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Researchers Investigate Sex Differences in Systemic Lupus Erythematosus

Dr. Jorgensen and team have uncovered the role of S100a9 as a molecule integral in determining sex-specific immune responses in lupus.


Findings published by Department of Inflammation & Immunity researchers in Frontiers of Immunology point to a possible explanation behind why systemic lupus erythematosus (SLE) is more common in women than men.  

Systemic lupus erythematosus is an autoimmune disease in which the body’s immune system mistakenly attacks itself, causing widespread inflammation. There are a wide variety of symptoms associated with SLE, including fatigue, skin rashes, fever and pain or swelling in the joints and certain organs. In previous studies, the disease has been shown to be modulated by both immunostimulatory and immunosuppressive functions.   

Because SLE has a strong female predominance, especially in childbearing years, numerous investigations have focused on the role of female sex hormones, including estrogen, in driving disease, but few have studied the mechanisms of testosterone. This is significant because testosterone has been found to exert immunoprotective functions, correlating with the reduced incidence of lupus in males.   

“There’s always two sides to a story,” said Trine Jorgensen, PhD, assistant staff and the study’s lead author. “The majority of SLE research has focused on women and female sex hormones, but we believed that there is just as much to be learned about sex-specific disease risk and pathology by investigating why men don’t get sick in the same way. This was the key to how we began studying testosterone.” 

Prior research leads to S100a9 investigations 

In a prior study conducted by the research team and published in Arthritis & Rheumatology, investigators showed that higher testosterone levels were associated with increased levels of a population of myeloid cells composed of neutrophils and myeloid-derived suppressor cells (MDSCs). In the absence of testosterone, or when the neutrophils and MDSCs were removed, the male mice developed autoimmunity similar to the females. This confirmed that testosterone drove a population of myeloid cells capable of suppressing autoimmunity. 

In the current study, the researchers sought to identify the immunosuppressive mechanisms of MDSCs. They focused specifically on a molecule that is expressed on both neutrophils and MDSCs and has been known to be immunosuppressive in cancer and inflammation, called S100a9.   

The researchers studied S100a9-deficient preclinical models of SLE. They monitored disease progression, looking closely at levels of self-reactive antibodies in the blood to determine when SLE developed. The team found that male mice experienced autoimmunity similar to female mice, while female mice displayed no difference in disease progression or incidence. Dr. Jorgensen and her team therefore concluded that the S100a9 molecule plays a pivotal role in how MDSCs help to reduce disease risk in males.  

The second key finding in the study was the observation of higher levels of type I interferons in male mice that were lacking S100a9. “Type I interferons are known as drivers of lupus disease in animals, as well as humans,” said Dr. Jorgensen. “That leads us to conclude there is a link between MDSCs, their production of S100a9 and levels of type I interferons.”  

Next steps 

Ongoing studies in the lab will investigate what makes S100a9 behave in a sex-dependent manner and how type I interferon levels are targeted. Continuing their collaboration with Dr. Thomas Vogl, University of Muenster, Germany, the team’s ultimate goal is to find therapeutic targets for the treatment of women and men with lupus.   

Laura M. Davison, PhD, a research scientist at Teneobio, Inc., is first author on the study, which was supported in part by the National Institutes of Health.

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