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传输。微嵌合是指一个人的少量细胞（或DNA）被另一个人所容纳。目前的建议是研究母体微嵌合（MMc）在免疫能力个体中长期存在的假设的第一次更新。初步研究的结果是，我们知道MMc会在她的后代身上持续存在到成年。在之前的资助期间，我们在一次抽血中发现近四分之一的健康成年人存在MMc。MMc在健康成人中并不罕见，这表明窝藏半同种异体细胞本质上对宿主并不有害，但回避了如何避免对自身造成伤害的问题。该建议的总体假设是MMc和异体免疫是正常健康的组成部分，但MMc也可能导致自身免疫性疾病，母亲和后代的特异性HLA基因是结果的关键决定因素。鉴于从婴儿期到成年的持续存在，MMc不太可能对其后代产生单一的持续影响。然而，没有关于MMc随个人年龄变化的信息。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）微嵌合来源时，它可能会产生什么影响。本提案的研究首先在具体目标1中确定老年、儿童、生殖和老年阶段MMc的定量和定性方面。特异性目标2将根据妇女妊娠积累新的（胎儿）微嵌合来源的后果来研究MMc。特异性目标3和4将研究MMc在多关节类风湿性关节炎（RA）中的作用，因为“非遗传性”母体HLA基因与疾病风险有关，并且因为在本建议的初步研究中，我们发现MMc和胎儿微嵌合与RA相关HLA等位基因在自身缺乏RA相关HLA等位基因的患者中。因此，特异性目标3和4验证了个体可以通过微嵌合获得疾病风险（或保护）的假设；特异性目标5将研究先证-母亲配对中MMc的表型和功能，以及在分娩妇女的多代微嵌合背景下。对分离产物的研究将允许调查跨代微嵌合的添加剂来源，其中暴露程度因年龄、免疫系统发育和在另一个宿主居住数十年（“移民身份”）的影响而不同。本提案的总体方法旨在为健康和自身免疫性疾病的同种免疫界面提供一个洞察窗口，目前可获得的信息很少。

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.