Alloimmunity in autoimmune disease

描述(由申请人提供)：在怀孕期间，现在已经认识到一些细胞在母亲和胎儿之间进行交流。微嵌合体是指来自一个个体的少量细胞(或DNA)被另一个个体藏匿。目前的建议是首次更新研究，调查母体微嵌合体(MMC)在免疫能力强的个体中长期存在的假设。作为初步研究的结果，我们知道MMC会在她的后代中坚持到成年。在之前的资助期间，我们发现几乎四分之一的健康成年人在一次抽血中就发现了MMC。MMC在健康成年人中并不少见，这表明拥有半异基因细胞并不本质上对宿主有害，但却回避了如何避免对自身造成损害的问题。这一建议的总体假设是，MMC和同种异体免疫是正常健康不可或缺的方面，但MMC也可能导致自身免疫性疾病，母亲和子代的特定HLA基因是结果的关键决定因素。考虑到从婴儿期到成年的持久性，MMC不太可能对她的后代产生单一的持续影响。然而，随着个人年龄的增长，没有关于MMC的信息。此外，尚不清楚MMC是如何受到影响的，以及当先证者通过自己的怀孕获得新的(胎儿)微嵌合体来源时，它可能会产生什么影响。这项建议中的研究首先在特定目标1中确定MMC在衰老、儿童、生殖和老年阶段的定量和定性方面。特定目标2将根据妇女通过怀孕积累(胎儿)微嵌合体的新来源的后果来调查MMC。特定的AIMS 3和4将研究多关节类风湿性关节炎(RA)中的MMC，因为“非遗传”的母体HLA基因与疾病风险有关，而且在这项建议的初步研究中，我们发现MMC和胎儿微嵌合体与RA相关的HLA等位基因有关，这些患者本身缺乏RA相关的HLA等位基因。因此，特定目标3和4验证了个人可以通过微嵌合体获得疾病风险(或保护)的假设；特定目标5将在先母配对和临产妇女多代微嵌合体的背景下研究MMC的表型和功能。对分离产品的研究将允许跨世代调查微嵌合体的添加来源，在这些世代中，暴露于不同年龄、免疫系统发育和在另一宿主居住数十年(“移民身份”)的影响不同。这项提案的总体方法旨在为了解同种免疫在健康和自身免疫性疾病中的接口提供一个洞察窗口，目前几乎没有信息可用。

DESCRIPTION (provided by applicant): During pregnancy it is now recognized that some cells traffic between the mother and fetus. Microchimerism refers to a small number of cells (or DNA) from one individual harbored by another. The current proposal is the first renewal of studies investigating the hypothesis that maternal microchimerism (MMc) persists long-term in immune competent individuals. As a result of initial studies we know that MMc persists in her progeny into adult life. In the prior grant period we found MMc in almost one-fourth of healthy adults in a single blood draw. That MMc is not uncommon in healthy adults suggests harboring semiallogeneic cells is not intrinsically detrimental to the host, but begs the question of how damage to self is avoided. An overall hypothesis of this proposal is that MMc and allo-immunity are integral aspects of normal health, but that MMc can also contribute to autoimmune disease, with specific HLA genes of mother and progeny key determinants of the result. It is unlikely that MMc has a single continuous effect on her progeny given persistence from infancy through adult life. However no information is available regarding MMc as the individual ages. Moreover, it is unknown how MMc is affected and what effects it might have when the proband acquires new sources of (fetal) microchimerism through her own pregnancies. Studies in this proposal begin by determining quantitative and qualitative aspects of MMc in the stages of aging, childhood, reproductive and older years in Specific Aim 1. Specific Aim 2 will investigate MMc according to consequences of accumulating new sources of (fetal) microchimerism through pregnancy in women. Specific Aims 3 and 4 will investigate MMc in polyarticular rheumatoid arthritis (RA), because "noninherited" maternal HLA genes have been implicated in disease risk and because in preliminary studies for this proposal we identified MMc and also fetal microchimerism with RA-associated HLA alleles in patients who themselves lack an RA-associated HLA allele. Thus Specific Aims 3 and 4 test the hypothesis that an individual can acquire disease risk (or protection) through microchimerism; Specific Aim 5 will investigate phenotype and functionality of MMc in proband-mother pairs and in the context of multi-generational microchimerism in parous women. Studies of apheresis products will permit investigation of additive sources of microchimerism across generations where exposures differ according to age, immune system development, and the effects of residing in another host for decades ("immigrant status"). The overall approach of this proposal is intended to generate a window of insight into the interface of allo-immunity in health and auto-immune disease where little information is currently available.