Systemic sclerosis is a slow and painful hardening of the body’s tissue. People with a mild form of the disease develop thick patches on their skin. More serious cases involve trouble breathing and swallowing, and can lead to death. “[It’s] a very mysterious disorder,” says HHMI Investigator Harry Dietz of the Johns Hopkins University. “There’s been a lot of descriptive work on what happens to patients, but very little information about what causes it.” Until now.
Dietz and his colleagues had traced a less severe form of scleroderma, called stiff skin syndrome, to mutations in the protein fibrillin-1. When they engineered mice with the same gene mutation, however, the mice showed symptoms of the more aggressive systemic sclerosis. As Dietz reported November 7, 2013, in Nature, the symptoms were caused by an immune reaction triggered by the protein’s inability to do its job. As part of the extracellular matrix—the material that exists between cells—fibrillin-1 provides structural support and helps cells communicate with the matrix via molecules called integrins. Mutant fibrillin-1 can’t interact with integrins. To compensate, more integrins are produced, causing an autoimmune reaction and fibrosis—the excessive production of connective tissue that results in scleroderma.
By interfering with the immune response, Dietz’s team prevented fibrosis and even reversed the disease in mice. “This is one of the first, and the most dramatic, illustrations that fibrosis can be reversed,” says Dietz. “I was quite surprised and quite thrilled.”