DIFFERENTIAL REGULATION OF ALTERNATIVE 3' SPLICING OF EPSILON-MESSENGER-RNA VARIANTS

Alternative 3' splicing of the one active human epsilon heavy chain ge ne results in variants of epsilon mRNA encoding distinct IgE proteins. The same relative amounts of these < epsilon mRNA variants were produ ced by non-atopic donor B cells when driven in a variety of T-dependen t or T-independent systems. The most abundant variants were those for classic secreted epsilon and a novel secreted form (CH4-M2''). In cont rast, cells from subjects with high levels of serum IgE secondary to p arasitic infection or atopy spontaneously produced higher relative lev els of the CH4-M2' epsilon mRNA variant, lower relative amounts of bot h the membrane and CH4-M2'' secreted variants, and very low levels of the CH4'-CH5 variant. The existence of and corresponding changes in le vels of the CH4-M2'-encoded secreted protein were demonstrated. IL-10 induced this same differential expression of epsilon splice variants i n vitro when used to costimulate IL-4 plus CD40-driven B cells and cou ld differentially enhance the production of CH4-M2' protein by establi shed IgE-secreting cell lines. Inhibition of IgE by cross-linking the low affinity IgE receptor (CD23) decreased the levels of epsilon mRNA and resulted in a distinct pattern of epsilon mRNA characterized by a dramatic decrease in CH4-M2' splice variant. IL-6, IL-2, or IFN-gamma did not change the epsilon mRNA pattern. Overall, the absolute and rel ative amounts of the different epsilon mRNA splice variants produced a ppear to be controlled in a differentiation-related fashion.