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.

Narrative: One of the principle cells involved in allergic reactions is the basophil. This application proposes to study one of the reasons that this cell type is more or less sensitive to stimulation. These studies will investigate how the cell controls expression of a critically important protein involved in cell activation.