Negative Regulation of Immunoglobulin E–dependent Allergic Responses by Lyn Kinase

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 thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.

Regulation of allergy by Fc receptors

“…Csk phosphorylates regulatory tyrosines in Fyn and thereby inhibits its catalytic activity. Supporting this model, the hyper-responsiveness of Lyn -/-mast cells to IgE was abrogated in Lyn -/-/Fyn -/-BMMCs [29]. Interestingly, the phenotype of Lyn -/-mice was reminiscent of an "allergic" phenotype which could not be accounted for by the hyper-reactivity of mast cells only.…”

“…Interestingly, the phenotype of Lyn -/-mice was reminiscent of an "allergic" phenotype which could not be accounted for by the hyper-reactivity of mast cells only. As these mice grew older, they displayed increased serum IgE concentrations, an increased FcεRI expression, increased numbers of peritoneal mast cells and eosinophils, and elevated levels of plasma histamine [29]. Most of these allergy-associated traits could be ascribed to a biased isotypic switch toward IgE due to the hyper-responsiveness of Lyn -/-B cells to IL-4, and to the consequences of an increased IgE serum concentration.…”

Negative Signaling in Fc Receptor Complexes

“…Noticeably, the catalytic activity of Fyn was increased in these cells, and hyperactive Fyn was phosphorylated on tyrosine 417, in the activation loop of the kinase. The hyper-responsiveness of Lyn -/-mast cells to IgE could be ascribed to this kinase as this phenotype was abrogated in BMMC derived from doubly deficient Lyn -/-/Fyn -/-mice (Odom et al, 2004). Altogeteher these data provided the following explanation to the negative role of Lyn in mast cell activation.…”

“…No marked effect was observed on the activation of PLC-γ, the Ca 2+ response, the generation of leukotrienes and the release of β-hexosaminidase, suggesting that this tyrosine is not critical in signal amplification. These altered responses were reminiscent of the phenotype of mast cells derived from Lyn-deficient mice (Odom et al, 2004). Indeed, pull-down experiments using beads coated with phopsho-peptides corresponding to a w.t.…”

“…In wt cells, Lyn phosphorylates Cbp which recruits Csk. Csk phosphorylates the regulatory tyrosines 508 and 528 of Fyn and thereby inhibits its catalytic activity (Odom et al, 2004). Interestingly, the phenotype of Lyn -/-mice was reminiscent of an "allergic" phenotype which could not be accounted for by the hyper-reactivity of mast cells only.…”