BASIC AND CLINICAL INTERVENTION IN OVARIAN FAILURE

卵巢衰竭的基本和临床干预

• 批准号: 2889141
• 负责人: Denise L Faustman
• 金额: $ 18.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-10 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889141
• 关键词: MHC class I antigen; antigen presentation; antigenic peptide transporter; autoimmune disorder; clinical research; estradiol; gene expression; gene mutation; genetic regulation; glucocorticoids; hormone therapy; human subject; human therapy evaluation; immunofluorescence technique; immunopathology; immunopathology therapy; membrane proteins; ovary disorder; ovulation; serum; women's health

DESCRIPTION: (Taken from the investigator s abstract) Premature Ovarian Failure (POF) affects approximately 10 percent of amenorrheic women, and can be devastating because of the young age of onset, the presumed irreversible infertility, and the long-term consequences of estrogen deficiency. Although certain conditions, including chemo and radiation therapy, and X chromosomal deletions, are known to cause POF, the precise prevalence of the different etiologies is unknown. However, tests for organ specific serum antibody titers by the investigator and others, indicates that up to 50 percent of women with POF may have an underlying autoimmune abnormality. Recently, investigators have identified a functional defect in endogenous presentation of self-peptide fragments in the groove of major histocompatibility complex (MHC) class I molecules in patients with autoimmune disease with linkage to the HLA region. This defect results in decreased cell surface expression of conformationally correct class I antigens. Normally the complex of HLA class I and self peptide selects both positively and negatively T cells. Disruption of this process might explain the lack of self-antigen recognition and of self tolerance that leads to the autoimmune cell destruction in autoimmune diseases. The Tap-1 and Tap-2 intracellular peptide transporter genes, which map to the HLA class II region and control the delivery and association of endogenous peptides with class I molecules, may be responsible for the functional defect. Their preliminary data indicates that this same functional defect of class I antigen presentation is present in women with POF associated with the syndrome of Type II autoimmune polyglandular failure (PFG). Many autoimmune diseases are worse in women, presumably due to immunostimulatory effects of estrogen, but it is not known whether estrogen deficiency or estrogen replacement in women with POF affects the progression of their disease. In this proposal, they plan to capitalize on the collaborative expertise between clinical studies of women with POF in the Reproductive Endocrine Unit and the immunologic developments of the Immunobiology Laboratories. They wish to determine: 1) the prevalence of Tap controlled class I antigen presentation defects in women with POF; 2) the association of class I antigen defects with other manifestations of autoimmune diseases in POF; 3) the role of serum estrogen levels in the expression of autoimmune POF; 4) the efficacy of immunosuppressive therapy in those women with automimmune dysfunction; and 5) the presence and/or the prevalence of Tap-1 and Tap-2 gene defects as the basis of abnormal class I antigen presentation in women with autoimmune POF.

描述：（摘自研究者摘要）卵巢早衰 失败（POF）影响大约10%的闭经妇女， 由于发病年龄小，被认为是不可逆的， 不孕症，以及雌激素缺乏的长期后果。 虽然某些情况下，包括化疗和放射治疗，以及X 染色体缺失，已知会导致POF， 不同的病因是未知的。 然而，器官特异性血清检测 研究者和其他人的抗体滴度表明，高达50 %的POF患者可能存在潜在的自身免疫异常。 最近，研究人员发现了一种内源性的功能缺陷， 自我肽片段在大细胞沟中的呈递 组织相容性复合体（MHC）I类分子在患者中的表达 与HLA区域相关的自身免疫性疾病。 该缺陷导致 构象正确I类的细胞表面表达降低 抗原 通常，HLA I类和自身肽的复合物选择两者 阳性和阴性T细胞。 这一过程的中断可以解释 缺乏自身抗原识别和自身耐受性，导致 自身免疫性疾病中的自身免疫细胞破坏。 Tap-1和Tap-2 细胞内肽转运蛋白基因，其映射到HLA II类 区域和控制内源性肽的递送和缔合， I类分子，可能是功能缺陷的原因。 他们的 初步数据表明，这种I类功能缺陷 抗原呈递存在于POF女性中， II型自身免疫性多腺体衰竭（PFG）综合征。 许多自身免疫性 疾病在女性中更严重，可能是由于免疫刺激作用， 雌激素，但不知道是否雌激素缺乏或雌激素 POF妇女的替代治疗影响其疾病的进展。 在 在这个提议中，他们计划利用 卵巢早衰女性生殖内分泌的临床研究 单位和免疫生物学实验室的免疫学发展。 他们希望确定：1）Tap控制的I类抗原的患病率 POF妇女的表现缺陷; 2）I类 POF中的抗原缺陷伴其他自身免疫性疾病表现; 3） 血清雌激素水平在自身免疫性POF表达中的作用; 4） 免疫抑制治疗对自身免疫性乳腺癌的疗效 功能障碍;以及5）Tap-1和Tap-2的存在和/或患病率 基因缺陷是女性I类抗原呈递异常的基础 自身免疫性卵巢早衰