Scleroderma or systemic sclerosis (SYS) 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. Two new studies led by researchers at Hospital for Special Surgery have uncovered key biological mechanisms driving SYS, 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.
In one study, a team of researchers led by Franck Barrat, PhD, found that two immune-related receptors called TLR7 and TLR8, which are present on the X chromosome, are important drivers for the activation of plasmacytoid dendritic cells (pDECs), fueling chronic fibrosis. pDECs 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 pDECs. In healthy individuals, 10 to 15% of cells can evade the deactivation process. But in scleroderma patients, the escape occurred in more than 35% of the pDECs. This was a significant and unexpected difference.
In a separate study, armed with insights about the role of pDECs in driving fibrosis, scientists 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 chemokine 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 pDECs in a state of chronic activation and promoting skin fibrosis. But there is more to these data.
Scientists from the Hannover Medical School, Germany, have discovered an aberrant toll-like receptor (TLR) 8 transcripts in pDECs and addressed the functional role of TLR8 signaling in different immune cell subsets of patients with the condition. To identify relevant alterations specific for patients with SSc (n = 16), patients with primary Sjögren disease (n = 10) and healthy controls (n = 13) were included into the study. In all individuals, TLR8 was expressed in monocytes and cDCs but not in pDCs. The TLR8 expression levels were overall similar in patients with SSc and pSS and HCs. Additionally, in all study participants, TLR8 stimulation of pDECs did not induce IFN-I expression. In contrast, monocytes from patients with SSc revealed increased interleukin (IL)-10 responses upon TLR8 and TLR7/8 stimulation.
Therefore, CXCL4 chemokine drives skin sclerotization while TLR8 signaling in monocytes participates in SSc pathogenesis by conferring aberrant IL-10 expression in systemic sclerosis.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Du Y et al. J Exp Med 2025 Mar 3; 222(3):e20231809.
Ehlers C et al. Arthritis Rheumatol. 2025; 77(1):59-66.
Youness A, Cenac C et al. Biol Sex Differ. 2023; 14(1):60.
