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.