MICROCHIMERISM IN THE PATHOGENESIS OF PBC

描述(摘自摘要)：大多数自身免疫性疾病优先 影响女性。女性与男性的比例在(PBC)中特别明显 已经报道了哪些比例为10：1。女性PBC的发病高峰 在生育年月之后。由于分子的应用 用生物技术来研究人类怀孕现在已知 细胞从胎儿到母亲和母亲到母亲的双向运输 胎儿。此外，最近发现胎儿细胞在母体中持续存在。 妊娠完成后数十年外周血。慢性 移植物抗宿主病是一种已知的嵌合体状态，发生在 异基因干细胞移植。这种疾病既有临床上的，也有 病理上与一些自身免疫性疾病相似，特别是PBC和SSC。 当把这些观察结果放在一起考虑时，调查员提出了 微嵌合体参与PBC和PBC发病机制的假说 SSC.对患有自闭症的女性的初步研究支持这一假设 持续的胎儿微嵌合体在这种疾病中起着一定的作用。在美国的研究 目前的提案将调查微嵌合体是 参与了PBC的病因和发病机制。拟议的研究将 重点关注在PBC发病前有孩子的妇女。然而， 有关微嵌合体的假说也适用于 从来没有怀孕过，因为有其他来源 微嵌合体，包括来自输血、双胞胎或 从母亲那里。第一个特别的目标是研究微嵌合体在 PBC患者的肝脏样本。将从肝脏样本中提取DNA 并对患有Y染色体特异性序列的女性进行了聚合酶链式反应 生男孩，以及对有女儿的妇女进行人类白细胞抗原特异的聚合酶链式反应。 对有儿子的妇女的组织样本也将进行原位研究 Y和X特定序列的双标记杂交。具体而言 目的2.对有儿子的妇女外周血进行定量研究 男性DNA和外周血单个核细胞亚群的PCR将 研究荧光激活细胞分选后的微嵌合体。在……里面 具体目标3母子人类白细胞抗原的关系将作为一个 母亲继发PBC的潜在危险因素。虽然PBC和SSC 这两种疾病在中年女性中都有显著的优势吗 以前没有研究将怀孕作为这些疾病的危险因素 疾病。现有的治疗药物对这两种疾病的治疗效果很差。 如果微嵌合体参与了PBC的发病机制，新的治疗方法可能会 在此基础上发展起来的。

DESCRIPTION (adapted from abstract): Most autoimmune diseases preferentially affect women. The female to male ratio is particularly marked for (PBC) in which ratios of 10 to 1 have been reported. The peak incidence of PBC in women follows childbearing years. As a result of the applications of molecular biological techniques to the study of human pregnancy it is now known that there is bi-directional traffic of cells from fetus to mother and mother to fetus. Moreover, fetal cells have recently been found to persist in maternal peripheral blood for decades after pregnancy completion. Chronic grant-versus-host disease is a condition of known chimerism that occurs after allogeneic stem cell transplantation. This disorder has both clinical and pathological similarities to some autoimmune diseases, mot notably PBC and Ssc. These observations, when considered together, led the investigator to propose the hypothesis that microchimerism is involved in the pathogenesis of PBC and Ssc. Preliminary studies in women with Ssc support the hypothesis that persistent fetal microchimerism plays a role in this diseases. Studies in the current proposal will investigate the hypothesis that microchimerism is involved in the etiology and pathogenesis of PBC. The proposed studies will focus on women who had children prior to the onset of their PBC. However, the hypothesis regarding microchimerism also has applicability to men and women who have never been pregnant because there are alternative sources on microchimerism including engraftment from a blood transfusion, from a twin or from the mother. The first specific aim is to investigate microchimerism in liver specimens from women with PBC. DNA will be extracted from liver specimens and subjected to PCR for a Y-chromosome specific sequence in women who have given birth to sons, and to HLA-specific PCR for women who have had daughters. Tissue samples from women with sons will also be studied using in situ hybridization with double labeling for Y and X specific sequences. In specific aim 2, peripheral blood of women with sons will be studied using quantitative PCR for male DNA and peripheral blood mononuclear cell subpopulations will be investigated for microchimerism after fluorescence-activated-cell-sorting. In specific aim 3 the mother/child HLA relationship will be investigated as a potential risk factor for subsequent PBC in the mother. Although PBC and Ssc are both diseases with a striking predominance for middle-aged women there are no previous studies that have examined pregnancy as a risk factor in these diseases. Both disorders are poorly treated with available therapeutic agents. If microchimerism is involved in the pathogenesis of PBC, new therapies might be developed on this basis.