Mast cells: Beyond IgE

Constitutive versus reactive tissue mast cell development on the basis of the prototype of the intestine. Basal homing of blood-borne committed mast cell progenitors (PrMC) depends on the intact function of the β7 integrin subunit forming a heterodimer with the α4 integrin subunit that interacts with mucosal adressin cell adhesion molecule 1 (MadCAM1) and vascular cell adhesion molecule 1 (VCAM1) . Differentiation of all mast cells requires the input of SCF and its receptor, c-kit. Development of the reactive subtype, observed in the epithelial compartment in mucosal inflammation, requires additional cytokines derived from activated T cells. The subtypes differ in protease content and effector profile. CPA, Carboxypeptidase A.

Constitutive versus reactive tissue mast cell development on the basis of the prototype of the intestine. Basal homing of blood-borne committed mast cell progenitors (PrMC) depends on the intact function of the β7 integrin subunit forming a heterodimer with the α4 integrin subunit that interacts with mucosal adressin cell adhesion molecule 1 (MadCAM1) and vascular cell adhesion molecule 1 (VCAM1) . Differentiation of all mast cells requires the input of SCF and its receptor, c-kit. Development of the reactive subtype, observed in the epithelial compartment in mucosal inflammation, requires additional cytokines derived from activated T cells. The subtypes differ in protease content and effector profile. CPA, Carboxypeptidase A.

Regulatory effects of IL-4 on biosynthesis and reception of cysLTs by mast cells. Human mast cells express the CysLT1 receptor constitutively, which transduces a calcium flux to both cysLTs and UDP. With IL-4 priming, both LTC₄ and UDP elicit mast cell activation at 3 log-fold lower doses and elicit cytokine generation through a nuclear factor of activated T cells– and extracellular regulated kinase–dependent pathway, without exocytosis. The priming effect occurs without changes in CysLT1 receptor expression. IL-4 priming also upregulates FcϵRI-dependent generation of cysLTs by inducing LTC₄S expression. Autocrine actions of cysLTs are indicated by partial antagonism of FcϵRI-dependent cytokine generation by the CysLT1 receptor selective antagonist MK571 and by MK886, a biosynthetic inhibitor. MIP, Macrophage inflammatory protein.

Hypothetic consequences of non–IgE-dependent activation of constitutive and reactive mast cell phenotypes. Under baseline conditions, mast cell activation by microbes, toxins, and humoral factors elicits neutrophil recruitment, contains invasive pathogens, and facilitates tissue healing. Under conditions of T-cell priming (particularly IL-4) in asthma and allergic diseases, the same activating stimuli produce an amplified mast cell response, resulting in sustained inflammation, tissue dysfunction, and remodeling.