BASIC AND CLINICAL INTERVENTION IN OVARIAN FAILURE

描述：(摘自研究员S摘要)卵巢早熟 月经衰竭(POF)影响大约10%的闭经妇女，并且可以 由于发病年龄小，被认为是不可逆转的 不孕不育和雌激素缺乏的长期后果。 尽管某些情况，包括化疗和放射治疗，以及X 染色体缺失，已知会导致POF，确切的患病率 不同的病因尚不清楚。然而，器官特异性血清的检测 调查人员和其他人的抗体滴度表明，高达50 患有POF的女性中有1%可能存在潜在的自身免疫异常。 最近，研究人员发现了内源性的一种功能缺陷。 自体多肽片段在大脑沟的呈递 慢性粒细胞白血病患者组织相容性复合体(MHC)I类分子的研究 与人类白细胞抗原区域连锁的自身免疫性疾病。这一缺陷导致 构象正确的第I类分子细胞表面表达减少 抗原。正常情况下，人类白细胞抗原I类和自体多肽的复合体选择两者 阳性T细胞和阴性T细胞。这一过程的中断可能解释了 缺乏自我抗原识别和自我容忍导致 自身免疫疾病中的自身免疫细胞破坏。TAP-1和TAP-2 与人类白细胞抗原II类分子相对应的胞内肽转运蛋白基因 区域和控制内源性多肽的传递和结合 I类分子，可能是导致功能缺陷的原因。他们的 初步数据显示，同样的I类功能缺陷 与POF相关的女性POF患者存在抗原提呈 II型自身免疫性多腺体衰竭综合征。许多自身免疫性疾病 女性的疾病更严重，可能是由于 雌激素，但尚不清楚是雌激素缺乏还是雌激素 POF妇女的替代治疗会影响她们的疾病进展。在……里面 在这项提议中，他们计划利用合作专业知识 卵巢早衰患者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类抗原的流行率 卵巢早衰妇女的外观缺陷；2)I类的关联 POF伴自身免疫性疾病其他表现的抗原缺陷；3) 血清雌激素水平在自身免疫性卵巢早衰表达中的作用 免疫抑制治疗对自身免疫性疾病的疗效观察 功能障碍；5)TAP-1和TAP-2的存在和/或流行 基因缺陷是女性I类抗原提呈异常的基础 患有自身免疫性POF。

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.