Characterisation of Lupus Candidate Genes Identified by Expression Profiling

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology, characterised by the .production of autoantibodies to a number of nuclear antigens. Resultant immune complex formation and deposition causes the multiple symptoms observed in lupus patients, which can include kidney glomerulonephritis. The BXSB strain is a good murine model of the human condition, presenting autoantibodies to both single- and double-stranded DNA, as well as an aggressive glomerulonephritis which causes significantly increased mortality. Previously, four BXSB-derived loci (Bxsl-4) were mapped to chromosome one and congenic strains were generated which contained overlapping regions of these four loci. cRNA from each of these congenic strains was generated and hybridised to the Affymetrix gene expression array chips MgU74 A, Band C. In this study, the resultant expression data has been analysed on the 'Rosetta Resolver' gene expression analysis platform. A number of candidate genes were chosen based on significant expression difference between the relevant congenic strain and the parental strains, and these were analysed using quantitative real time polymerase chain reaction (qPCR) in relevant tissues and cells~ .Thesestudies resulted in further analysis of two genes: lji202, an interferon responsive transcription regulator; and Marco, a macrophage-specific cell surface scavenger receptor. Both of these genes are promising functional candidates for the autoimmune phenotypes displayed by the BXSB and BXSBderived congenic mouse strains. The primary basis for the differential expression was sought by characterisation of the promoter and transcript of these genes. In the case oflji202 an analysis of the Hin-200 locus, which harbours all members of the lji gene family, was conducted in order to explain the differential expression seen. lji202 was previously characterised as a lupus c~nd~date gene in the NZB autoimmune mouse model, whereas Marco represents a highly promising novel candidate gene in autoimmunity. The analysis of both ofthese candidate genes in human SLE is now warranted.EThOS - Electronic Theses Online ServiceGBUnited Kingdo