Inherited and acquired deficiencies of proteins of the classical pathway of complement activation (C1q, C1r, C1s, C4, C2) have a strong association with immune complex-mediated diseases, particularly systemic lupus erythematosus (SLE). Two not mutually exclusive mechanisms are believed to contribute to susceptibility to SLE in individuals with low serum levels of these proteins, inefficient clearance of immune complexes from the circulation and abnormal regulation of B cell responses. This project proposes that abnormal regulation of C2 gene expression resulting in persistently low serum C2 levels may contribute to susceptibility to SLE in a subpopulation of patients. To test this hypothesis the following specific aims will be pursued: 1) Identification and characterization of the human C2 gene promoters. Preliminary data indicate the presence of at least two promoters utilized in a tissue-specific manner. These will be identified and characterized by using transient expression of CAT gene hybrid constructs, DNase footprinting, and gel mobility shift assays. 2) Identification and characterization of cis-acting elements and nuclear transcription factors responsible for IFNgamma-induced C2 gene transcription. Additional regulatory elements will be sought in the SINE-R.C2 retroposon. 3) Investigation of the possible effects of alternatively-initiated and alternatively-spliced C2 gene transcripts on C2 gene expression. Tissue-and stimulus-specificity of these processes will be examined. 4) Investigation of possible abnormalities of C2 gene expression in SLE. This will include comparisons among three main groups, SLE patients with persistently low serum C2, SLE patients with normal C2 levels during remission, and healthy individuals. Defects in cis-acting elements and in abundance and/or distribution of transcription factors will be sought.
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