What are mast cells?

Mast Cells: Key Immune System Sentinels

Mast cells are tissue-resident immune cells found in multiple organs including the lungs, intestines, and skin that play critical roles in both innate and adaptive immunity through their ability to store and rapidly release potent inflammatory mediators. 1

Structure and Distribution

Mast cells originate from bone marrow-derived progenitor cells that complete their maturation in peripheral tissues. They are characterized by:

• Presence of numerous cytoplasmic granules containing preformed mediators
• Expression of high-affinity IgE receptors (FcεRI) on their surface
• Strategic location near blood vessels, nerves, and epithelial surfaces
• Distribution in virtually all vascularized tissues, with highest concentrations in areas that interface with the external environment (skin, airways, gastrointestinal tract) 2

Types of Mast Cells

Two major subtypes of human mast cells have been identified based on their protease content:

1. MCT cells (containing tryptase only)

   • Predominant in mucosal surfaces like lung and intestine
   • T-lymphocyte dependent

2. MCTC cells (containing both tryptase and chymase)

   • Predominant in skin and connective tissues
   • T-lymphocyte independent 2

Mast Cell Mediators

Mast cells store and release three categories of mediators:

1. Preformed mediators (stored in cytoplasmic granules):

   • Proteases (tryptase, chymase)
   • Histamine
   • Heparin and other proteoglycans
   • Preformed cytokines (TNF-α)

2. Newly synthesized lipid mediators:

   • Prostaglandins (especially PGD2)
   • Leukotrienes (LTC4, LTD4, LTE4)
   • Platelet-activating factor (PAF)

3. Cytokines and chemokines (synthesized upon activation):

   • IL-4, IL-5, IL-6, IL-13
   • TNF-α, TGF-β
   • Various chemokines 1, 3

Activation Mechanisms

Mast cells can be activated through:

1. IgE-dependent pathway: Allergen cross-linking of IgE bound to FcεRI receptors
2. Non-IgE pathways:
   • Complement components (C3a, C5a)
   • Neuropeptides (substance P)
   • Toll-like receptor ligands
   • Physical stimuli (temperature changes, pressure)
   • Medications
   • Venoms 4, 3

Physiological Functions

Mast cells serve multiple important physiological functions:

1. Innate immunity: First-line defense against pathogens

   • Release of TNF-α and other cytokines during bacterial infections
   • Expression of Toll-like receptors for pathogen recognition

2. Regulation of adaptive immunity:

   • Antigen presentation
   • T-cell activation and polarization
   • Dendritic cell maturation 5

3. Tissue homeostasis and repair:

   • Wound healing
   • Angiogenesis
   • Tissue remodeling 6

Pathological Roles

Mast cells are implicated in numerous pathological conditions:

1. Allergic disorders:

   • Anaphylaxis
   • Allergic rhinitis
   • Asthma
   • Atopic dermatitis 7

2. Inflammatory conditions:

   • Mastocytosis
   • Mast Cell Activation Syndrome (MCAS)
   • Autoimmune disorders 4

3. Fibrotic disorders:

   • Systemic sclerosis
   • Pulmonary fibrosis
   • Cardiac fibrosis 6

Clinical Significance

Diagnostic Markers

Mast cell activation can be assessed by measuring:

• Serum tryptase (peaks 1 hour after activation, half-life ~2 hours)
• Urinary histamine metabolites
• Urinary prostaglandin D2 or 11β-PGF2α
• Urinary leukotriene E4 1, 4

Therapeutic Targets

Medications targeting mast cells include:

1. Mast cell stabilizers: Prevent degranulation

   • Cromolyn sodium 8
   • Ketotifen

2. Mediator antagonists:

   • H1 antihistamines (cetirizine, fexofenadine)
   • H2 antihistamines (ranitidine, famotidine)
   • Leukotriene antagonists (montelukast) 4

3. Tyrosine kinase inhibitors:

   • For systemic mastocytosis with KIT D816V mutation 1

Important Clinical Considerations

• Mast cells play a crucial role in anaphylaxis, which can be life-threatening and requires immediate treatment with epinephrine 4
• Elevated baseline tryptase levels may indicate systemic mastocytosis or hereditary α-tryptasemia 1, 4
• Mast cell activation can occur without mast cell proliferation (as in MCAS) 1, 4
• Children with cutaneous mastocytosis generally have better prognosis than adults 1

Understanding mast cell biology is essential for diagnosing and managing allergic, inflammatory, and mast cell proliferative disorders.