PhD ceremony Ms. D.A. Abdulahad Al-Qas Alias: The role of nuclear protein High Mobility Group Box-1 (HMGB1) in the pathogenesis of Systemic Lupus Erythematosus (SLE)

PhD ceremony: Ms. D.A. Abdulahad Al-Qas Alias, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The role of nuclear protein High Mobility Group Box-1 (HMGB1) in the pathogenesis of Systemic Lupus Erythematosus (SLE)

Promotor(s): prof. C.G.M. Kallenberg, prof. P.C. Limburg

Faculty: Medical Sciences

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with involvement of many organ systems in the disease process. Autoantibodies are present directed against nuclear components such as DNA, but also against other cellular constituents. One of these constituents is HMGB1 (high mobility group box-1), a DNA-binding protein that is released from apoptotic cells but also following activation of cells. This HMGB1 is a so-called alarmin that, when released, contributes to an inflammatory reaction. In this thesis, it was shown that patients with SLE produce antibodies to HMGB1 and that their levels correlate with disease activity. This is also the case for HMGB1 itself which means that levels of HMGB1 are a marker of disease activity. In addition, it was found that disease activity of SLE in the kidneys was associated with the appearance of HMGB1 in the urine. As such, measurement of HMGB1 in the urine can be a diagnostic tool for assessing renal disease activity. A next step was to assess whether exposition to sunlight (UVB) can result in release of HMGB1 from skin cells contributing to inflammation of the skin. The results of these studies indeed supported this hypothesis: SLE patients showed a much stronger release than healthy controls which may explain why SLE patients have such a strong hypersensitivity to sun exposure. In conclusion, HMGB1 is an important inflammatory protein in SLE and, additionally, an autoantigen against which antibodies are produced. Measuring levels of HMGB1 in blood and urine can be helpful for assessing disease activity in SLE. Currently we are investigating whether targeting of HMGB1 in a lupus mouse model could be a new therapeutic option for SLE.