Further supporting the involvement of HMGB1 in renal pathology are immunohistochemical studies performed on kidney tissue from lupus nephritis patients. These studies have revealed increased HMGB1 expression. It was shown that HMGB1 expression was greater in lupus kidneys compared to controls and it was mainly observed in glomerular cells, tubular cells, as well as infiltrates of mononuclear cells.17 Despite these findings, the questions regarding the origin of HMGB1 in kidney tissues as well as its precise role in pathogenesis remain unresolved. Thus, it is possible that circulating HMGB1 in its free form or complexed form (i.e., DNA-containing immune complexes) binds to RAGE and TLRs (2, 4, and 9) expressed on renal tissue. This binding could initiate an inflammatory response. In this case, the HMGB1 could be produced outside the kidney and arrive via the immune complexes, almost as a Trojan horse. Alternatively, damaged renal cells could secrete HMGB1, creating a local supply that has the ability to act as chemokine, attracting monocytes and lymphocytes. These cells could further secrete cytokines amplifying the inflammation (see Figure 2).
Conclusion
As inflammatory mediator and prototypic alarmin, HMGB1 could play an important role in the pathogenesis of autoimmune diseases especially those with renal manifestations. In SLE, immune complex–mediated nephritis is considered the main cause of mortality. Cellular and molecular mechanisms underlying the pathogenesis of lupus nephritis are still unknown. Considering the data discussed here, HMGB1, whether in its free or complexed form (as components of immune complexes), could play an important role in the pathogenesis of lupus nephritis. It is tempting to speculate that measurement of HMGB1 (in the blood or possibly the urine) could represent a potentially useful new marker for kidney disease that could signify both inflammation and damage.
In addition to highlighting the value of HMGB1 as a biomarker, ongoing studies are investigating this protein as a new therapeutic target in SLE. This role is consistent with studies on the efficacy of strategies to reduce HMGB1 levels in experimental arthritis and shock in animals. While much work on HMGB1 remains for the future, the study of this dual function protein has nevertheless provided important new insights into the operation of the innate immune system and the way in which nuclear molecules in lupus can promote inflammation.
Clearly, in the immune system as in real estate, location is everything and, when HMGB1 escapes from the confines of the nucleus, it takes on another identity and can drive inflammation in a way entirely unexpected for a protein of this kind. The future will tell whether alarmins can be targets of new types of immunosuppression, demonstrating a safety and toxicity profile that can be a meaningful advance over that of current agents. the rheumatologist
