Lymphatic System Molecule Implicated in Autoimmune Diseases Identified

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, and colleagues launched the study 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 scientists can elucidate the underlying mechanism that causes autoimmune and inflammatory conditions, they can develop ways to correct the immune system flaws that lead to disease.

Dr. Lu's study focused on the lymphoid tissues, which house immune cells and are sites of immune cell activation. Lymphoid tissues, which include the tonsils, spleen and lymph nodes, 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, according to Dr. Lu.

"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," she explained. "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."

The findings have implications for better understanding autoimmune diseases, according to Dr Lu. Plasma cells in autoimmune diseases generate autoantibodies that then deposit and cause inflammation in organs such as the kidneys and skin. "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," she notes.

"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 a musculoskeletal injury, fighting cancer and fighting infections," she adds. "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."

Dr. Lu's lab and colleagues have been studying the vasculature and fibroblasts of lymph nodes for 16 years. Dragos Dasoveanu, PhD, was the first author of the current study. He conducted the research at HSS with Will Shipman, PhD; Susan Chyou, BA; and Varsha Kumar, PhD. In addition, scientists at research centers in New York, Switzerland and Australia collaborated on the study.

Reference
Lymph node stromal CCL2 limits antibody responses. Dragos C. Dasoveanu, Hyeung Ju Park, Catherine L. Ly, William D. Shipman, Susan Chyou, Varsha Kumar, David Tarlinton, Burkhard Ludewig, Babak J. Mehrara and Theresa T. Lu. Science Immunology  20 Mar 2020: Vol. 5, Issue 45, eaaw0693, DOI: 10.1126/sciimmunol.aaw0693.

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