Postural Orthostatic Tachycardia Syndrome (POTS) is a complex medical condition classified as a disorder of the autonomic nervous system, which regulates involuntary bodily functions like heart rate, blood pressure, and digestion. Individuals with POTS experience an abnormally large increase in heart rate when moving from a lying-down to an upright position, leading to symptoms like lightheadedness, fatigue, and brain fog. While the primary issue involves blood flow regulation, research suggests that the immune system plays a significant role in the development and perpetuation of POTS in many individuals. This indicates an immune-mediated or autoimmune basis for the condition, shifting the focus from purely circulatory problems to systemic immune dysregulation.
The Autoimmune Connection
The strongest evidence linking the immune system to POTS centers on the presence of autoantibodies, which are proteins mistakenly produced by the immune system that target the body’s own tissues. In many patients, these antibodies attack components of the autonomic nervous system, interfering with its normal function. The primary targets are receptors located on nerve cells and blood vessels that regulate heart rate and vascular constriction.
Research has focused extensively on G-protein coupled receptor (GPCR) autoantibodies, which disrupt the signaling pathways that control cardiovascular stability. Studies have identified elevated levels of autoantibodies targeting the alpha-1 adrenergic receptor in a significant percentage of POTS patients, sometimes reported in up to 89% of cohorts. Since these receptors tighten blood vessels, their blockade by autoantibodies can cause blood to pool in the lower body upon standing.
Similarly, autoantibodies against muscarinic acetylcholine receptors, such as the M4 subtype, have been detected in a subset of patients. These muscarinic receptors are involved in parasympathetic nervous system activity, including heart rate control. The presence of these specific autoantibodies suggests an acquired, immune-driven breakdown of communication within the autonomic nervous system, leading directly to orthostatic intolerance and tachycardia.
Chronic Inflammation and Immune Cell Activation
Beyond the specific autoantibody attack, many people with POTS exhibit signs of chronic, low-grade systemic inflammation, indicating broader immune system activation. This is often reflected in elevated levels of pro-inflammatory cytokines, which are signaling proteins immune cells use to communicate. Cytokines like interleukin-6 (IL-6) and interferon-gamma (INFγ) have been found at higher concentrations in the blood of POTS patients compared to healthy controls.
This persistent inflammatory state can contribute to symptoms throughout the body, including the cognitive impairment and generalized fatigue frequently experienced. Furthermore, this cytokine elevation may intensify sympathetic nervous system activity, leading to a hyperadrenergic state characterized by excessive adrenaline-like responses and an elevated heart rate.
Mast Cell Activation Syndrome (MCAS)
A significant co-occurrence exists between POTS and Mast Cell Activation Syndrome (MCAS). MCAS involves mast cells, a type of white blood cell found in connective tissues throughout the body. These cells inappropriately release large amounts of inflammatory mediators such as histamine, prostaglandins, and leukotrienes. This excessive release contributes to autonomic dysfunction by destabilizing blood vessel tone and increasing vascular permeability, which exacerbates the blood pooling seen in POTS. Up to 42% of patients initially diagnosed with POTS have shown symptoms consistent with a mast cell activation disorder.
The Role of Infectious Triggers
A common pattern observed in the onset of POTS is the development of symptoms following an acute illness, known as post-infectious POTS. Viral infections, such as Epstein-Barr virus (mononucleosis), influenza, and SARS-CoV-2 (COVID-19), are frequently cited as preceding events. The immune response to these external pathogens appears to act as a trigger, initiating the cascade that results in autonomic nervous system dysfunction.
The mechanism connecting an infection to autoimmunity is often explained by “molecular mimicry.” This occurs when a component of the invading pathogen, such as a viral protein, shares a highly similar molecular structure with a protein found on the body’s own cells, like a neural receptor. The immune system produces antibodies to neutralize the pathogen.
Once the infection resolves, these antibodies, due to the structural similarity, mistakenly begin to attack the host’s nervous system receptors. This cross-reactivity teaches the immune system to target the body, bridging the gap between an acute infection and the subsequent onset of a chronic autoimmune-like condition. The high incidence of POTS diagnoses following the COVID-19 pandemic has bolstered the understanding of this post-infectious autoimmune pathway.
Immune-Targeted Treatment Strategies
The recognition of an immune-mediated component in POTS has led to the investigation of therapies that specifically target the immune system, moving beyond standard circulatory management. These treatments are reserved for patients with severe, refractory symptoms that have not responded to conventional therapies like increased salt and water intake or standard medications. The goal is to either remove the harmful autoantibodies or dampen the overall immune response.
Intravenous Immunoglobulin (IVIG) involves infusing pooled antibodies from healthy donors, which helps neutralize the patient’s circulating autoantibodies and modulate inflammatory signals. Plasma exchange (PLEX), or plasmapheresis, is another approach where the patient’s blood plasma containing autoantibodies is physically removed and replaced with a substitute. Both IVIG and PLEX are designed to reduce the pathogenic antibody load in the bloodstream.
In cases where a strong autoimmune or inflammatory mechanism is suspected, immunosuppressive medications may also be considered. These medications quiet the overactive immune cells that produce autoantibodies and pro-inflammatory cytokines. While these immune-targeted interventions show promise in small case series and are being explored in clinical trials, they represent a specialized treatment path for a subset of POTS patients with an autoimmune contribution to their illness.