MICROCHIMERISM IN THE PATHOGENESIS OF PBC

描述（改编自摘要）：大多数自身免疫性疾病优先 影响女性。妇女与男子的比例在以下方面特别显著： 已经报道了10比1的比率。女性PBC发病高峰期 遵循生育年龄。由于分子的应用， 生物技术用于人类妊娠的研究，现在已知， 细胞从胎儿到母亲和母亲到 胎儿此外，最近发现胎儿细胞在母体中持续存在。 妊娠结束后数十年的外周血。慢性 赠款抗宿主病是一种已知的嵌合状态，发生在 异基因干细胞移植这种疾病具有临床和 与某些自身免疫性疾病的病理相似性，尤其是PBC和Ssc。 综合考虑这些观察结果，研究人员提出 微嵌合体参与PBC发病机制的假说， Ssc.对Ssc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作用。的研究 目前的提议将调查微嵌合体是 参与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。但 关于微嵌合体的假说也适用于 我从来没有怀孕过，因为有其他来源， 微嵌合体，包括来自输血、来自双胞胎或 从母亲那里。第一个具体的目标是研究微嵌合体， PBC患者的肝脏标本将从肝脏样本中提取DNA 并对患有以下疾病的女性进行Y染色体特异性序列的PCR， 对生过儿子的妇女进行HLA特异性PCR检测。 来自有儿子的妇女的组织样本也将使用原位 用Y和X特异性序列的双标记进行杂交。在特定 目的2：采用定量分析方法， 将对男性DNA和外周血单核细胞亚群进行PCR， 研究荧光激活细胞分选后的微嵌合体。在 具体目标3：研究母亲/儿童HLA关系， 母亲中随后PBC的潜在危险因素。虽然PBC和SSC 这两种疾病在中年妇女中占明显优势， 以前没有研究将妊娠作为这些疾病的风险因素， 疾病这两种疾病的治疗效果都很差。 如果微嵌合体与PBC的发病机制有关，新的治疗方法可能 在此基础上发展。

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.