MOLECULAR REGULATION OF MHC CLASS III GENES

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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.