A research team from the Johns Hopkins Division of Rheumatology led by Livia Casciola-Rosen, Ph.D. found that cells which repair blood vessels have high levels of the proteins that are targeted by the immune system in some people with scleroderma. The work was a team effort and included physicians and laboratory scientists within the Division including Zsuzsanna McMahan, M.D, Fredrick Wigley, M.D, Brendan Antiochos, M.D, Laura Gutierrez-Alamillo, M.D, Raffaello Cimbro, M.S, Tricia Cottrell, M.D, Ph.D., Antony Rosen, M.D., as well as others researchers from the Institute for Cell Engineering, Division of Pediatric Oncology, and Department of Pathology.
Why was this study done?
A group of people with scleroderma are at high risk of developing severe blood vessel complications including digital loss and gangrene. These patients often have antibodies in their blood that can bind to proteins normally found in the body called centromere and IFI16. The goal of this study was to determine whether these two proteins are found at high levels in blood vessel cells and cells that repair blood vessels after damage. If this turned out to be the case, we reasoned that this could explain why patients who make antibodies to these proteins have damage to the vessels that cannot be repaired and end up having digital loss.
How was this study done?
We measured precisely how much IFI16 and centromere proteins were expressed in cells which have the ability to become blood vessels, called vascular progenitor cells. We also looked at which cells in the blood and skin had high levels of the IFI16 protein by studying blood samples and tiny pieces of skin tissue obtained from skin biopsies from scleroderma patients and healthy donors. All the research volunteers were people seen at the Johns Hopkins Scleroderma Center.
What were the major findings?
We found that high levels of centromere and IFI16 proteins were present in vascular progenitor cells. IFI16 was also present at high levels in blood vessels in the skin and in the cells in the blood that are responsible for repairing damaged blood vessels. The levels of the IFI16 protein were the same in samples from scleroderma patients and healthy donors.
What is the impact of this work?
The proteins targeted by antibodies in people with scleroderma who have severe blood vessel disease, are present at the highest levels in blood vessel cells (including cells that become blood vessels during development and those that repair blood vessel damage later in life). This was not known prior to this study and may be an important link that explains why people with these antibodies have severe blood vessel injury that cannot be repaired. The immune system may damage blood vessels and then prevent repair by attacking the repair cells themselves, since they express high levels of these specific proteins. Learning more about how vessels are damaged in people with scleroderma, and the barriers to repair is important for understanding why people get digital loss and maybe even how to prevent it in the future.
This research was supported by:
The Johns Hopkins Rheumatic Disease Research Core Center (RDRCC), and grants from the Jerome L. Greene Foundation, the Scleroderma Research Foundation, the Rheumatology Research Foundation Scientist Development Award, the Maryland Stem Cell Research Fund, and the National Institutes of Health (P30-AR053503, RO1 DE-12354-15A1, and R56-AR-062615).
Link to original research article:
Autoantigens targeted in scleroderma patients with vascular disease are enriched in endothelial lineage cells. McMahan ZH, Cottrell TR, Wigley FM, Antiochos B, Zambidis ET, Park TS, Halushka MK, Gutierrez-Alamillo L, Cimbro R, Rosen A, Casciola-Rosen L. Arthritis Rheumatol. 2016 May 9. doi: 10.1002/art.39743. PMID: 27159521