ALLOIMMUNITY IN AUTO IMMUNE DISEASE

分子生物学技术的进步使人们认识到，怀孕期间细胞是双向流动的。在大多数首次怀孕的孕妇外周血中发现了胎儿细胞，在超过40%的脐带血样本中发现了母体细胞的证据。最近，令人惊讶的观察结果被报道，胎儿细胞也可以在妊娠结束后在母体血液中持续存在数十年。这一观察结果提出了一个重要的问题，即母体细胞是否也会在某些后代中长期存在。众所周知，在患有严重联合免疫缺陷的婴儿中，母体细胞会植入并持续存在，但之前没有研究调查过母体细胞在正常个体中的长期存在。为了支持这种可能性，一项细胞遗传学研究显示，在子宫内接受母亲输血的男婴在5岁以上时，一些淋巴细胞是XX。在我们实验室的初步研究中，我们报告了一些个体在出生后47年母体细胞长期存在的证据。当考虑到在实验模型和以嵌合（非宿主细胞）为特征的人类疾病中的观察结果时，怀孕期间细胞的双向运输和某些个体的长期微嵌合现象，导致研究者提出异体免疫可能导致某些自身免疫性疾病的假设。系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其公认的实验模型涉及将亲代细胞引入F1后代。同种异体造血干细胞移植后发生的人类慢性移植物抗宿主病也模仿SLE的一些表现。本提案的研究旨在探讨母体细胞和/或DNA在某些后代中持续存在的假设，以及母体微嵌合有助于某些自身免疫性疾病，特别是SLE的发病机制。拟议的研究将调查持续母体微嵌合的定性和定量方面。为了进一步研究SLE患者的致病性，将对SLE患者受疾病影响的组织进行母体DNA和细胞检测。母亲和她的后代的HLA-关系将被研究作为一个潜在的因素在持久性和/或致病性的持久性母体微嵌合。提出的研究可能会导致对免疫方面和妊娠后果的新认识。如果持续的母体微嵌合参与SLE的发病机制，可以在此基础上开发新的治疗方式。

Advances with molecular biological techniques have led to the appreciation that there is bi-directional traffic of cells during pregnancy. Fetal cells are found in maternal peripheral blood in the majority of first pregnancies and evidence for maternal cells has been found in over 40 percent of cord blood samples. Recently, the surprising observation was reported that fetal cells also can persist in maternal blood for decades after pregnancy completion. This observation raises the important question as to whether maternal cells also persist long-term in some offspring. It is well known that maternal cells engraft and persist in infants with severe combined immunodeficiency, but no previous study has investigated long-term persistence of maternal cells in normal individuals. In support of this probability, a cytogenetic study of male infants who received in utero transfusions from their mothers revealed some lymphocytes were XX at more than five years of age. In initial studies from our laboratory we report evidence for long-term persistence of maternal cells in some individuals up to 47 years after birth. Bi-directional traffic of cells during pregnancy, and long-term persistence of microchimerism in some individuals, when considered together with observations in experimental models and in human diseases characterized by chimerism (nonhost cells), led the investigator to propose the hypothesis that alloimmunity may contribute to some autoimmune disease. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease for which a well-recognized experimental model involves the introduction of parental cells into F1 progeny. Some manifestations of SLE are also mimicked in human chronic graft-versus-host-disease that occurs after allogenic hematopoietic stem cell transplantation. The studies in this proposal are designed to investigate the hypothesis that maternal cells and/or DNA persist in some progeny and that maternal microchimerism contributes to the pathogenesis of some autoimmune diseases, specifically SLE. The proposed studies will investigate qualitative and quantitative aspects of persistent maternal microchimerism. To further address pathogenicity disease-affected tissues of SLE patients will be examined for maternal DNA and cells. The HLA- relationship of mother and her progeny will be investigated as a potential factor in the persistence and/or pathogenicity of persistent maternal microchimerism. The studies that are proposed may result in a new understanding of immunologic aspects and consequences of pregnancy. If persistent maternal microchimerism is involved in the pathogenesis of SLE new therapeutic modalities could be developed on this basis.