Pain evoked by passive transfer of IgG from fibromyalgia patients to mice
Lead Research Organisation:
King's College London
Department Name: Wolfson Centre for Age Related Diseases
Abstract
Fibromyalgia is one of the most common causes of chronic pain worldwide. There is no diagnostic test available and patients are diagnosed based on how severe and widespread their pain is and whether they have other symptoms, such as fatigue, sleep problems and depression. Treatment of fibromyalgia is focused on exercise and education, which help patients become more active and cope better with pain. Drugs that are used to treat pain in fibromyalgia are effective in some patients, but often cause problematic side effects and regularly become less effective with time. Fibromyalgia has a severe impact on quality of life, but the fact that patients look healthy can make it difficult for them to qualify for benefits and to convince others about how they feel.
Although fibromyalgia affects more than 1 in 50 people, the cause of disease remains unknown. A better understanding of the cause of fibromyalgia, is likely to dramatically accelerate development of improved treatments and invention of diagnostic tests.
We have discovered that the body's normal defence machinery, the immune system, is responsible for pain in fibromyalgia patients. Our immune system normally help us destroy bacteria and other parasites, thereby helping us fight infections, and to become immune to them. Our results show that the immune system in fibromyalgia patients attack their own bodies, in addition to fighting infections. Activation of the immune system stimulates pain-sensing nerves throughout the body, making patients too sensitive to pressure and temperature, and thereby experiencing unrelenting pain. In our pilot experiments, we have used samples purified from fibromyalgia patients and healthy volunteers and injected these to mice. Remarkably, mice that were given patient samples developed similar symptoms to the patients that the samples were taken from, whereas samples from healthy volunteers were without effect. During this project, we will investigate how the immune system causes pain in fibromyalgia and thereby also identify new ways that fibromyalgia patients can be treated. It is likely that our work will lead to improved treatment of fibromyalgia.
Although fibromyalgia affects more than 1 in 50 people, the cause of disease remains unknown. A better understanding of the cause of fibromyalgia, is likely to dramatically accelerate development of improved treatments and invention of diagnostic tests.
We have discovered that the body's normal defence machinery, the immune system, is responsible for pain in fibromyalgia patients. Our immune system normally help us destroy bacteria and other parasites, thereby helping us fight infections, and to become immune to them. Our results show that the immune system in fibromyalgia patients attack their own bodies, in addition to fighting infections. Activation of the immune system stimulates pain-sensing nerves throughout the body, making patients too sensitive to pressure and temperature, and thereby experiencing unrelenting pain. In our pilot experiments, we have used samples purified from fibromyalgia patients and healthy volunteers and injected these to mice. Remarkably, mice that were given patient samples developed similar symptoms to the patients that the samples were taken from, whereas samples from healthy volunteers were without effect. During this project, we will investigate how the immune system causes pain in fibromyalgia and thereby also identify new ways that fibromyalgia patients can be treated. It is likely that our work will lead to improved treatment of fibromyalgia.
Technical Summary
Fibromyalgia syndrome (FMS) is a common chronic pain diagnosis worldwide, with a prevalence of about 2.5% in the general population. FMS is characterized by chronic, widespread pain, typically in combination with other neurological symptoms, such as sleep disturbances, anxiety, depression and memory problems. FMS is more common in women than men, and much more prevalent in patients with autoimmune rheumatological conditions, e.g. rheumatoid arthritis, lupus erythematosus. Patients report very poor scores for health-related quality of life, regularly worse than is the case for other chronic pain disorders, such as neuropathic pain. The aetiology and pathophysiology of FMS are unknown, and the available therapies are of limited efficacy, and consequently, many patients seek help from alternative medicine. This project builds on our recent, original discovery that FMS is an autoimmune disorder that can be transferred from patient to mouse. This finding will produce a paradigm shift in how FMS is viewed, and will enable experimental studies of the pathophysiology of FMS. Our observations demonstrate that mice that have undergone transfer of FMS, faithfully recapitulate the sensory abnormalities experienced by FMS patients, with pressure (in paw and thigh) and cold hypersensitivity, but essentially normal sensitivity to noxious heat and to punctate stimulation with von Frey filaments. Our pilot data show that transfer of FMS produces ectopic action potential discharge in nociceptors and a gain of function of cold sensitivity in A-fibres. During this project we will identify the effects of FMS IgG in vivo (behaviourally and using in vivo Ca2+-imaging) and on sensory afferent nerve fibres in vitro. Finally, we will combine [Ca2+]i-measurements and patch-clamp investigations of isolated sensory neurons to identify the ionic mechanisms responsible for FMS induced ectopic activity and sensitization of nociceptors.
