Allergen-independent immunomodulatory activities of immunoglobulin E.

In 1966, IgE was identified as the principal antibody responsible for mediating the type I hypersensitivity response[1]. This molecular insight ushered in a new era in our understanding of allergic diseases. More recently, it has come to light that IgE molecules also have allergen-independent immunomodulatory activities. In this month’s issue of Clinical and Experimental Allergy, Dr Mathias and colleagues demonstrate that circulating IgE impacts on the ability of mice to become sensitized to an inhaled hapten[2]. The observation is consistent with previous studies in demonstrating that IgE has immunomodulatory activities that are not mediated by allergen cross-linking. Future studies will need to determine the mechanisms underlying IgE’s allergen-independent immunomodulatory activities and their impact on human health and disease. The level of total IgE in a subjects serum was reported to correlate with the level of high affinity IgE receptor (FceRI) expression on their basophils[3] in the 1970s, and Furuichi et al. went on to demonstrate that incubation of RBL-2H3 rat mast cells with IgE enhances their expression of FceRI[4] in the 1980s. Two laboratories further established that serum IgE directly regulates mast cell FceRI expression in the mid-90s[5, 6]. Functionally, IgE engagement of FceRI has been found to prime mast cells for enhanced granule release and cytokine production upon IgE cross-linking[7]. In addition to FceRI, serum IgE has been shown to regulate the expression of its low affinity receptor, CD23 [8, 9]. For example, while all B cells express CD23, expression levels are far higher on B cells from wild-type mice than on B cells from IgE-deficient mice. Moreover, injection of IgE into IgE-deficient mice leads to increased B cell CD23 expression. Interestingly, CD23-deficient mice have higher serum IgE levels and CD23 transgenic mice have lower IgE levels than wild-type mice, suggesting that CD23 signaling helps to regulate IgE production[10, 11]. It was reported in 2001 that monomeric IgE can protect growth factor-deprived mast cells from apoptotic death by inducing FceRI aggregation[12, 13]. Thus, IgE did not protect FceRI-deficient mast cells from cell death. Furthermore, survival was found to depend on autocrine secretion of IL-3[14]. Although several laboratories have reported that FceRI cross-linking induced with IgE plus antigen also promotes mast cell survival, other laboratories have failed to detect this anti-apoptotic effect. The discordant modulatory effects of monomeric and cross-linked IgE on mast cells are likely to be explained by the fact that only weak, but not strong FceRI-aggregating stimuli, induce mast cell survival[14, 15]. In this context, it is worth noting that comparative studies of monoclonal IgE molecules derived from different hybridomas have found that they exhibit remarkable heterogeneity in their ability to promote mast cell survival and induce activation events, including degranulation, cytokine production, migration, and others[16]. While questions remain, studies have come a long way toward identifying the mechanisms by which monomeric and cross-linked IgE regulate the activation status and longevity of mast cells[17]. An earlier publication from Dr Oettgen’s laboratory[18] established that IgE-deficient mice were unable to mount immune responses to skin contact sensitizing haptens. In these investigations, preformed IgE was found to be required for the sensitization but not the effector phase of the contact hypersensitivity response. The current issue of Clinical and Experimental Allergy contains an article by Drs Mathias, Oettgen and co-workers, which establishes that allergen non-specific IgE is also required for the development of airway hypersensitivity to an inhaled hapten, trinitrobenzene sulfonic acid[2]. The mechanistic basis for an IgE requirement in the development of hapten hypersensitivity has not been adequately worked out. While basophilic cells are responsive to monomeric IgE, it has yet to be established that they mediate IgE’s adjuvant influence on hapten sensitization. It is also unclear whether high-affinity FceRI, low-affinity CD23, or both receptors mediate IgE’s adjuvant activities. Finally, the signaling/inflammatory cascades that IgE renders competent, in order that mice are capable of mounting a hapten hypersensitivity response, have not been identified. In previous studies, IgE was found to be required for adequate dendritic cell migration from the epithelial surface during hapten sensitization [18]. The influence of IgE on dendritic cell migratory behavior appears to be FceRI and mast cell dependent, as mast cell-deficient mice also displayed resistance to contact hypersensitivity with the application of oxazolone to the skin and reduced dendritic cell migration from the epidermis. These observations suggest one potential mechanistic scenario for IgE’s role in the development of hapten hypersensitivity, improving dendritic cell migration to draining lymph nodes, leading to more efficient antigen presentation to naive T cells. Allergen non-specific immunomodulatory activities attributed to IgE include signaling through FceRI to promote mast cell survival and responsiveness to allergen exposure, as well as the ability to license the immune system for hapten sensitization. From a clinical perspective, it is worth noting that it is difficult to detect IgE in the blood of healthy newborns but with age, serum IgE levels increase to adult levels, which are achieved by age 16 [19]. If IgE serves to up-regulate immune responsiveness in an antigen independent manner, than one might speculate that rising serum levels could have a more global effect on immune homeostasis during childhood. For example, physiologically low IgE levels at birth may help explain why infants are particularly vulnerable to certain pathogens, including tuberculosis, which is cleared and sequestered by cells (i.e. CD8 cells) that also participate in hapten induced type IV hypersensitivities [20, 21]. Likewise, IgE mediated hypersensitivities are rarely seen in the neonatal period and while the prevalence of food allergies peaks in the first years of life, peak prevalence rates for hypersensitivities to aeroallergens occur late in childhood [22]. Results presented in Dr Mathias’ current paper and others suggest that the genesis of allergic diseases may require that basal IgE levels reach a threshold level before cells are adequately primed to cooperate in the development of hypersensitivities to allergens contained in foods and ambient air. While highly speculative, such theories are consistent with currently available evidence and readily testable in murine models of allergic disease. Ongoing and future investigations will no doubt lead to a far more comprehensive understanding of IgE’s antigen-independent bioactivities and could lead to the development of novel therapies to manipulate FceRI and CD23 signaling in order to prevent and/or treat allergic diseases.