On the etiology and pathogenesis of systemic lupus erythematosus with special reference to environmental factors

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which environmental factors interact with genetic factors in the development of the disease process and evolution of clinical manifestations. In this thesis both exogenous factors and host factors were investigated, as well as important immunopathological aspects including involvement of immune complex (IC), the complement system and interferon-alpha (IFN-α). Both exogenous retrovirus and human endogenous retrovirus (HERV) have been implicated in the etiology of SLE. To identify endogenous retroviral antigens of importance in SLE, IgG antibody reactivity against a panel of synthetic peptides derived from HERV sequences were investigated. Increased immune reactivity against a restricted set of HERV derived synthetic peptides was observed. Retroviral immune reactivity was not associated with serum levels of the anti-viral and immunomodulating cytokine IFN-α in SLE patients. However, increased IFN-α was detected in most patients with active disease, and a close relation between SLE disease activity, disease course and serum levels of IFN-α was observed. Furthermore, it was demonstrated that sera from SLE patients, especially with active disease, contained soluble factors that induced the production of IFN-α in PBMC from healthy donors. A decrease of nucleosomal DNA containing circulating IC (IC-DNA) in patients who developed hypocomplementemia with low C1q levels, was also observed. This probably reflects tissue deposition of IC-DNA, a main pathogenic pathway in IC mediated SLE manifestations. Human parvovirus B19 has been suggested as an environmental trigger of SLE. Exposure to this virus, measured as IgG and IgM anti-parvovirus antibodies, was not increased in SLE patients compared to controls. Instead, a significantly low parvovirus B19 IgG seroprevalence was observed in the SLE patients most likely because of impaired antibody production. To identify exogenous and endogenous risk factors of importance in the development of SLE, a case-control study was performed. Using a multivariate model, smoking, a history of hypertension, drug allergy, constitutional skin-type as determined by sun-reactivity, and a family history of SLE were all associated with increased risk for developing SLE, whereas consumption of alcohol was inversely associated with SLE risk