Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase

Sandra Odom, Gregorio Gomez, Martina Kovarova, Yasuko Furumoto, John J. Ryan, Harry V. Wright, Claudia Gonzalez-Espinosa, Margaret L. Hibbs, Kenneth W. Harder, Juan Rivera

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178 Citations (Scopus)

Abstract

A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn-/- bone marrow-derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn-/- mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn-/- mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcεRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcεRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn-/- mice because both lyn-/- and lyn-/- fyn-/- mice showed high IgE levels. Thus, lyn -/- mice and mast cells there of show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.

Original languageEnglish
Pages (from-to)1491-1502
Number of pages12
JournalJournal of Experimental Medicine
Volume199
Issue number11
DOIs
Publication statusPublished - 7 Jun 2004

Keywords

  • Allergy
  • Degranulation
  • IgE
  • Lyn kinase
  • Mast cells

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