Immediate hypersensitivity reactions are dependent on IgE-mediated activation of
basophils and mast cells. There are many elements that regulate expression of the
response that distribute up and down the cascade of events from the generation of IgE
to the tissue end-organ response and the positive and negative feedback loops that link
the various elements together. One of the early necessary elements is related to the
intrinsic ability of the basophil and mast cell to respond to aggregation of the IgE
receptor. It is now apparent that for human basophils, this intrinsic responsiveness
primarily relates the expression of one of the early receptor associated kinases, SYK.
Several studies have established that SYK activity is likely a rate-limiting step in the IgE-
dependent signal transduction cascade and expression levels determine its activity.
Studies have also demonstrated that the very low expression levels of SYK in basophils
are unique to this leukocyte. Recent studies demonstrate 5 regulatory pathways of SYK
expression, two of which have recently been excluded for further consideration as an
explanation for the natural heterogeneity of expression in the population. Based on
preliminary results, the application proposes to examine one of newly described
pathways in greater detail. A large international study established the association of a
SNP family in the SYK gene promoter, in 100% linkage disequilibrium, with SYK
expression is multiple cell types. In a pilot study we found that the same SNP family
strongly associates with the magnitude of IgE-mediated secretion. Aim 1 of the proposal
will expand in both size and detail the pilot study observations. Aim 2 will address a
question raised by the possible association of genotype with function, the reversal of
suppressed SYK expression in patients with omalizumab. Aim 3 will determine which
SNP is relevant to SYK gene expression and examine several hypotheses regarding the
transcription factors that modulate the effect.