Pain evoked by passive transfer of IgG from fibromyalgia patients to mice

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.

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.

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