NYC Gazette

Researchers at the Hospital for Special Surgery (HSS) have made significant progress in understanding systemic sclerosis (SSc), commonly known as scleroderma. This rare autoimmune disease, characterized by tissue hardening and inflammation, predominantly affects women. Two new studies published in the Journal of Experimental Medicine reveal key biological mechanisms behind this gender disparity and suggest potential treatment strategies.

Scleroderma impacts around 300,000 people in the United States, with one-third developing systemic disease that can affect vital organs like the lungs, kidneys, or heart. Women are diagnosed four times more often than men, but until now, the reasons for this difference were unclear.

One study led by Dr. Franck Barrat identified two genetic receptors on the X chromosome—TLR7 and TLR8—as crucial in activating plasmacytoid dendritic cells (pDCs), which drive chronic fibrosis. These immune cells are present in fibrotic skin but not healthy skin and contribute to scleroderma. The study found that TLR7 and TLR8 can escape X chromosome deactivation in pDCs of scleroderma patients.

"The magnitude of this escape was striking," said Dr. Barrat. In healthy individuals, only 10 to 15 percent of cells evade deactivation; however, in scleroderma patients, more than 35 percent of pDCs do so. "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," Dr. Barrat concluded.

In another study focusing on fibrosis drivers, researchers discovered why natural mechanisms fail to halt inflammation in scleroderma patients. Normally, immune cells trigger an inflammatory response following a skin wound until scarring begins when a pause signal resolves inflammation. In scleroderma patients, this process is disrupted by CXCL4—a cytokine highly expressed in their skin—that prevents immune suppression.

“We show that CXCL4 prevents the normal termination of the immune response in the skin,” explained Dr. Barrat. Instead of being suppressed as expected during fibrosis attraction, CXCL4 keeps pDCs active contributing to ongoing fibrosis cycles.

While there is no cure for scleroderma yet, research suggests promising therapeutic strategies targeting pDCs interference could be explored further with existing drugs under development showing potential against lupus-related skin lesions.

The collaborative studies involved contributions from various institutions including HSS's Scleroderma Center; University of Toulouse; Institut Toulousain des Maladies Infectieuses et Inflammatoires; Université Paris Cité; Institut Cochin; ImmunoConcEpt at University Bordeaux among others alongside co-authors like Dr Jean-Charles Guéry PhD from University Toulouse adding valuable insights into this important research field.