MedImmune Inc. has announced the publication of preclinical study data demonstrating a role for high mobility group box protein-1 (HMGB1), a nuclear DNA-binding protein, in the pathology of systemic autoimmune diseases such as systemic lupus erythematosus (SLE or lupus) and rheumatoid arthritis.
Data to be published in the May 2007 issue of Nature Immunology show that HMGB1 is an essential component of DNA-immune complexes that stimulate immune cells to produce potent inflammatory proteins. The data supplement earlier preclinical evidence that HMGB1 may be an important factor in the sequence of events that result in severe tissue damage following injury or during chronic inflammation. The data also suggest that a blocking antibody to HMGB1 may provide protection in chronic inflammatory diseases.
"MedImmune is committed to developing innovative treatments for inflammatory diseases, and among our key areas of focus are the disease pathology of lupus and the role of B cells in autoimmunity," said Anthony J Coyle, vice president, research and development, and head, inflammation and autoimmunity research. "These data, applicable to several programs within our pipeline, demonstrate a novel mechanism by which HMGB1 mediates B cell activation and may contribute to the pathogenesis of autoimmune disorders."
HMGB1's potential role in chronic inflammatory diseases is the focus of ongoing preclinical research conducted by MedImmune in collaboration with its partner, Critical Therapeutics, Inc. The Nature Immunology article, titled "Toll-like receptor 9-dependent activation by DNA containing immune complexes is mediated by HMGB1 and RAGE," contains data showing that HMGB1 is a key component of DNA-immune complexes that stimulate activation of B cells and plasmacytoid dendritic cells (pDCs) via the toll-like receptor 9 pathway (TLR9). Both B cells and pDCs are associated with immune system disorders such as lupus. The data also suggest that HMGB1 DNA-immune complexes augment production of inflammatory proteins by interacting with the receptor for advanced glycation end products (RAGE).
HMGB1, a pro-inflammatory protein secreted by different cell types, is part of the body's response to trauma and infection. HMGB1 is expressed at high levels beginning 12 to 72 hours after an injury, which is about the time inflammation-associated tissue damage begins. Because of the timing and duration of expression of HMGB1, it may be an important factor in the sequence of events that result in severe tissue damage following injury or during chronic inflammation.