One type of antibody, IgE, triggers allergic responses, and the overproduction of IgE causes an over-zealous allergic reaction. Lymphocytes are the cells that make IgE. Recent studies have shown that a messenger molecule, leukotriene B4 (LTB4), can stimulate lymphocytes to overproduce IgE. Furthermore, mice that lack the enzyme 5-lipoxygenase (5-LO), which synthesizes LTB4, make less IgE than do normal mice. These results indicate that high amounts of the messenger LTB4 might cause the overproduction of IgE and that inhibiting the enzyme 5-LO would decrease IgE levels. The long-term objectives of this project, then, are to identify the source of lymphocyte-regulating LTB4 in humans, to determine what causes abnormally high amounts of LTB4 to be made at that site, and to gauge the importance of LTB4 overproduction to diseases, including those involving IgE overproduction. Tonsils are an example of mucosa-associated lymphoid tissue (MALT), a site of lymphocyte development. Preliminary results indicate that the epithelium of tonsils contains 5-LO and makes LTB4. This places LTB4 production, in MALT epithelium, in a place where it can affect lymphocyte development and IgE production. Also, tonsils from some patients appear to have dramatically greater amounts of 5-LO, suggesting that they may synthesize much more LTB4 than normal. Finally, preliminary results indicate that the 5-LO enzyme expressed in tonsils is different from the known 5-LO.
The specific aims of this project are 1) to isolate and characterize the gene for the tonsil 5-LO enzyme, as well as its regulatory region, 2) to determine the properties of this novel 5-LO, with emphasis on how its action is regulated, and 3) evaluate its expression in MALT other than tonsils. These studies on this new 5-LO enzyme will provide the foundation for studies on the factors that cause the overproduction of LTB4 and IgE, and for studies on the impact of blocking 5-LO action on IgE generation and allergic responses. Notably, 5-LO inhibitors have been approved for use in humans to treat asthma. These studies will indicate whether 5-LO inhibitors may also be useful in reducing allergic responses.
