With LRI funding, Dr. Pisetsky and colleagues examined the role of “high mobility group 1 protein” (HMGB1) in the cause and development of systemic lupus.
HMGB1 is a nuclear molecule that can serve as a so-called alarmin to activate the immune stystem after it has left the cell. Dr. Pisestky’s team showed that levels of HMGB1 are increased in the blood of patients with lupus, as well as in lupus mice.
“Our studies were among the first to document this finding,” he explained in 2010. “Subsequently, other investigators showed that HMGB1 is part of immune complexes in lupus and that HMGB1 can stimulate immune changes associated with disease. This information has led to interest in therapies to eliminate HMGB1 or block its downstream effects which include production of interferon. In addition, our findings have suggested the use of HMGB1 as a biomarker.”
“I have been active in lupus research for many years,” he reflected, “but the studies on HMGB1 were a new direction which has turned out to be very productive. Funding by the LRI allowed us to start a program in lupus and we were fortunate to have been among the first explore the relevance of this molecule in SLE, providing a framework for its use as a biomarker or target of therapy,” said Dr. Pisetsky in 2010.
Discovery: Old Arthritis Drug—Gold Salts—Blocks a Cause of Inflammation in Autoimmune Disease
HMGB1 has been implicated in a broad range of immune-mediated diseases. When the immune system is fighting disease, HMGB1 signals immune cells such as T-cells, white blood cells of the immune system that can kill infected cells directly and produce substances that help white blood cells produce antibodies to the infection, to travel to the infection site.
“There’s a lot of interest in the role of HMGB1 in lupus,” Dr. Pisetsky said. “One therapeutic approach is to use antibodies to lower levels of HMGB1 and thereby reduce inflammation. But our data suggest that existing drugs can do that.”
In 2007, Dr. Pisetsky and colleagues reported that gold salts, which are a well-established arthritis treatment, interfere with white blood cells and to prevent them from releasing the inflammation-causing molecule, HMGB1.
Might blocking this molecule reduce the inflammatory symptoms of lupus? His findings provide are the first to demonstrate that a disease-modifying anti-rheumatic drug (DMARD) can decrease the release of the inflammatory mediator HMGB1.
Dr. Pisetsky doubts that existing gold-based drugs, which have fallen from favor because of their side effects, will be reintroduced as lupus treatments. But if his team can identify the molecular pathway that gold salts act on they might be able to screen for other less toxic drugs that similarly block HMGB1.
“Our findings have focused attention on the role of nuclear molecules in disease pathogenesis and the conditions under which these molecules are released into the blood,” Dr. Pisetsky said in 2010. “These studies provide a context for understanding events in lupus (e.g., flare) and the role of different therapies in reducing their levels.”
The effects of CpG DNA on HMGB1 release by murine macrophage cell lines. Jiang W, Li J, Gallowitsch-Puerta M, Tracey KJ, Pisetsky DS. J Leuk Biol 78:930-936, 2005.
The role of IFN-α and nitric oxide in the release of HMGB1 by RAW 264.7 cells stimulated with polyinosinic-polycytidylic acid and lipopolysaccharide. Jiang W, Pisetsky DS. J Immunol 177:3337-43, 2006.
The extracellular release of HMGB1 during apoptotic cell death. Bell CW, Jiang W, Reich CF III, Pisetsky DS. Am J Physiol Cell Physiol 291:C1318-C1325, 2006.
The role of HMGB1 in the pathogenesis of inflammatory arthritis. Jiang W, Pisetsky DS. Nature Clin Pract Rheumatol 3:52-8, 2007.
The relationship between apoptosis and high-mobility group protein 1 release from murine macrophages stimulated with lipopolysaccharide or polyinosinic-polycytidylic acid. Jiang W, Bell CW, Pisetsky DS. J Immunol 178:6495-503, 2007.
The role of Toll-like receptors in HMGB1 release of macrophages. Pisetsky DS, Jiang W. Ann N Y Acad Sci., 1109:58-65, 2007.
Pivotal Advance: Inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate. Zetterström CK, Jiang W, Wähämaa H, Östberg T, Aveberger AC, Schierbeck H, Lotze MT, Andersson U, Pisetsky DS, Harris HE. J Leukoc Biol 83:1-7, 2008.
High-mobility group box protein 1 (HMGB1): an alarm in mediating the pathogenesis of rheumatic disease. Pisetsky DS, Erlandsson-Harris H, Andersoon U. Arthritis Research & Therapy 10:209, 2008.
The induction of HMGB1 release from RAW 264.7 cells by transfected DNA. Jiang W, Pisetsky DS. Molecular Immunology 45:2038-44, 2008.
Dr. Pisetsky won a 5-year, $1.8 million grant from the NIH, as well as a $300,000 Veteran’s Association award to continue the work that he initiated with LRI funding.
Rev. July 2010