Planned Impact
Patients
Fibromyalgia patients will welcome the identification of a biological cause of their chronic condition. The lack of external symptoms and the absence of a known cause, can make it difficult for this patient group to convince friends, colleagues, authorities and employers that their condition is genuine. It is likely that our discovery of an autoimmune basis for fibromyalgia pain, will improve the outlook for patients. Some possible treatment strategies are available, and others will be identified. We expect a diagnostic kit to become available rapidly after identification of autoantibody targets.
Experimental and clinical pain researchers
There is a large community of experimental and clinical scientists focused on pain mechanisms. There is an emerging interest in autoimmune pain that has followed identification of autoantibodies that cause pain in rheumatoid arthritis, complex regional pain syndrome (primarily by the CI, Andreas Goebel) and in patients with autoantibodies to voltage-gated potassium channel complex proteins. We believe that our studies will identify fibromyalgia as an autoantibody mediated condition, at least in a subset of patients. Even if our studies would demonstrate a heterogenous basis for fibromyalgia, with some patient not producing autoantibodies, it is likely that our studies will establish fibromyalgia as the most common of all autoimmune conditions.
Pharmaceutical industry, academic scientists
It is likely that other studies will stimulate widespread efforts to identify autoantibody targets and this will also be an important aim for our own efforts. Identification will lead to rapid development of diagnostic tests. Identification of the ionic mechanisms responsible for pain and hypersensitivity in our passive transfer model may lead to rapid evaluation of candidate targets, in animals and man. Passive transfer models present investigators with the rare opportunity to validate a human therapeutic target in an animal model, which may accelerate efforts from the pharmaceutical industry.
Fibromyalgia patients will welcome the identification of a biological cause of their chronic condition. The lack of external symptoms and the absence of a known cause, can make it difficult for this patient group to convince friends, colleagues, authorities and employers that their condition is genuine. It is likely that our discovery of an autoimmune basis for fibromyalgia pain, will improve the outlook for patients. Some possible treatment strategies are available, and others will be identified. We expect a diagnostic kit to become available rapidly after identification of autoantibody targets.
Experimental and clinical pain researchers
There is a large community of experimental and clinical scientists focused on pain mechanisms. There is an emerging interest in autoimmune pain that has followed identification of autoantibodies that cause pain in rheumatoid arthritis, complex regional pain syndrome (primarily by the CI, Andreas Goebel) and in patients with autoantibodies to voltage-gated potassium channel complex proteins. We believe that our studies will identify fibromyalgia as an autoantibody mediated condition, at least in a subset of patients. Even if our studies would demonstrate a heterogenous basis for fibromyalgia, with some patient not producing autoantibodies, it is likely that our studies will establish fibromyalgia as the most common of all autoimmune conditions.
Pharmaceutical industry, academic scientists
It is likely that other studies will stimulate widespread efforts to identify autoantibody targets and this will also be an important aim for our own efforts. Identification will lead to rapid development of diagnostic tests. Identification of the ionic mechanisms responsible for pain and hypersensitivity in our passive transfer model may lead to rapid evaluation of candidate targets, in animals and man. Passive transfer models present investigators with the rare opportunity to validate a human therapeutic target in an animal model, which may accelerate efforts from the pharmaceutical industry.
Organisations
Publications
Berwick R
(2022)
Aftersensations and Lingering Pain After Examination in Patients with Fibromyalgia Syndrome
in Pain Medicine
Berwick RJ
(2021)
A Systematic Review Into the Influence of Temperature on Fibromyalgia Pain: Meteorological Studies and Quantitative Sensory Testing.
in The journal of pain
Gilding EK
(2020)
Neurotoxic peptides from the venom of the giant Australian stinging tree.
in Science advances
Goebel A
(2022)
Research Recommendations Following the Discovery of Pain Sensitizing IgG Autoantibodies in Fibromyalgia Syndrome.
in Pain medicine (Malden, Mass.)
