Systemic lupus erythematosus : Pathogenesis and genetics with special reference to multicase families

Abstract: Systemic lupus erythematosus (SLE) is a prototype for systemic autoimmune disease. The etiology is largely unknown although valuable knowledge has been accomplished through intensive research in this field in recent years. The aim of this thesis was to achieve increased knowledge of the etiology and pathogenesis, in particular the role of genetic and environmental factors, by the use of a combined epidemiologic and experimental approach. Both Icelandic and Swedish SLE patients were investigated. The Icelandic population is rather homogeneous and offers unique possibilities for this kind of studies. The Swedish population has similar ethnic background. In the first study patients and their relatives and spouses in Icelandic SLE multicase families were characterised and a high frequency of autoimmune disorders (AID) was documented in these families. This was observed in the first-degree relatives, and also to some extent in the spouses of SLE patients (AID/ANA). These findings suggest that both genetic and environmental factors could be important in the susceptibility to autoimmune diesases. Cytokines are important molecules involved in regulation of the immune system. The second study deals with the possible role of cytokines, in particular interleukin- 10 (IL- 10), in the pathogenesis of SLE. Production and serum levels of type I and type 2 cytokines in Swedish SLE patients with various disease activity and clinical profile were investigated. Both the production and serum levels of the type 2 cytokines IL-10 and IL-6 were increased in SLE patients regardless of disease activity or clinical manifestations. However, there was a correlation between serum levels of IL-10 and anti-ds DNA antibody titres. These results support a role of IL- 10 in the pathogenesis of SLE and, furthermore, as IL-10 production was independent of disease activity and manifestations it could be constitutively increased. These findings were confirmed in the third study in which increased IL-10 production was found in SLE patients in Icelandic SLE- multicase families. In this study IL-10 production was also increased in first-degree relatives and in a limited number of spouses of SLE patients suggesting that not only genetic but also environmental factors could be involved in this abberrant cytokine production. One way that IL-10 could be involved in the pathogenesis of SLE is via apoptosis, which was investigated in the Icelandic SLE-multicase families in the fourth study. An increased degree of apoptosis of lymphocytes was observed in SLE patients and their spouses but not in their nonhousehold first-degree relatives, supporting a role of environmental factors to be involved in the disturbed apoptosis evident in SLE patients. No correlation, however, was found between IL- 10 and apoptosis. To further clarify the role of genetics in SLE a first approach was made by performing a genome scan of the Icelandic SLE-multicase families as well as Swedish SLE multicase families. A linkage to a region on chromosome 2q37 was determined, this locus was named hSLE1, now officially called SLEB2 and it is not syntenic to any hitherto described mouse SLE locus. In addition, genetic linkage analysis of SLE multicase families from Iceland, Sweden and Mexico revealed no linkage between the IL- 10 gene and SLE. In conclusion, the results of this thesis support a role of IL-10 as well as of apoptosis in the pathogenesis of SLE. Both environmental and genetic factors are important in the disturbed regulation of the immune system and complex interactions between these factors may lead to clinical disease.