Alloimmunity in autoimmune disease

描述（由申请人提供）：在怀孕期间，现在认识到一些细胞在母亲和胎儿之间运输。微嵌合体是指来自一个个体的少量细胞（或DNA）被另一个个体所携带。目前的建议是第一次更新的研究调查的假设，母体微嵌合体（MMc）长期存在于免疫能力强的个人。作为初步研究的结果，我们知道，MMc坚持在她的后代到成年生活。在之前的研究期间，我们在一次抽血中发现了近四分之一的健康成年人的MMc。MMc在健康成人中并不罕见，这表明携带半同种异体细胞对宿主并没有本质上的危害，但回避了如何避免对自身损害的问题。该建议的总体假设是MMc和同种免疫是正常健康的组成部分，但MMc也可导致自身免疫性疾病，母亲和后代的特定HLA基因是结果的关键决定因素。鉴于MMc从婴儿期到成年期的持续性，MMc不太可能对其后代产生单一的连续影响。然而，没有关于MMc随个体年龄增长的信息。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妊娠获得新的（胎儿）微嵌合体来源时，它可能产生什么影响。本提案中的研究开始，首先确定具体目标1中的衰老、儿童、生殖和老年阶段MMc的定量和定性方面。具体目标2将根据女性在妊娠期间积累新的（胎儿）微嵌合体来源的后果研究MMc。具体目标3和4将研究多关节类风湿性关节炎（RA）中的MMc，因为“非遗传性”母体HLA基因与疾病风险有关，并且因为在该提议的初步研究中，我们在自身缺乏RA相关HLA等位基因的患者中鉴定了MMc和具有RA相关HLA等位基因的胎儿微嵌合体。因此，具体目标3和4检验了个体可以通过微嵌合体获得疾病风险（或保护）的假设;具体目标5将研究先证者-母亲对和经产妇女多代微嵌合体背景下MMc的表型和功能。对单采产品的研究将允许调查跨代微嵌合体的附加来源，其中暴露因年龄、免疫系统发育和在另一宿主中居住数十年的影响（“移民身份”）而不同。该提案的总体方法旨在为了解健康和自身免疫疾病中同种免疫的界面提供一个窗口，目前信息很少。

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.