What triggers mast cell activation?

Mechanisms of Mast Cell Activation

Mast cells are activated through multiple pathways including IgE/FcεRI binding, IgG/FcγRI/IIa engagement, G protein-coupled receptors, complement anaphylatoxin receptors, Mas-related G protein receptors, and Toll-like receptors, resulting in the release of inflammatory mediators that cause symptoms in various organ systems. 1

Primary Activation Pathways

Mast cell activation occurs through several key mechanisms:

Immunologic Pathways

• IgE-mediated activation: The classical pathway where allergen cross-links IgE antibodies bound to high-affinity FcεRI receptors on mast cell surfaces 1, 2
• IgG-mediated activation: Occurs through FcγRI/IIa receptors, providing an alternative immune activation route 1

Non-immunologic Pathways

• G protein-coupled receptors (GPCRs): Various ligands can trigger mast cell activation through GPCRs 1, 2
• Physical stimuli: Pressure, temperature, or vibration can directly activate mast cells 1
• Hyperosmolar stimuli: Studies have shown that hyperosmolar environments can trigger histamine release from mast cells 1
• MRGPRX2 receptor activation: This receptor responds to cationic substances and many peptidergic drugs, causing pseudo-allergic reactions 3

Mediators Released Upon Activation

When activated, mast cells release three categories of mediators:

1. Preformed mediators (stored in granules):

   • Histamine
   • Tryptase
   • Proteases
   • Heparin
   • Preformed cytokines 2

2. Newly synthesized lipid mediators:

   • Prostaglandins (particularly PGD2)
   • Leukotrienes (LTC4, LTD4, LTE4)
   • Platelet-activating factor 2, 1

3. Cytokines and chemokines (synthesized upon activation) 2

Clinical Relevance of Different Activation Pathways

Primary Mast Cell Activation Disorders

• Systemic mastocytosis: Associated with clonal proliferation and KIT D816V mutation 1, 2
• Clonal MCAS: Features KIT mutations and/or aberrant CD25 expression 1
• Hereditary α-tryptasemia: Linked to increased copy numbers of the TPSAB1 gene 1, 2
• Idiopathic MCAS: No identifiable trigger, mutation, or genetic trait 1

Secondary Mast Cell Activation

Normal mast cells activated by external triggers:

• Allergens (via IgE/FcεRI)
• Physical factors (cold, pressure)
• Drugs and medications (particularly those with cationic properties) 3
• Environmental conditions (cold dry air can increase osmolality of respiratory secretions) 1

Diagnostic Considerations

Mast cell activation can be assessed by measuring:

• Serum tryptase (during symptomatic episodes)
• Urinary histamine metabolites (N-methylhistamine)
• Urinary prostaglandin D2 or 11β-PGF2α
• Urinary leukotriene E4 1, 2

Clinical Implications

Understanding the mechanisms of mast cell activation is crucial for:

1. Diagnosis: Distinguishing between different types of mast cell activation disorders 4
2. Treatment selection: Different mediators may require specific targeted therapies 5
   • H1/H2 antihistamines for histamine-mediated symptoms
   • Leukotriene modifiers for leukotriene-mediated symptoms
   • Aspirin for prostaglandin-mediated symptoms (with caution)
   • Mast cell stabilizers like cromolyn sodium to prevent degranulation 6

Important Considerations and Pitfalls

• Beyond histamine and tryptase: Many symptoms of mast cell activation cannot be explained by these two mediators alone; multiple mediators contribute to the diverse clinical presentations 5

• Heterogeneity of mast cells: Different tissue-resident mast cells may respond differently to various stimuli and release different mediator profiles 7

• Medication-induced activation: Many FDA-approved drugs can activate mast cells through MRGPRX2 receptors, leading to pseudo-allergic reactions 3

• Diagnostic challenges: Mast cell activation can be difficult to confirm, especially in cases where symptoms are less severe or more localized 4

Understanding these diverse activation pathways is essential for proper diagnosis and management of mast cell-related disorders, as targeting specific activation mechanisms may provide more effective therapeutic approaches than simply blocking individual mediators.