Periodic Reporting for period 3 - ANTIBODYPAIN (Autoantibodies and chronic pain - Unraveling new mechanisms contributing to pain in rheumatic disease)
Reporting period: 2023-10-01 to 2025-03-31
Chronic pain deeply affects the daily lives of millions and creates a major burden on society—not only through the high costs of healthcare and treatment, but also by reducing people's ability to work and participate fully in life. Pain is one of the most difficult symptoms to manage in rheumatic diseases such as rheumatoid arthritis (RA) and fibromyalgia (FM). Yet, the biological reasons behind this pain—especially in FM—are still poorly understood. For many years, FM was unfairly dismissed as a psychological or imaginary condition. This stigma has caused lasting harm to those living with FM, worsening their symptoms and delaying effective care. FM affects about 2–5% of the population, mostly women, and leads to persistent pain and fatigue. However, there are still no clear diagnostic tests, and current treatments often don’t work well. To improve the lives of people with FM, we urgently need to better understand what drives their pain.Our research focuses on a key part of the immune system—antibodies, specifically immunoglobulin G (IgG)—and their role in chronic pain. We are investigating how IgG from people with FM and RA may trigger pain by affecting how cells in the body and nervous system interact.
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.
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.
A New Paradigm for Understanding Chronic Pain
Our research challenges the traditional understanding of fibromyalgia (FM) and rheumatoid arthritis (RA) pain, which has largely focused on central nervous system dysfunction in FM and joint inflammation in RA. Here we uncover that the immune system interacts directly with the peripheral nervous system, specifically within the dorsal root ganglia (DRG), to drive chronic pain.
In fibromyalgia, we show that FM involves a systemic antibody component. We identified antibodies targeting satellite glial cells (SGCs) in FM patients, which correlate with symptom severity, small nerve fiber loss, and changes in brain regions linked to spontaneous pain. When transferred to mice, these antibodies reproduced core FM symptoms, establishing a causal link between the immune system and the disease. We also uncovered a novel connection between lipid profiles and immune activation, suggesting an interplay between metabolism and immune-driven pain.
In rheumatoid arthritis, we found that RA-related autoantibodies enhance pain sensitivity by acting on SGCs in the DRG. We identified two distinct molecular pathways involved in this process—JAK/STAT and AAK1/AP2M1—offering promising new targets for pain treatments beyond conventional anti-inflammatories.
Our work also revealed new biology of the DRG. We discovered that its blood vessels have region-specific permeability. We also identified a specialized subgroup of macrophages that regulate this environment, helping to control what reaches nerve cells and potentially influencing pain outcomes.
Looking ahead, our goals include:
- Identifying the specific autoantigens targeted by SGC-binding antibodies in FM and RA, to develop precise diagnostic tools.
- Developing therapies that block the molecular pathways driving pain within the DRG, using targeted pharmacological agents.
- Investigating how immune signals, lipid metabolism, and neuronal function interact to sustain or resolve chronic pain.
These advances lay the groundwork for new diagnostic and therapeutic strategies that could transform chronic pain care moving toward personalized treatments based on individual immune profiles.
Our research challenges the traditional understanding of fibromyalgia (FM) and rheumatoid arthritis (RA) pain, which has largely focused on central nervous system dysfunction in FM and joint inflammation in RA. Here we uncover that the immune system interacts directly with the peripheral nervous system, specifically within the dorsal root ganglia (DRG), to drive chronic pain.
In fibromyalgia, we show that FM involves a systemic antibody component. We identified antibodies targeting satellite glial cells (SGCs) in FM patients, which correlate with symptom severity, small nerve fiber loss, and changes in brain regions linked to spontaneous pain. When transferred to mice, these antibodies reproduced core FM symptoms, establishing a causal link between the immune system and the disease. We also uncovered a novel connection between lipid profiles and immune activation, suggesting an interplay between metabolism and immune-driven pain.
In rheumatoid arthritis, we found that RA-related autoantibodies enhance pain sensitivity by acting on SGCs in the DRG. We identified two distinct molecular pathways involved in this process—JAK/STAT and AAK1/AP2M1—offering promising new targets for pain treatments beyond conventional anti-inflammatories.
Our work also revealed new biology of the DRG. We discovered that its blood vessels have region-specific permeability. We also identified a specialized subgroup of macrophages that regulate this environment, helping to control what reaches nerve cells and potentially influencing pain outcomes.
Looking ahead, our goals include:
- Identifying the specific autoantigens targeted by SGC-binding antibodies in FM and RA, to develop precise diagnostic tools.
- Developing therapies that block the molecular pathways driving pain within the DRG, using targeted pharmacological agents.
- Investigating how immune signals, lipid metabolism, and neuronal function interact to sustain or resolve chronic pain.
These advances lay the groundwork for new diagnostic and therapeutic strategies that could transform chronic pain care moving toward personalized treatments based on individual immune profiles.