Mast Cell Activation Syndrome (MCAS): A Neuroimmune Perspective

Mast Cell Activation Syndrome (MCAS) has become an important—though still evolving—diagnostic category within allergy, immunology, and neuroimmune medicine. Many patients experience years of multi-system symptoms without a clear explanation, and clinicians often struggle to integrate the immune, autonomic, and stress-related components involved. This page summarizes the current state of knowledge in 2025, grounded in peer-reviewed literature while acknowledging areas where research is rapidly developing.

1. How MCAS Is Defined Today

Although terminology varies between clinicians and research centers, most recent publications distinguish MCAS from other mast-cell disorders by emphasizing recurrent episodes of mast-cell mediator release without evidence of a clonal mast-cell population. MCAS is one subset of the broader category of mast cell activation disorders (MCADs), which also includes:

• clonal disorders such as systemic mastocytosis or monoclonal MCAS

• secondary mast-cell activation driven by IgE allergy, autoimmune disease, infection, or other triggers

• idiopathic MCAS, where no clear trigger is found

A 2024 review in The Journal of Allergy and Clinical Immunology (JACI Online, 2024) notes that MCAS has been used inconsistently in medical practice. Some patients with clear, recurrent anaphylactoid episodes remain undiagnosed, while others receive the label despite lacking objective evidence. For this reason, major organizations such as the AAAAI and ECNM continue to emphasize three core diagnostic criteria:

• Recurrent, multi-system symptoms typical of mast-cell mediator release (for example, flushing, hives, abdominal pain, diarrhea, headaches, tachycardia, or sudden drops in blood pressure).

• Objective evidence of mast-cell activation, such as a rise in serum tryptase during an episode or elevated urinary prostaglandins, leukotrienes, or histamine metabolites.

• Clinical response to medications that block or dampen mast-cell activity (antihistamines, cromolyn, leukotriene antagonists).

This framework is now widely accepted, even by groups expressing concern about the overuse of the MCAS label. A 2024 JACI: In Practice dilemma paper (JACI In Practice, 2024) reinforces the importance of adhering to these criteria, both to avoid missed diagnoses and to prevent mislabeling patients whose symptoms arise from other causes.

MCAS is also increasingly viewed as a spectrum rather than a singular entity. Guidance from Mast Cell Action (Mast Cell Action, 2024) emphasizes that some individuals experience unmistakable mast-cell–driven episodes without neatly fitting the formal criteria; others sit at a border where immune, autonomic, and environmental factors overlap.

2. What Mast Cells Actually Do—and Why They Matter in MCAS

Mast cells are highly specialized immune cells located at the body’s environmental interfaces: the skin, the respiratory and gastrointestinal mucosa, the dura and meninges surrounding the brain, and the perivascular and perineural tissues that regulate blood flow and nerve signaling. Their job is to sense danger—whether infection, allergen exposure, physical injury, or stress—and mobilize rapid responses.

When activated, mast cells release pre-stored and newly synthesized inflammatory mediators. These mediators affect vascular tone, permeability, smooth muscle contraction, nerve sensitivity, and immune-cell recruitment. Recent articles emphasize the importance of non-histamine mediators such as leukotrienes, prostaglandins, and cytokines (WJGNet; mastcellmaster.com).

Mast cells are activated through pathways far broader than classic IgE allergy, including complement fragments, TLR ligands, neuropeptides, CRH (corticotropin-releasing hormone), temperature changes, mechanical pressure, infections, and hormonal shifts (Cell; Frontiers).

3. The Neuroimmune Interface: Mast Cells and the Autonomic Nervous System

Among the most significant developments in the last decade is the recognition that mast cells and the autonomic nervous system (ANS) are deeply intertwined. Mast cells sit close to sympathetic, parasympathetic, and sensory nerves. Reviews in Cell and Frontiers (Cell; Frontiers in Cellular Neuroscience) describe mast cells as integral components of the somatosensory and neuroimmune systems. They influence pain sensitivity, vascular tone, thermoregulation, gut motility, and the brain’s immune environment.

Emerging models such as neuroimmune organoids—co-cultures of human iInduced pluripotent stem cells (iSPC)-derived mast cells, neurons, microglia, and endothelial cells—demonstrate bidirectional mast-cell/nerve signaling (ScienceDirect).

Clinically, this dovetails with the frequently observed triad of hEDS (hypermobile Elhers-Danlos, POTS, and MCAS-like presentations, discussed in CGH Journal reviews and guidance from Mast Cell Action and EDS Clinic (CGH Journal; Mast Cell Action; EDS Clinic).

A 2025 AGA update on disorders of gut–brain interaction highlights GI symptoms driven by mast cells in patients with hEDS and POTS (CGH Journal).

4. Stress, Trauma, and Mast-Cell Reactivity

Psychological stress activates the HPA (hypothalamic pituitary axis) and sympathetic nervous system, increasing circulating catecholamines and CRH. Mast cells both release and respond to CRH, and CRH can directly provoke degranulation (Frontiers in Cellular Neuroscience).

Research in Annals of Allergy, Asthma & Immunology and Frontiers links stress-induced mast-cell activation to worsening atopic disease, visceral hypersensitivity, pain syndromes, and blood–brain barrier permeability (Ann Allergy; Frontiers).

