Experimental Induction of SLE by Altered Ia

描述(申请人提供)：小鼠的自身免疫慢性移植物抗宿主(CGVH)反应是研究B细胞耐受丧失的机制以及这种耐受失败导致系统性红斑狼疮(SLE)的系统性自身免疫特征的机制的有力模型。 1)假说：不同的耐受机制在调节不同Ig转基因引起的抗dsDNA反应中起重要作用，在一系列免疫球蛋白定点(敲门)转基因小鼠品系中将诱导cGVH。 1)假设：在系统性红斑狼疮的cGVH模型中，B细胞的耐受性丧失伴随着基因表达的变化，这可以在RNA水平上得到证实。这些基因及其蛋白产物将是量化疾病活动性、了解B细胞耐受性丧失的分子机制和干预治疗的有吸引力的目标。 1)假说：在SLE的cGVH模型中，B细胞的耐受性丧失是由于异常的(同种)T细胞帮助与处于不同发育阶段的B细胞相互作用所致。转基因B细胞将通过个体发育的表面标记进行纯化，并在过继的cGVH系统中转移。 1)假设：在系统性红斑狼疮的cGVH模型中，B细胞的耐受性丧失发生在一个很小的亚群中，即使在具有高度扭曲的B细胞谱系的受体小鼠中也是如此。这意味着容忍检查站的进一步失败，可能是在随机的基础上，需要加以阐明。 1)假设：受体特异性T细胞在cGVH自身免疫反应中起关键作用。CD4T细胞允许自身反应性B细胞通过尚待探索的机制接受同种异体帮助。 这些研究将阐明对一种重要的狼疮特异性抗原(DsDNA)具有特异性的B细胞如何失去耐受性并成为自身反应。由于这种耐受性丧失的过程是系统性红斑狼疮发病机制的核心，研究结果将有助于阐明这种疾病的一些基本机制。

DESCRIPTION (provided by applicant): The autoimmune chronic graft-versus-host (cGVH) reaction in mice is a powerful model to investigate the mechanisms of loss of B-cell tolerance and the mechanisms whereby failure of such tolerance can lead to systemic autoimmunity characteristic of systemic lupus erythematosus (SLE). 1) Hypothesis: Different mechanisms of tolerance are important in regulating the anti-dsDNA response resulting from different Ig transgenes, cGVH will be induced in a series of immunoglobulin site-directed (knockin) transgenic mouse strains. 1) Hypothesis: The loss of tolerance in B cells in the cGVH model of SLE is accompanied by changes in gene expression that can be documented at the RNA level. Such genes and their protein products will be attractive targets for quantifying disease activity, understanding the molecular mechanisms that underlie the loss of B-cell tolerance and intervening therapeutically. 1) Hypothesis: The loss of tolerance in B cells in the cGVH model of SLE occurs because of the interaction of abnormal (allo-) T-cell help with B cells at discrete developmental stages. Transgenic B cells will be purified by surface markers of ontogeny and transferred in an adoptive cGVH system. 1) Hypothesis: The loss of tolerance in B cells in the cGVH model of SLE occurs in a small subpopulation, even in recipient mice with a highly skewed B-cell repertoire. This implies further failures of tolerance checkpoints, perhaps on a stochastic basis, that needs to be elucidated. 1) Hypothesis: Specific T cells from the recipient are critical for the cGVH autoimmune reaction. CD4 T cells permit autoreactive B cells to become receptive to allohelp by mechanisms to be explored. These studies will elucidate how a B cell with specificity for an important lupus specific antigen (dsDNA) can lose tolerance and become autoreactive. Since this process of tolerance loss is central to the pathogenesis of SLE, the results will help clarify some of the fundamental underlying mechanisms of this disease.