Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE‐secreting cells

Abstract

Immunoglobulin E (IgE) is the key effector element in allergic diseases ranging from innocuous hay fever to life-threatening anaphylactic shock. Compared to other Ig classes, IgE serum levels are very low. In its membrane-bound form (mIgE), IgE behaves as a classical antigen receptor on B lymphocytes. Expression of mIgE is essential for subsequent recruitment of IgE-secreting cells. We show that in activated, mIgE-bearing B cells, mRNA for the membrane forms of both murine and human epsilon (e) heavy chains (HC) are poorly expressed compared to mRNA for the secreted forms. In contrast, in mIgG-bearing B cells, mRNA for the membrane forms of murine gamma-1 (c1) and the corresponding human c4 HC are expressed at a much higher level than mRNA for the respective secreted forms. We show that these findings correlate with the presence of deviant polyadenylation signal hexamers in the 3 0 untranslated region (UTR) of both murine and human e genes, causing inefficient processing of primary transcripts and thus poor expression of the proteins and poor recruitment of IgEproducing cells in the immune response. Thus, we have identified a genetic steering mechanism in the regulation of IgE synthesis that represents a further means to restrain potentially dangerous, high serum IgE levels.

Fluorescent In Vivo Detection Reveals that IgE+ B Cells Are Restrained by an Intrinsic Cell Fate Predisposition

“…Other studies have established that membrane IgE splicing and polyadenylation may be unusually regulated (Anand et al, 1997;Karnowski et al, 2006). It seems plausible that the expression and/or subcellular localization of membrane versus secreted IgE may also affect cell fate determination.…”

“…The 2A peptide strategy has been successfully applied to the coexpression of a range of proteins, including immunoglobulin heavy and light chain genes (de Felipe et al, 2006). In our construct design, we did not introduce any exogenous polyadenylation signals and instead left the endogenous IgE 3 0 untranslated region intact, because this region contains atypical polyadenylation signal hexamers that have been shown to limit membrane IgE expression (Anand et al, 1997;Karnowski et al, 2006). We subsequently refer to this reporter as Verigem (Venus reporter for IgE membrane form).…”

Historic overview of allergy research in the Netherlands

“…These data are not fully compatible with recent data by Berkowska et al [104]. Lamers et al provided a further reason why the IgE-switched B cell has an unusual fate by showing that the membrane form of IgE is poorly produced [105,106]. These data suggest that the low level of IgE production is not only due to low frequency of the IgE class switch, but also by a post-switch expansion/differentiation blockade.…”

IgE knock‐in mice suggest a role for high levels of IgE in basophil‐mediated active systemic anaphylaxis

“…Recently, mem- [11,12]. These cellular differences, but also genetic differences like the IgE-specific 3 -region with the membrane exons and the polyadenylation sites critically determine the low expression of IgE [17]. These IgE-specific features keep the expression of IgE several orders lower than that of IgG, reflecting fundamental differences in biologic function between these two immunoglobulins.…”