Studies may shed light on gender disparity in scleroderma

Photo by: AVM via Wikimedia Commons

Recent studies conducted by researchers at the Hospital for Special Surgery (HSS) in New York contribute to understanding the biological mechanisms underlying systemic sclerosis, or scleroderma. Their findings may help to explain why women are four times more likely to be diagnosed with scleroderma than men.

The research, published in the March issue of the Journal of Experimental Medicine, identifies genetic receptors TLR7 and TLR8 on the X chromosome as key drivers of the disease. These receptors activate plasmacytoid dendritic cells (pDCs), which contribute to chronic fibrosis. In healthy individuals, one X chromosome is typically inactivated, but in scleroderma patients, TLR7 and TLR8 evade this deactivation process in pDCs, leading to their overactivation.

“The magnitude of this escape was striking,” noted lead researcher Dr. Franck Barrat in a press release. In healthy individuals, about 10 to 15% of cells can evade X chromosome deactivation, but in scleroderma patients, this occurs in more than 35% of pDCs. Dr. Barrat noted that “The expression of two copies of the TLR7 and TLR8 in such a large number of cells can very well explain the chronic activation of these immune cells and why this disease is so prevalent in female patients.”

In a separate study, Dr. Barrat and colleagues investigated why inflammation fails to resolve in scleroderma patients. They identified the cytokine CXCL4 as a primary culprit, which prevents immune suppression and keeps pDCs in a state of chronic activation, promoting fibrosis. “We show that CXCL4 prevents the normal termination of the immune response in the skin,” Dr. Barrat said. “Basically, the pDCs are attracted by the fibrosis, but instead of being suppressed as they should be, CXCL4 keeps them active, in turn contributing to the cycle of fibrosis in these patients.”

These findings may also highlight potential therapeutic strategies. Dr. Barrat said several therapies targeting pDCs in clinical trials have shown promise in blocking pDCs and preventing skin lesions in patients with lupus.

“This body of research makes a very strong case for exploring drugs that target and interfere with pDCs. There are already drugs in development that we can try,” Dr. Barrat said.

Both studies were collaborative efforts involving researchers from HSS and international institutions.