Two new studies led by researchers at Hospital for Special Surgery (HSS) have uncovered key biological mechanisms driving systemic sclerosis (SSc), or scleroderma – a rare and often devastating autoimmune disease that causes fibrosis (tissue hardening) and inflammation. The research, published in the March issue of the Journal of Experimental Medicine, helps explain why the disease disproportionately affects women and reveals potential treatment targets, some of which are already in development.
Scleroderma affects approximately 300,000 people in the U.S., with about one-third developing systemic disease, which can affect major organs such as the lungs, kidneys or heart. Women are four times more likely than men to be diagnosed with the disease, but until now, the underlying reason for this gender disparity had remained elusive.
In one study, a team of researchers led by Franck Barrat, PhD , found that two genetic receptors called TLR7 and TLR8, which are present on the X chromosome, are important drivers for the activation of plasmacytoid dendritic cells (pDCs), fueling chronic fibrosis. pDCs are immune cells found in fibrotic skin but not in healthy skin and have previously been shown to contribute to scleroderma.
In healthy cells, one X chromosome is typically deactivated, however, the study revealed that in patients with scleroderma, this process is disrupted due to the ability of TLR7 and TLR8 to escape X chromosome deactivation in pDCs.
"The magnitude of this escape was striking," says Dr. Barrat.
In healthy individuals, 10 to 15 percent of cells can evade the deactivation process. But in scleroderma patients, the escape occurred in more than 35 percent of the pDCs. This was a significant and unexpected difference.
"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," concludes Dr. Barrat.
In a separate study, armed with insights about the role of pDCs in driving fibrosis, Dr. Barrat and colleagues set out to understand why the body's natural mechanisms fail to shut down inflammation in scleroderma patients. Normally, following a wound in the skin, immune cells infiltrate the skin and trigger an inflammatory response until the scarring process begins. A pause signal is then delivered to the immune cells to resolve the inflammation. But in scleroderma patients, this process stalls.
The culprit? A cytokine (a type of protein that helps control inflammation in the body) called CXCL4, which researchers found to be highly expressed in the skin of scleroderma patients. Instead of allowing inflammation to subside, CXCL4 prevents immune suppression, keeping pDCs in a state of chronic activation and promoting skin fibrosis.
"We show that CXCL4 prevents the normal termination of the immune response in the skin," explains Dr. Barrat. "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."
While there is currently no cure for scleroderma, the research highlights the potential of several therapeutic strategies.
"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," says Dr. Barrat, noting that several therapies in clinical trials have shown promise in blocking pDCs and preventing skin lesions in patients with lupus.
Both new studies were a collaborative work. Co-authors from the first study include Dr. Jean-Charles Guéry, PhD, of the University of Toulouse, as well as clinicians from the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS and investigators from the HSS Research Institute. Co-authors from the second study include investigators from the HSS Research Institute; the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS; Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, INSERM, France; Institut Cochin, Université Paris Cité, INSERM, France; and ImmunoConcEpt, CNRS, UMR 5164, University of Bordeaux, France.