Goebel A
(2022)
The autoimmune aetiology of unexplained chronic pain.
in Autoimmunity reviews
Goebel A
(2023)
The biology of symptom-based disorders - time to act.
in Autoimmunity reviews
Goebel A
(2021)
Passive transfer of fibromyalgia symptoms from patients to mice.
in The Journal of clinical investigation
Goebel A
(2019)
Passive transfer of fibromyalgia pain from patients to mice
Jami S
(2023)
Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function
in Nature Communications
Paskins Z
(2022)
Research priorities to reduce the impact of musculoskeletal disorders: a priority setting exercise with the child health and nutrition research initiative method.
in The Lancet. Rheumatology
Description | Research recommendations (consensus report) based on our findings. |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Contribution to new or Improved professional practice |
Guideline Title | The Diagnosis of Fibromyalgia Syndrome (FMS): UK CLINICAL GUIDELINES |
Description | The first RCP guidelines for fibromyalgia |
Geographic Reach | National |
Policy Influence Type | Citation in clinical guidelines |
Description | Eli Lilly Ltd |
Amount | £189,000 (GBP) |
Organisation | Eli Lilly & Company Ltd |
Sector | Private |
Country | United Kingdom |
Start | 01/2020 |
End | 12/2021 |
Description | MICA ADVANTAGE visceral pain consortium: Advanced Discovery of Visceral Analgesics via Neuroimmune Targets and the Genetics of Extreme human phenotype |
Amount | £4,101,153 (GBP) |
Funding ID | MR/W002426/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2021 |
End | 06/2025 |
Description | Mapping complexity of pain with the Advanced Pain Discovery Platform |
Amount | £640,952 (GBP) |
Funding ID | MR/W027585/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2022 |
End | 03/2025 |
Description | Pain Mechanisms in long-Covid |
Amount | £866,903 (GBP) |
Funding ID | MR/W027623/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2022 |
End | 05/2025 |
Description | Pain and fatigue in rheumatic diseases |
Amount | € 599,950 (EUR) |
Organisation | Foundation for Research in Rheumatology |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 08/2021 |
End | 08/2024 |
Description | Project 3.2: Discovery for the basis of fibromyalgia |
Amount | £120,000 (GBP) |
Funding ID | 2290885 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 03/2024 |
Description | Sir Jules Thorn Award for Biomedical Research 2022 |
Amount | £1,699,572 (GBP) |
Funding ID | 22/JTA |
Organisation | Sir Jules Thorn Charitable Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2023 |
End | 06/2028 |
Title | Face and construct validity |
Description | Complex diseases, such as most pain conditions are almost exclusively studied in mice. The relevance of the findings from experimental animal models is often unclear, since the models employed often have little in common with the pathophysiological basis of the human condition (which is regularly unknown). In the studies from this award, and on the further funding from MRC, we have established passive transfer of chronic pain conditions from patients to mice. This approach has the advantage that we know that the phenotype observed is caused by the human pathogenic antibodies. As a consequence, the face and construct validity of our work superior to other experimental approaches. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Passive transfer led to the identification of myasthenic disorders as autoantibody mediated. We are using these techniques to explain the pathophysiological basis of well-established human pain disorders for the first time. This work will lead to a detailed understanding of CRPS and other chronic pain conditions and will very likely provide novel treatments for the condition. |
Description | Autoantibody mediated pain |
Organisation | Karolinska Institute |
Country | Sweden |
Sector | Academic/University |
PI Contribution | This collaboration has added benefits by giving both parties access to leading expertise. |
Collaborator Contribution | Prof Camilla Svensson's lab are leading at histochemical and transcriptional analysis of expression patterns. We are performing collaborative studies on pain conditions caused by autoantibodies. |
Impact | The first manuscript is under review. It has been a rather fraught process, since our work will reposition the world's understanding of fibromyalgia, and call much of the published literature into doubt. We have secured a first joint international grant (Foreum, €600,000). https://www.foreum.org/autoimmune_molecular_mechanisms_pf_fibromyalgia.cfm |
Start Year | 2016 |
Description | Cambridge- Regional and widespread pain |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Identification of fibromyalgia (and complex regional pain syndrome) as an autoantibody mediated disease. |
Collaborator Contribution | We are (together with additional parties) seeking funds from the "Advanced Pain Discovery Platform" funded by the UKRI and Versus Arthritis. |
Impact | - |
