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Medline ® Abstract for Reference 18

of 'Rapid drug desensitization for immediate hypersensitivity reactions'

18
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Antigen-induced reduction in mast cell and basophil functional responses due to reduced Syk protein levels.
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Kepley CL
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Int Arch Allergy Immunol. 2005;138(1):29. Epub 2005 Aug 8.
 
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 responsivenessis 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.
CONCLUSION: 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.
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Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University Health Systems, Richmond, VA 23298, USA. clkepley@vcu.edu
PMID