HMGB1 Expression in Sickle Cell Disease: A Pro-Inflammatory Cytokine and Potential Therapeutic Target.

Background: HMGB1 is traditionally known as a DNA binding protein involved in gene transcription. When released into the extracellular milieu, HMGB1 activates vascular endothelial cells and macrophages/monocytes to express proinflammatory cytokines, chemokines, and adhesion molecules. Therefore, HMGB1 may be a good marker for disease activity in Sickle Cell Disease (SCD), a chronic inflammatory state.

Methods: After informed consent as per Institutional guidelines, plasma was obtained, frozen, and batch run for HMGB1 levels by ELISA technique in patients with SCD during non-crisis and crisis states. The detection limit of HMGB1 was achieved at concentrations above 1 ng/ml. Each experiment was repeated at least five times to ensure reproducibility.

Results: 12 patients enrolled, 6 patients have gone into crisis. HMGB1 levels were measured on consecutive days for 5 five days during a crisis. We established mean HMGB1 expression levels of 32.83 ± 27.13ng/ml during a non-crisis state and 52.57± 15.22 ng/ml during a crisis, respectively (p< .028). In noninflammatory states, HMGB1 is < 5 ng/ml.

Conclusion: We have demonstrated, for the first time, a persistent expression of HMGB1 in SCD patients. Although recruitment is on going, this data is consistent with pre-clinical data indicating that HMGB1 may be an important diffusible signal of necrosis-mediated inflammation. Additionally, our laboratory has previously demonstrated therapeutic benefit by neutralization of HMGB1 in sepsis. Thus if confirmed in a larger cohort, anti-HMGB1 therapy to reduce the effects of inflammation may be an attractive therapeutic target in sickle cell disease.