MOLECULAR REGULATION OF MHC CLASS III GENES

MHC III类补体基因C2、因子B、C4 A和C4 B构成 经典和替代扩增途径中的关键要素 激活宿主防御的重要效应器， 免疫病理学 细胞特异性组成型和调节型表达 这些基因在内胚层、中胚层和外胚层来源的组织中的表达， 人类疾病中肝外C2、C4和Bf表达的显著变化 需要进一步了解控制 这些现象。因此，我们建议阐明结构和 顺式和反式元件的功能， Bf、C2、C4 A和C4 B基因表达。C4 A无效基因型与 与系统性红斑狼疮和C4 A反应的差异， C4 B对细胞因子的刺激可能是部分原因 协会C2和因子B是代谢中的限速成分。 活化过程，使得每一种的局部浓度在活化过程中至关重要。 特别重要的调节和效应机制的平衡 将分析这些互补基因表达的差异， 与间充质细胞相反， 上皮表面的补体只是知之甚少。 来自II型C2缺乏症患者的材料的可用性（在 分泌阻滞导致了这一缺陷） 这种疾病的细胞/分子生物学基础，并将导致 对正常的C2分泌途径的理解。 最后，缺乏纯合因子B缺陷个体或 迄今为止，实验动物阻止了在体内分析 旁路途径中的孤立缺陷。基因的发展 靶向技术现在使我们能够产生Bf（-/-）表型， mice来直接回答这些问题。 理解在一个特定的时间点III类MHC补体基因的调节， 基础水平提供了更有效的治疗潜力， 以慢性炎症为特征的疾病。

The MHC class III complement genes C2, factor B, C4A and C4B constitute critical elements in the classical and alternative amplification pathways that activate this important effector of host defenses and immunopathology. Cellular specific constitutive and regulated expression of these genes in tissues of endo-, meso- and ectodermal origin and the marked change in extrahepatic C2, C4 and Bf expression in human diseases requires further understanding of the molecular mechanisms controlling these phenomena. Accordingly, we propose to elucidate the structure and function of cis and trans elements governing constitutive and regulated Bf, C2, C4A and C4B gene expression. The C4A null genotype is associated with systemic lupus erythematosus and differences in response of C4A and C4B to cytokine stimulation may be in part responsible for this association. C2 and factor B are rate limiting constituents in the activation process so that local concentrations of each is critical in the balance of regulatory and effector mechanisms of particular importance will be an analysis of differences between expression of these complement genes in epithelia as opposed to mesenchymal cells because the role of complement at epithelial surfaces is only poorly understood. The availability of material from patients with C2 deficiency type II (in which a secretory block accounts for the deficiency) permits a dissection of the cellular/molecular biological basis for the disorder and will lead to an understanding of the normal C2 secretory pathway. Finally, the absence of homozygous factor B deficient individuals or experimental animals has heretofore prevented an in vivo analysis of an isolated defect in the alternative pathway. The development of gene targeting technology now allows us to generate a Bf (-/-) phenotype in mice to address these questions directly. An understanding of the regulation of class III MHC complement genes at a fundamental level offers the potential for more effective therapies of disorders characterized by chronic inflammation.