Cytokines and Growth Factors in Autoimmune Diseases

细胞因子和生长因子在 免疫功能的正常内稳态。转化生长因子-1占主导地位 炎症反应的负调节因子。我们之前有过 产生的转化生长因子-1基因缺失的小鼠表现出多灶性炎症 与白细胞与内皮细胞的粘附性增加有关， MHC-I和-II类抗原的异常表达，以及 类似于干燥综合征的自身免疫表现。此外， 去除CD8细胞改善转化生长因子-1缺失的健康状态 老鼠。为了阐明转化生长因子-1在MHC异常表达中的作用， 在MHC-I和MHC-II中产生转化生长因子-1缺失的小鼠 背景不足。转化生长因子-‘1X MHC-I缺失小鼠展示 延长寿命与减少炎症有关， 自身免疫表现减弱，显著升高 骨髓再生。尽管转化生长因子-1X MHC-II小鼠表现出缺乏 炎症和自身免疫反应，他们显示为新生儿 与骨髓生成和化生增加有关的死亡率。 这些结果表明转化生长因子-1在白细胞中起主导作用。 成熟和功能。巨噬细胞移动抑制因子 (MIF)是垂体前叶的主要蛋白质成分。 在内毒素血症期间释放到血液中。多年来, MIF曾被认为是一种T细胞产物，与 迟发性超敏反应。MIF AS的鉴定 一种脑下“应激”荷尔蒙在 中枢神经系统对全身炎症反应的调节。 此外，有令人信服的证据表明， MIF与细胞周期的关系提示MIF是一种血管内皮细胞生长抑制因子 G0期。为了描述MIF在体内的确切作用，我们 发起了有针对性的重组，以生成MIF NULL 老鼠。在产生ES细胞克隆的过程中 破坏了我们发现的异常重组克隆的MIF基因。 对这些克隆的详细分析揭示了特定的序列基序 这会影响同源重组过程。这些 基序包括短的同源序列同一性区域， 已被证明可以促进DNA比对，这是一种优势 四聚体(5‘-AAGG/TTCC 3’)，拓扑异构酶I共识位点， 和富含AT的序列，可以促进DNA切割和 重组。一个类似逆转录病毒的序列，脑池内的A粒子， 被鉴定为小鼠MIF基因上游的2kb。其中一个 重组发生在该IAP的长末端重复序列附近 序列。这些序列基序可能会影响计划中的干扰 这一遗传位点及其特征将有助于描绘 重组的机制。

Cytokines and growth factors play critical roles in normal homeostasis of immune functions. TGF-'1 is the dominant negative regulator of inflammatory responses. We have earlier generated TGF-'1 null mice that exhibit multifocal inflammation associated with increased adhesion of leukocytes to endothelium, aberrant expression of MHC class-I and -II antigens, and autoimmune manifestations similar to Sjogren syndrome. Moreover, depletion of CD8 cells ameliorated health status of TGF-'1 null mice. To delineate role of TGF-'1 in aberrant MHC expression, TGF-'1 null mice were generated in the MHC-I and MHC-II deficient backgrounds. TGF-'1 X MHC-I null mice exhibit increased longevity associated with reduced inflammation, diminished autoimmune manifestations and significantly elevated myelopoiesis. Although the TGF-'1 X MHC-II mice exhibited lack of inflammation and autoimmune response, they showed neonatal mortality associated with increased myelopoiesis and metaplasia. These results indicate a dominant role of TGF-'1 in leukocyte maturation and function. Macrophage migration inhibitory factor (MIF) is a major protein constituent of the anterior pituitary gland released into the bloodstream during endotoxemia. For many years, MIF had been thought to be a T cell product associated with delayed-type hypersensitivity reactions. The identification of MIF as a pituitary "stress" hormone provides an important link in the regulation of systemic inflammatory responses by CNS. Additionally, there is a compelling evidence that suggests a strong link between MIF and cell cycle suggesting MIF as an inhibitor in G0 phase. In order to delineate the precise role of MIF in vivo, we have initiated targeted recombination for the generation of MIF null mice. During the process of generating ES cell clones that have disrupted MIF gene we found abnormally recombined clones. Detailed analysis of these clones revealed specific sequence motifs that can affect the homologous recombination process. These motifs include short regions of homologous sequence identity that have been shown to promote DNA alignment, a preponderance of tetramers (5'-AAGG/TTCC 3'), topoisomerase I consensus sites, and AT-rich sequences that can promote DNA cleavage and recombination. A retrovirus-like sequence, intracisternal-A particle, is identified 2 kb upstream of the murine MIF gene. One of the recombinations occurred near the long terminal repeat of this IAP sequence. These sequence motifs may affect planned disruption of this genetic locus and their characterization will help to delineate the mechanism of recombination.