Antigen-induced reduction in mast cell and basophil functional responses due to reduced Syk protein levels.
BACKGROUND
The high-affinity IgE receptor, FcepsilonRI, is unresponsive on mast cells and basophils from people in several populations through an unknown mechanism. Similarly, FcepsilonRI-positive basophils from 'nonreleasers' are IgE-unresponsive and are deficient in the tyrosine kinase Syk.


OBJECTIVE
To test the hypothesis that cross-linking FcepsilonRI on mast cells and basophils leads to FcepsilonRI nonresponsiveness through reduction in Syk protein levels.


METHODS
Human mast cells and basophils were used to determine if FcepsilonRI hyporesponsiveness correlated with reduced Syk levels.


RESULTS
It is shown that suboptimal antigen challenge, that did not lead to significant mediator release, induced nonresponsiveness and correlated with reduced Syk. Other IgE-associated signaling molecules were unaffected by the same treatment. The ability of IgE-unresponsive mast cells to regain FcepsilonRI responsiveness is paralleled by increased cellular Syk levels in vitro. The reduction of Syk levels with suboptimal antigen concentrations was calcium independent and mediated through a proteasome-dependent mechanism.


CONCLUSIONS
These findings confirm and extend our knowledge about a novel regulatory mechanism for maintaining FcepsilonRI in a quiescent state. This mechanism may also explain why low concentrations of allergen given to patients during allergen immunotherapy induce FcepsilonRI nonresponsiveness and therapeutic benefit without inducing systemic anaphylaxis.
Kepley
Christopher L
CL
Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University Health Systems, Richmond, VA 23298, USA. clkepley@vcu.edu
D001491:Basophils / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D015550:Cell Degranulation / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D004591:Electrophoresis, Polyacrylamide Gel; D004792:Enzyme Precursors / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006636:Histamine Release / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering; D017455:Receptors, IgE / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase
D016207:Cytokines; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase