ALLOIMMUNITY IN AUTO IMMUNE DISEASE

随着分子生物学技术的进步，人们认识到在怀孕期间存在细胞的双向运输。大多数第一次怀孕的孕妇外周血中都发现了胎儿细胞，超过40%的脐带血样本中发现了母体细胞的证据。最近，有报道称，怀孕完成后，胎儿细胞也可以在母体血液中存活数十年，这一现象令人惊讶。这一观察提出了一个重要的问题，即母细胞是否也在某些后代中长期存在。众所周知，母体细胞在严重联合免疫缺陷的婴儿体内植入并持续存在，但此前还没有研究发现母体细胞在正常个体中长期持续存在。为了支持这种可能性，一项对在子宫内接受母亲输血的男婴进行的细胞遗传学研究显示，一些淋巴细胞在五岁以上时是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长达47年的母体细胞长期存在的证据。怀孕期间细胞的双向运输，以及一些个体微嵌合体的长期存在，与实验模型和以嵌合体(非宿主细胞)为特征的人类疾病的观察相结合，使研究人员提出了同种免疫可能与某些自身免疫性疾病有关的假设。系统性红斑狼疮(SLE)是一种典型的自身免疫性疾病，一种公认的实验模式是将亲本细胞导入F1后代。在异基因造血干细胞移植后发生的人类慢性移植物抗宿主病中，SLE的一些表现也被模仿。这项建议中的研究旨在调查这样一种假设，即母体细胞和/或DNA在某些后代中持续存在，以及母体微嵌合现象有助于某些自身免疫性疾病的发病，特别是SLE。拟议的研究将调查持续的母体微嵌合体的定性和定量方面。为了进一步解决致病问题，将对SLE患者受疾病影响的组织进行母体DNA和细胞检查。母亲和她的后代的人类白细胞抗原的关系将被作为持续的母体微嵌合体持续和/或致病的潜在因素进行调查。拟议的研究可能会导致对免疫学方面和怀孕后果的新理解。如果持续的母体微嵌合体参与SLE的发病机制，可能会在此基础上开发新的治疗方法。

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.