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Investigating Mast Cell Secretory Granules; from Biosynthesis to Exocytosis
Published on: January 26, 2015
Analysis of Fc(epsilon)RI-mediated mast cell stimulation by surface-carried antigens
R Schweitzer-Stenner1, I Tamir, I Pecht
1Institut für Experimentelle Physik, Universität Bremen, Germany.
Insights
Clustering of the high-affinity IgE receptor (FcεRI) on mast cells is crucial for inflammatory mediator release. Immobilization of as few as two FcεRI complexes triggers mast cell activation and secretion.
Area of Science:
- Immunology
- Cellular Biology
- Biochemistry
Background:
- Clustering of the type I receptor for IgE (FcεRI) on mast cells initiates inflammatory mediator secretion.
- Understanding the proximity, cluster size, and mobility requirements for FcεRI signaling is essential.
Purpose of the Study:
- To determine the FcεRI proximity, cluster size, and mobility requirements for initiating the FcεRI cascade.
- To investigate the elementary stimulatory unit for mast cell secretory response.
Main Methods:
- Developed a novel experimental protocol using mast cells reacted with glass surfaces of varying antigen and IgE densities.
- Measured the secretory response of mast cells to surface-bound stimuli.
- Analyzed results using a model based on random antigen distribution, FcεRI immobilization, and secretory stimulus units.
Main Results:
- A model based on specific assumptions provided a self-consistent fit for all experimental data.
- FcεRI immobilization was identified as essential for initiating the signaling cascade.
- As few as two immobilized FcεRI complexes at van der Waals contact constitute an elementary stimulatory unit.
Conclusions:
- FcεRI immobilization is a critical step in initiating the mast cell signaling cascade.
- The study provides evidence that a minimal cluster of two FcεRI molecules can trigger mast cell secretion.
- This finding supports the concept of an 'elementary stimulatory unit' in mast cell activation.
Abstract:
Clustering of the type I receptor for IgE (Fc[epsilon]RI) on mast cells initiates a cascade of biochemical processes that result in secretion of inflammatory mediators. To determine the Fc(epsilon)RI proximity, cluster size, and mobility requirements for initiating the Fc(epsilon)RI cascade, a novel experimental protocol has been developed in which mast cells are reacted with glass surfaces carrying different densities of both antigen and bound IgE, and the cell's secretory response to these stimuli is measured. The results have been analyzed in terms of a model based on the following assumptions: 1) the glass surface antigen distribution and consequently that of the bound IgE are random; 2) Fc(epsilon)RI binding to these surface-bound IgEs immobilizes the former and saturates the latter; 3) the cell surface is formally divided into small elements, which function as a secretory stimulus unit when occupied by two or more immobilized IgE-Fc(epsilon)RI complexes; 4) alternatively, similar stimulatory units can be formed by binding of surface-carried IgE dimers to two Fc(epsilon)RI. This model yielded a satisfactory and self-consistent fitting of all of the different experimental data sets. Hence the present results establish the essential role of Fc(epsilon)RI immobilization for initiating its signaling cascade. Moreover, it provides independent support for the notion that as few as two Fc(epsilon)RIs immobilized at van der Waals contact constitute an "elementary stimulatory unit" leading to mast cell (RBL-2H3 line) secretory response.
