Experimental Induction of SLE by Altered Ia

描述（由申请人提供）：小鼠中的自身免疫性慢性移植物抗宿主（cGVH）反应是研究B细胞耐受性丧失机制以及这种耐受性失败可导致系统性红斑狼疮（SLE）特征性系统性自身免疫的机制的有力模型。 1)假设：不同的耐受机制在调节由不同的IG转基因引起的抗dsDNA应答中是重要的，cGVH将在一系列免疫球蛋白定点（敲入）转基因小鼠品系中被诱导。 1)假设：SLE cGVH模型中B细胞的耐受性丧失伴随着基因表达的变化，这些变化可以在RNA水平上记录。这些基因及其蛋白质产物将成为量化疾病活动、理解B细胞耐受性丧失的分子机制和治疗干预的有吸引力的靶点。 1)假设：由于异常（同种）T细胞帮助与离散发育阶段的B细胞相互作用，导致SLE cGVH模型中的B细胞耐受性丧失。转基因B细胞将通过个体发育的表面标志物纯化并转移到过继性cGVH系统中。 1)假设：SLE的cGVH模型中B细胞的耐受性丧失发生在小的亚群中，甚至在具有高度偏斜的B细胞库的受体小鼠中。这意味着公差检查点的进一步失败，可能是随机的，需要阐明。 1)假设：来自受体的特异性T细胞对于cGVH自身免疫反应至关重要。CD4 T细胞允许自身反应性B细胞通过有待探索的机制变得接受同种异体帮助。 这些研究将阐明对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性的。由于耐受性丧失的过程是SLE发病机制的核心，因此这些结果将有助于阐明这种疾病的一些基本潜在机制。

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.