How the Immune System May Contribute to Pain in Fibromyalgia and Rheumatoid Arthritis
Our research explores how the immune system and specifically a type of antibody called IgG may contribute to chronic pain in fibromyalgia (FM) and rheumatoid arthritis (RA).
Fibromyalgia
In FM, we studied blood samples and skin biopsies from patients and transferred purified antibodies into mice to observe their effects. The results were striking: mice given antibodies from FM patients became more sensitive to touch and cold, showed weaker grip strength, and moved around less closely reflecting the symptoms seen in people with fibromyalgia. These mice also lost small nerve fibers in the skin, a change also seen in around half of FM patients. We found that these antibodies gather in a part of the nervous system called the dorsal root ganglia (DRG), which contains the cell bodies of nerve cells that transmit pain signals. In the DRG, the antibodies mainly bind to satellite glial cells (SGCs), which support nerve cells, and to a lesser extent, to immune cells including macrophages. Importantly, we saw the same antibody binding in human DRG tissue, showing that what we observe in mice is relevant to humans.
We developed a test to detect whether someone has antibodies that bind to SGCs. People with higher levels of these antibodies reported more severe pain, suggesting a direct link between the immune system and symptom intensity. These antibodies were also linked to changes in certain brain chemicals involved in how pain is regulated suggesting they may be responsible for the ongoing, spontaneous pain that many FM patients experience.
Another important finding was that FM patients had different levels of certain fats (lipids) in their blood compared to healthy individuals. These changes in lipid levels were also linked to pain severity and to the presence of the SGC-targeting antibodies.
Rheumatoid Arthritis
In RA, we focused on the type of pain that continues even when joint inflammation is under control. Our findings suggest that autoantibodies may play a key role in driving this long-lasting pain sensitivity by directly or indirectly affecting the nervous system. One particular RA-related autoantibody binds to cells in the DRG, increasing pain sensitivity. These autoantibodies primarily target SGCs and activate macrophages. This immune response is triggered through a receptor called Fc gamma receptor, creating a localized inflammatory effect that contributes to pain.
We identified two separate molecular pathways involved in this process. The first, called the JAK/STAT pathway, drives inflammation and increases the sensitivity of both glial and nerve cells. This can be blocked using a drug called baricitinib, which reduces pain symptoms. The second pathway, AAK1/AP2M1, is involved in making nerve cells more sensitive to stimulation. Both pathways represent promising targets for new types of pain treatments.
Additionally, our work uncovered a previously overlooked role for macrophages within the DRG. A subgroup of these cells were found to be located near blood vessels in the DRG where they most likely have protective function by scavenge materials from the bloodstream, including antibodies. We are now exploring if dysfunction in this system can contribute to development of chronic pain such as in FM and RA.
Our findings challenge the traditional view that RA pain is purely inflammatory and that FM pain is entirely brain-based. Instead, they highlight a direct role of the immune system in driving pain via interactions with the peripheral nervous system—opening the door to new, immune-targeted treatments for chronic pain.
