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 immunological properties which is present in each cell of the body. Earlier studies 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 the 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 an anti-HMGB1 antibody affects the development of lupus nephritis in lupus mice. Contrary to our expectations it did not ameliorate glomerulonephritis. Also, we observed no differences with respect to other markers of disease or pro-inflammatory cytokines between mice treated with or without control antibody.
In summary, the results of 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.