Start Year | 2019 |
Description | FOREUM, international research consortium "AUTOIMMUNE AND MOLECULAR MECHANISMS FOR PAIN AND FATIGUE IN FIBROMYALGIA" |
Organisation | Karolinska Institute |
Country | Sweden |
Sector | Academic/University |
PI Contribution | This collaboration is based on the established collaboration between my lab and Camilla Svensson's lab. We have secured a €600k consortium award shared equally between 6 investigators (from Foreum). |
Collaborator Contribution | We are in the early stages of a long project, and each investigator brings separate skills, methods and experiences to the consortium. |
Impact | Multi-disciplinary consortium. |
Start Year | 2021 |
Description | FOREUM, international research consortium "AUTOIMMUNE AND MOLECULAR MECHANISMS FOR PAIN AND FATIGUE IN FIBROMYALGIA" |
Organisation | University of Eastern Finland |
Country | Finland |
Sector | Academic/University |
PI Contribution | This collaboration is based on the established collaboration between my lab and Camilla Svensson's lab. We have secured a €600k consortium award shared equally between 6 investigators (from Foreum). |
Collaborator Contribution | We are in the early stages of a long project, and each investigator brings separate skills, methods and experiences to the consortium. |
Impact | Multi-disciplinary consortium. |
Start Year | 2021 |
Description | FOREUM, international research consortium "AUTOIMMUNE AND MOLECULAR MECHANISMS FOR PAIN AND FATIGUE IN FIBROMYALGIA" |
Organisation | Uppsala University |
Country | Sweden |
Sector | Academic/University |
PI Contribution | This collaboration is based on the established collaboration between my lab and Camilla Svensson's lab. We have secured a €600k consortium award shared equally between 6 investigators (from Foreum). |
Collaborator Contribution | We are in the early stages of a long project, and each investigator brings separate skills, methods and experiences to the consortium. |
Impact | Multi-disciplinary consortium. |
Start Year | 2021 |
Description | MICA - Advanced Discovery of Visceral Analgesics via Neuroimmune Targets and the Genetics of Extreme human phenotypes |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I contribute a distinct set of investigations to the APDP (Advanced Pain Discovery Platform, UKRI, Versus Arthritis, Eli Lilly) funded consortium ADVANTAGE (MR/W002426/1, 48 months, £4.1 million). |
Collaborator Contribution | This is a multidisciplinary consortium, bringing translational pain medicine (me) together with clinicians (focus is on visceral pain), and ingeneers. |
Impact | As described, multi-disciplinary consortium. |
Start Year | 2021 |
Description | MICA - Advanced Discovery of Visceral Analgesics via Neuroimmune Targets and the Genetics of Extreme human phenotypes |
Organisation | University of Cambridge |
Department | Cambridge Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I contribute a distinct set of investigations to the APDP (Advanced Pain Discovery Platform, UKRI, Versus Arthritis, Eli Lilly) funded consortium ADVANTAGE (MR/W002426/1, 48 months, £4.1 million). |
Collaborator Contribution | This is a multidisciplinary consortium, bringing translational pain medicine (me) together with clinicians (focus is on visceral pain), and ingeneers. |
Impact | As described, multi-disciplinary consortium. |
Start Year | 2021 |
Description | MICA - Advanced Discovery of Visceral Analgesics via Neuroimmune Targets and the Genetics of Extreme human phenotypes |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I contribute a distinct set of investigations to the APDP (Advanced Pain Discovery Platform, UKRI, Versus Arthritis, Eli Lilly) funded consortium ADVANTAGE (MR/W002426/1, 48 months, £4.1 million). |
Collaborator Contribution | This is a multidisciplinary consortium, bringing translational pain medicine (me) together with clinicians (focus is on visceral pain), and ingeneers. |
Impact | As described, multi-disciplinary consortium. |
Start Year | 2021 |
Description | Interview with Nature Reviews Rheumatology |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Interview with the highest profile rheumatology journal, focused on our study: https://www.jci.org/articles/view/144201. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.nature.com/articles/s41584-021-00679-y |
Description | Interview with Pain Research Forum |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Pain Research Forum is read by most active in the field, and an effective means of routing attention to publications. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.painresearchforum.org/news/180579-antibodies-patients-cause-fibromyalgia-symptoms-mice |
Description | Interview with the Guardian |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I was interviewed by the Guardian about our transformational, paradigm shifting article: Passive transfer of fibromyalgia symptoms from patients to mice, https://www.jci.org/articles/view/144201 The publication has attracted worldwide attnetion from patients, clinicians and pharmaceutical companies, since it identifies the common disorder fibromyalgia as an autoimmune condition, rather than psychological condition. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.theguardian.com/society/2021/jul/01/fibromyalgia-may-be-a-condition-of-the-immune-system... |
