Study Finds Molecule in Lymphatic System Implicated in Autoimmune Diseases
A study by investigators at Hospital for Special Surgery (HSS) has discovered a molecule in the lymphatic system that has the potential to play a role in autoimmune disease. The study, “Lymph node stromal CCL2 limits antibody responses,” was published online today in the journal Science Immunology.
Lead investigator Theresa Lu, MD, PhD, senior scientist in the Autoimmunity and Inflammation Program at the HSS Research Institute, answered questions about her group’s study.
1 - What prompted you to launch this study?
We aim to gain a better understanding of how the immune system works. A healthy immune system defends the body against diseases and infection. When someone has an autoimmune disease, the immune system malfunctions and the body mistakenly attacks healthy cells, tissues and organs. Rheumatoid arthritis, lupus and scleroderma are examples of autoimmune diseases.
If we can elucidate the underlying mechanism that causes autoimmune and inflammatory conditions, we can develop ways to correct the immune system flaws that lead to disease.
2 – What was the focus of your study?
Our study focused on the lymphoid tissues, which house immune cells and are the sites of immune cell activation. The lymphoid tissues include the tonsils, spleen and lymph nodes.
3 - What were the main findings of your study?
The lymphoid tissues contain structural elements, such as fibroblasts and blood vessels. These structural elements were thought to mainly provide an infrastructure for the immune cells, but recent advances in the field have shown that they actively shape immune cell responses, and multiple populations of fibroblasts have different functions.
We found that one fibroblast population expressed a molecule called CCL2 in the area of antibody-secreting immune cells, called plasma cells. We focused on the CCL2-expressing fibroblasts to see if they regulate plasma cell function. We found that CCL2 limits the magnitude of plasma cell responses by acting on an intermediary cell to reduce plasma cell survival. This was surprising in some ways, as CCL2 can also promote inflammation, and yet we are finding a role in limiting immune responses. This underscores the multiple functions that any molecule can have in different contexts.
Our findings have implications for better understanding autoimmune diseases. Plasma cells in autoimmune diseases generate autoantibodies that then deposit and cause inflammation in organs such as the kidneys and skin.
4 - Why are your findings important?
By understanding that plasma cells can be controlled by this subset of fibroblasts, we can study these fibroblasts to see if they are perhaps not working properly in autoimmune and inflammatory diseases. We can then search for a way correct the malfunction, so they are less likely to cause disease.
As the immune system is so central to how well our bodies function and often acts in similar ways in a number of different settings, what we are learning about manipulating fibroblasts can also help the biomedical community better understand how to treat related processes, such as healing after musculoskeletal injury, fighting cancer and fighting infections. For example, medications used in adults and children with different forms of autoimmune inflammatory arthritis or lupus are being examined in the setting of coronavirus infections. We all learn from each other.
5 - Why is this an exciting line of research, and how long have you been studying this topic?
We have been studying the vasculature and fibroblasts of lymph nodes for 16 years.
Research entails a lot of people working together: Dragos Dasoveanu, PhD, was the first author of the study, and he did the work in my lab at HSS with Will Shipman, PhD; Susan Chyou, BA; and Varsha Kumar, PhD. In addition, we had collaborators at research centers in New York, Switzerland and Australia for this study.
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 11th consecutive year), No. 4 in rheumatology by U.S. News & World Report (2020-2021), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2021-2022). HSS is ranked world #1 in orthopedics by Newsweek (2020-2021). 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. The global standard total knee replacement was developed at HSS in 1969. 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 Global Innovation Institute was formed in 2016 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 130 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.