Auto-immune Contribution in Symptom-based Sensory and Autonomic Disorders

Postural Orthostatic Tachycardia Syndrome (POTS), Fibromyalgia (FM)

Postural orthostatic Tachycardia Syndrome, Fibromyalgia Syndrome, Widespread pain, Autoantibodies, Autonomic and sensory functions

Postural Orthostatic Tachycardia Syndrome (PoTS) is a condition where the heart rate increases when standing up, causing symptoms like dizziness and fainting. It primarily affects young women and can be very disabling, impacting daily life. In addition to the typical symptoms related to standing, people with PoTS also experience unexplained pain and fatigue, which worsen their quality of life. The exact causes of PoTS are still unknown, but it is often triggered by viral infections and some PoTS patients show signs of immune system involvement, such as the presence of certain autoantibodies and other autoimmune conditions. Research on other chronic pain disorders, including fibromyalgia syndrome (FMS), has found that autoantibodies can cause pain by affecting how the nerves work. This study aims to investigate if similar immune-related mechanisms are behind the widespread pain seen in PoTS. This study will also look at how PoTS affects the nervous system by testing nerve activity in participants and assessing the number of nerve fibres in the skin, to check if similar changes can be seen in mice. This study will also involve participants with fibromyalgia syndrome and healthy volunteers.

Postural orthostatic tachycardia syndrome (PoTS) is characterized by increased heart rate upon standing, light-headedness, and syncope. PoTS is a highly incapacitating condition affecting more than 0.2% of the population worldwide, mostly young women. The causes of this syndrome remain unknown and are still discussed, leading to unsatisfactory diagnostic tools and a delay in the recognition of PoTS as a medical condition with clear biomarkers. The onset of postural orthostatic tachycardia symptoms is often associated with traumatic episodes or acute viral infections. An increase in PoTS diagnostic has notably been observed in adults and children during the SARS-CoV-2 epidemic. Moreover, some characteristics present in a subset of patients, namely the presence of anti-nuclear antibodies, or ganglionic acetylcholine receptor immunoglobulins, and the high prevalence of comorbid auto-immune conditions, suggest a fundamental role of the immune system in the development of PoTS. PoTS patients report symptoms unrelated to orthostatic intolerance, including widespread pain, muscle weakness and fatigue, which remain unexplained. These symptoms contribute to lower quality of life and impair patients' daily life. Our group has a longstanding experience in the study of widespread pain conditions linked with autoimmunity. We have recently shown that the administration of immunoglobulins purified from fibromyalgia syndrome (FMS) and chronic regional pain syndrome (CRPS) patients replicates painful and non-painful phenotypes in mice. In contrast with the CRPS mice, where a physical injury is needed to induce hypersensitivity, intraperitoneal administration of IgG was sufficient to generate mechanical hyperalgesia and abnormal responses to non-noxious stimuli in rodents. The passive transfer of fibromyalgia symptoms from patients to mice via IgG administration presents many advantages, amongst which is the possibility of studying immune-mediated neuronal abnormalities in isolation. Upon FMS IgG administration, we observed an accumulation of pathological IgG in dorsal root ganglia (DRG), the organs relaying sensory information perceived in peripheral organs, to the spinal cord. Interestingly, the exploration of murine DRGs cells signalling revealed an increased activity of sensory neurons, canonically responsible for mechanical and thermal sensations, but also for the perception of painful stimuli. This enhanced activity was not observed with preparation isolated from mice injected with healthy volunteer immunoglobulins. This study has revealed immune-mediated mechanisms leading to hyperexcitability in sensory neurons and causing exacerbated pain and non-painful perception in fibromyalgia. We now intend to assess whether widespread pain, observed in PoTS patients presents a similar autoimmune pathophysiology. Moreover, we aim to investigate potential abnormalities of the autonomic system caused by the administration of PoTS IgG.

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