Description | Invest In ME |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | 14th Invest in ME Research International ME Conference 2019. This conference is an annual event, arranged to inform patients, patient groups and practitioners about research focused on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. It follows a more conventional 2-day symposium for researchers. Both events were held in London and i was invited to present my work on fibromyalgia at both by the charity. |
Year(s) Of Engagement Activity | 2019 |
URL | http://www.investinme.org/IIMEC14.shtml |
Description | Open lecture, Brisbane |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | During a visit to University of Queensland (Brisbane), i gave a lecture at a symposium open to the public (~200 attendees). |
Year(s) Of Engagement Activity | 2019 |
Description | Patient Research Day (PPI) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Andreas Goebel, co-investigator on this award, arranged a research day for patients (~60 patients, each accompanied by a family member/friend or carer), where we presented our findings, summarized the state of research on CRPS more broadly and had a long open discussion of any matter raised by the patients present. Separately, a meeting between 6 patients with better understanding of science and medicine and us investigators was held. These discussions have helped me improve the translational re |
Year(s) Of Engagement Activity | 2018 |
Description | Recorded interview with CONFESQ: Spanish national coalition of Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Multiple Chemical Sensitivity and Electrohypersensitivity. Interview was broadcast during the societies' annual conference. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | This event was a streamed and recorded discussion of the impact of our work on fibromyalgia on our understanding of ME/CFS and related syndromes. |
Year(s) Of Engagement Activity | 2021 |
URL | https://pae-eu.eu/confesq-invitation-to-the-ii-conference-latest-advances-in-research-on-fm-cfs-me-s... |
Description | Science day with fibromyalgia patients |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Patients who had donated serum for the funded study, some accompanied by carers, and some of the staff at the pain clinic at the Walton Trust took part in a workshop followed by an discussion. We presented our findings to patients, followed by questions (mutual) and discussions. The event has prompted me to prioritize studies of fatigue, in addition to pain in fibromyalgia. |
Year(s) Of Engagement Activity | 2019 |
Description | Science day with patients and clinicians |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Together with two colleagues from KCL and my regular co-investigator Andreas Goebel (Liverpool), we presented our progress and research plans to patients who had contributed samples to our studies, and the clinical and care staff that manage the patients. Patients regularly identify symptoms, experiences, and challenges that are not apparent in the medical literature. On this occasion, we realised that some of our experimental results (from studies of nerve fibres in preparations from mice) matched symptoms described by patients perfectly. Patients' accounts have formed the basis of a novel manuscript that will explain why fibromyalgia often is associated with parasthaesias and other aberrant sensations. Our findings raised many questions from patients, point to possible future interventions and trials, and the session was very positive, giving patient hope. |
Year(s) Of Engagement Activity | 2021 |
Description | The year's top 10 science stories, chosen by scientists (The Observer) |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | This list of the ten most important advances in science during 2021, featured our study alongside other fields. Our entry among the top 10 was the only one consisting of a single study, among major international initiatives such as COP26, the billionaire space race, and RNA vaccines for covid. The ten entries: The billionaire space race Racial biases in the healthcare system Cop26: time to act Fibromyalgia: new understanding could lead to treatments for chronic pain (OUR WORK) A boom in precise protein-structure prediction by AI Extreme weather becomes more extreme Record numbers of children living with obesity The Winchcombe meteorite: a gift from space Fatty RNA particles to the rescue, for some at least The role of nature in tackling global heating is finally recognised |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.theguardian.com/science/2021/dec/19/the-years-top-10-science-stories-chosen-by-scientist... |