HSS Research Uncovers How UV Light Triggers Immune Activation and Disease Flares in Lupus

After sun exposure, people with systemic lupus erythematosus (SLE) frequently develop skin rashes, which often are accompanied by a flare of their overall disease. This connection between ultraviolet (UV) light and disease flares in lupus is well known, but the way in which UV exposure actually triggers the disease has been poorly understood.

In a new study being presented at ACR Convergence 2022, the annual meeting of the American College of Rheumatology, researchers from Hospital for Special Surgery (HSS) report that they have found an underlying mechanism that explains this association: decreased lymphatic drainage, which contributes to both photosensitivity and an immune response in the lymph nodes. The research also suggests that boosting lymphatic drainage may be an effective treatment for lupus photosensitivity and autoimmunity.

“When people with lupus have a systemic flare of their disease, it can affect any organ that is part of their disease,” says senior author Theresa T. Lu, MD, PhD, who holds the St. Giles Chair for Research in the HSS Research Institute, is a faculty member in Pediatric Rheumatology and in Rheumatology at HSS and is a professor of microbiology and immunology and of pediatrics at Weill Cornell Medicine. “We wanted to look at why sun exposure at the level of the skin affects internal organs like the kidneys, heart and lungs.”

“This study sheds some light on how sun exposure and UV light cause people with lupus to have more autoantibodies in their blood,” adds first author William Ambler, MD, a former fellow at HSS in Dr. Lu’s lab who is now Metzger Scholar in Translational Medicine at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health.

The skin communicates with the immune system by sending cells and molecular signals via the lymphatic vessels to the lymph nodes, where immune responses begin. The signals that the skin sends to the lymph nodes control the type of immune responses that occur. Lymphatic vessels also serve the function of removing fluid and cells from the skin. If lymphatic vessels do not work properly to bring signals from skin to lymph nodes, there can be delayed resolution of skin inflammation, leading to faulty signals being sent to the lymph nodes.

Research in the Lu lab suggests that lymphatic flow from the skin to the draining lymph nodes is reduced in people with lupus. The investigators hypothesize that this decreased flow alters lymph node immune responses, making them more pathogenic. They decided to look more closely at this communication and how it impacts immune function. The current research employed both patient samples and mouse models of SLE.

The investigators studied skin biopsies from lupus patients as well as from healthy volunteers who served as controls. When they looked at the samples from the lupus patients, they found these more dilated lymphatic vessels compared with the healthy controls. This provided evidence that people with lupus have poor lymphatic flow.

They then studied mouse models of SLE, using a dye injected into the skin to visualize the flow of lymphatic fluid. They found that when lupus mice were exposed to UV radiation, more dye remained in the skin. This provided evidence that the lymphatics were not clearing the fluid as well as they should.

Importantly, the researchers then looked to see if they could improve certain hallmarks of disease in the mice by using manual lymphatic drainage techniques to manipulate the flow of lymph fluid. This type of therapy is used in people with certain types of cancer, especially breast cancer, to prevent lymphedema (fluid accumulation and swelling) after the surgical removal of lymph nodes. They found that performing lymphatic drainage in the mice reduced the numbers of plasmablasts and germinal center B cells, types of cells that are known to be important players in lupus.

Drs. Ambler and Lu are optimistic that manual lymphatic drainage may benefit lupus patients but emphasize that clinical trials in patients are needed to confirm it would be safe and effective.

The investigators note that this research is also important because it advances the broader field of understanding how skin and organs communicate through the lymph nodes and the immune system.

About HSS

HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 13th consecutive year), No. 3 in rheumatology by U.S. News & World Report (2022-2023), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2022-2023). In a survey of medical professionals in more than 20 countries by Newsweek, HSS is ranked world #1 in orthopedics for a third consecutive year (2023). Founded in 1863, the Hospital has the lowest complication and readmission rates in the nation for orthopedics, and among the lowest infection rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Innovation Institute works to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 145 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.