4 antibody and the function-inhibitory mAb S19 recognize carbohydrate epitopes present on the SAGA-1 glycoprotein. Microsequence analysis demonstrated that SAGA-1 is related to CDw52, a GPI-anchored protein first identified on lymphocytes and involved in signal transduction. The S19 and H6-3C4 carbohydrate epitopes are not present on the CDw252 glycoprotein. Therefore, SAGA-1 and CDw52 represent glycoforms, i.e. glycoprotein isoforms that have the same peptide sequence but possess different oligosaccharide side chains. The specific aims of this research proposal includes studies to elucidate the carbohydrate structure of the SAGA-1 glycoform. The tissue-specific expression of the SAGA-1 S19 carbohydrate epitope will be investigated with immunochemical analyses. The putative role of SAGA-1 in sperm-zona/cell-extracellular matrix interactions will be examined using the human hemi-zona assay. To investigate SAGA-1 as an auto-, iso-, antigen involved in immunologic infertility, female macaques will be immunized with SAGA-1. Anti-SAGA-1 antibody titers in sera, cervical mucus, and oviductal fluid will be monitored and the effect(s) of these antibodies on sperm function will be determined in vitro. The proposed research will contribute to understanding the roles of SAGA-1 and the sperm glycocalyx in sperm-zona/cell-extracellular matrix interactions and will provide a non-human primate model for the study of antibody- mediated infertility.