Although there is not yet a large trauma-specific MCAS cohort, the biological pathway—stress → autonomic shift → mast-cell reactivity—is well established.

5. How MCAS Presents Clinically

MCAS tends to follow characteristic episodic patterns—flushing, hives, abdominal pain, diarrhea, headaches, tachycardia, temperature sensitivity, and sometimes full anaphylactoid events. Reviews in WJGNet describe this multi-system pattern clearly.

Workup generally includes mediator testing, screening for clonal disease, and evaluation for comorbidities (WJGNet).

Therapy typically includes H1/H2 antihistamines, leukotriene blockers, cromolyn, ketotifen, aspirin (for prostaglandin-driven flushing), and targeted therapy for clonal disease (WJGNet; mastcellmaster.com).

6. How This Maps to Traditional Chinese Medicine

TCM offers a systems-level framework that aligns well with neuroimmune science. Many MCAS presentations map onto Liver, Spleen, Lung, and Kidney system patterns involving constraint, heat/wind, dampness, Wei Qi dysregulation, and constitutional depletion.

Modern neuroimmune mapping echoes classical descriptions: mast cells concentrate along nerves, fascia, vessels, and barrier layers—corresponding to channels, collaterals, and Wei Qi circuits. Reviews in Cell and Frontiers highlight this neuroimmune “switchboard” analogy.

7. ALH Vials and Allergy Relief Acupuncture (SAAT)

Allergies Lifestyle & Health (ALH) produces vials used for resonance-based testing

Originally derived from allergen dilutions, the vials now include imprinted representations of inflammatory mediators.

Solomon Allergy Treatment/Therapy (SAAT), developed by Nader Solomon, MD, integrates resonance testing with acupuncture and semi-permanent needles. Two case-series exist within professional acupuncture journals, including one documenting IgE test changes and another addressing alpha-gal syndrome (Lambert Health and Wellness; Katelyn James; Dove Medical Press).

Although not represented in indexed trials, SAAT’s mechanisms align with known effects of acupuncture on the ANS, vagal pathways, inflammatory signaling, and mast-cell regulation.

8. Where Research Is Heading

Promising directions include:

• integrated phenotyping of mast-cell mediators, ANS metrics, and stress markers (CGH Journal; Mast Cell Action)

• small clinical pilots evaluating acupuncture/neuromodulation with HRV, baroreflex, and mediator outcomes (Dove Medical Press)

• neuroimmune studies assessing mast-cell/ANS interactions (ScienceDirect)

• mapping TCM patterns onto neuroimmune biomarkers (Frontiers)

9. Summary

MCAS is a real multi-layered condition involving episodic mast-cell mediator release across multiple organ systems. Diagnostic criteria are becoming standardized. Research increasingly highlights mast-cell involvement in autonomic regulation, stress physiology, barrier function, and connective tissue biology.

For many patients, conventional allergy frameworks capture only part of the picture. Integrative modalities—including acupuncture, neuromodulatory techniques, herbal medicine, and SAAT in select cases—offer additional approaches to stabilizing neuroimmune regulation.

This page will be updated as new research emerges.

References

1. Castells M, Giannetti MP, Hamilton MJ, et al. Mast cell activation syndrome: Current understanding and research needs. Allergy Clin Immunol. 2024 Aug;154(2):255-263.

2. Dilemma of mast cell activation syndrome: Overdiagnosed or something else? J Allergy Clin Immunol Pract. 2024

3. Mast cell activation syndrome (MCAS): A primary care guide. 2025

4. Özdemir Ö, Kasımoğlu G, Bak A, Sütlüoğlu H, Savaşan S. Mast cell activation syndrome: An up-to-date review of literature. World J Clin Pediatr. 2024;13(2):92813

5. Forsythe P. Mast cells in neuroimmune interactions. Trends Neurosci. 2019;42(1):43-55..

6. Theoharis C. Theoharides, MS, MPhil, PhD, MD. Mast cell–sensory neuron interactions under stress. J Allergy Clin Immunol. 2024

7.. Alison Haley Kucharik 1, Christopher Chang. The relationship between hypermobile Ehlers-Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS). Clin Rev Allergy Immunol .2020 Jun;58(3):273-297

8. Chan K, et al. Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation. Ann Allergy Asthma Immunol. 2024;132(4): 440-454
9. Skaper SD, Facci L, Giusti P. Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease. Front Cell Neurosci.2019;13:54.

10. AGA Institute. AGA Clinical Practice Update on GI Manifestations and Autonomic or Immune Dysfunction in Hypermobile Ehlers-Danlos Syndrome: Expert Review. Clin Gastroenterol Hepatol.2025 23(8):1291-1302

11. Wang J, Wu S, Zhang J, et al. Treatment of allergic rhinitis with acupuncture based on pathophysiological mechanisms: A narrative review. Int J Gen Med. 2023;16:3917-3929.

A warm and generous provider, Dr Villanova enjoys applying her insights and experience in allopathy, medical acupuncture, Chinese herbal medicine and Ayurveda to integrate biological, emotional, social and spiritual aspects of individual and group healing/understanding. Dr Villanova is board certified in Family Medicine and Medical Acupuncture.

When not working with patients, she conceives, writes and executes music, theatre and film productions in New York City, and is a published essayist and poet. Currently, her multimodal theater work at the nexus of neuromodulation and healing is in production in NYC and heading for Europe