Involvement of high mobility group box 1 in the auto-inflammatory process in systemic lupus erythematosus

In this thesis we investigated the role of High Mobility Group Box-1 (HMGB1), in the auto-inflammatory process in Systemic Lupus Erythematosus (SLE). HMGB1 is a nuclear protein which is present in every cell in the body, but also has immunological properties. Earlier studies have demonstrated that HMGB1 levels are increased in patients with SLE and correlate with disease activity. Collectively, studies suggest that HMGB1 is an important factor in the pathogenesis of SLE and could constitute a potential therapeutic target. However, the underlying mechanisms by which HMGB1 contributes to SLE pathogenesis are not fully understood. First, we demonstrated that addition of HMGB1 results in a more pro-inflammatory phenotype of macrophages. It has been reported that HMGB1 can contribute to a decrease in phagocytic capacity of macrophages. In particular, we demonstrated that HMGB1 contributes to the impaired phagocytosis capacity of macrophages, as seen in SLE, by interfering with recognition of apoptotic cells as well as by influencing the macrophage itself. As such, HMGB1 can be considered an important factor in sustaining the auto-inflammatory processes in SLE. We investigated whether treatment with a anti-HMGB1 antibody affects the development of lupus nephritis in lupus mice. Contrary to our expectations did not ameliorate glomerulonephritis. Also, no differences were observed with respect to other markers of disease or pro-inflammatory cytokines between mice treated with control antibody or mice treated.In summary, the results from this thesis provide further evidence that HMGB1 is involved in SLE pathogenesis but treatment with anti-HMGB1 antibodies did not alter disease development in lupus mice