Seery, John Patrick; (1999) A transgenic mouse model of systemic lupus erythematosus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Systemic lupus erythematosus (SLE) is a relatively common autoimmune syndrome characterised by widespread organ damage secondary to autoantibody production against a broad range of self antigens. The disease primarily affects women and varies markedly between patients both in the pattern of organ involvement and the severity of damage to involved organs. SLE carries a significant mortality primarily as a result of antinuclear antibody mediated glomerulonephritis. The factors triggering and the mechanisms underlying autoantibody production are the subject of intense research. We have developed an IFN-γ transgenic mouse model of SLE and in this thesis I provide evidence that the skin immune system is at least capable of playing the central role in disease pathogenesis. In addition, dissection of the mechanisms involved in autoantibody production in these mice suggests that antinuclear antibodies arise via an antigen driven T cell-dependent process. Apoptotic keratinocytes may act as the source of self nuclear antigen and the mechanism of autoantibody production is relevant to the naturally occurring human disease. We investigated the efficacy of anti-apoptotic agents in IFN-γ transgenic mice and show that these agents may profoundly alter the pattern of autoantibody production in this lupus model. Our findings may aid in the development of new therapeutic options for this potentially devastating disease.

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