IgE Immune Complexes Research Articles

Neuronal Fc\u03b5RI\u03b1 directly mediates ocular itch via IgE-immune complex in a mouse model of allergic conjunctivitis

BackgroundClassical understanding of allergic conjunctivitis (ACJ) suggests that ocular itch results from a mast cell-dependent inflammatory process. However, treatments that target inflammatory mediators or immune cells are often unsatisfying in relieving the stubborn itch symptom. This suggests that additional mechanisms are responsible for ocular itch in ACJ. In this study, we aim to determine the role of neuronal FcεRIa in allergic ocular itch.MethodsCalcium imaging was applied to observe the effect of IgE-immune complex in trigeminal neurons. Genomic FcεRIa knockout mice and adeno-associated virus (AAV) mediated sensory neuron FcεRIa knockdown mice were used in conjunction with behavioral tests to determine ocular itch. In addition, immunohistochemistry, Western blot and quantitative RT-PCR were used for in vitro experiments.ResultsWe found that FcεRIα was expressed in a subpopulation of conjunctiva sensory neurons. IgE-IC directly activated trigeminal neurons and evoked acute ocular itch without detectible conjunctival inflammation. These effects were attenuated in both a global FcεRIa-knockout mice and after sensory neuronal-specific FcεRIa-knockdown in the mouse trigeminal ganglion. In an ovalbumin (OVA) induced murine ACJ model, FcεRIα was found upregulated in conjunctiva-innervating CGRP+ sensory neurons. Sensory neuronal-specific knockdown of FcεRIa significantly alleviated ocular itch in the ACJ mice without affecting the immune cell infiltration and mast cell activation in conjunctiva. Although FcεRIα mRNA expression was not increased by IgE in dissociated trigeminal ganglion neurons, FcεRIα protein level was enhanced by IgE in a cycloheximide-resistance manner, with concordant enhancement of neuronal responses to IgE-IC. In addition, incremental sensitization gradually enhanced the expression of FcεRIα in small-sized trigeminal neurons and aggravated OVA induced ocular itch.ConclusionsOur study demonstrates that FcεRIα in pruriceptive neurons directly mediates IgE-IC evoked itch and plays an important role in ocular itch in a mouse model of ACJ. These findings reveal another axis of neuroimmune interaction in allergic itch condition independent to the classical IgE-mast cell pathway, and might suggest novel therapeutic strategies for the treatment of pruritus in ACJ and other immune-related disorders.

The role of CD23 in the regulation of allergic responses.

IgE, the key molecule in atopy has been shown to bind two receptors, FcεRI, the high‐affinity receptor, and FcεRII (CD23), binding IgE with lower affinity. Whereas cross‐linking of IgE on FcεRI expressed by mast cells and basophils triggers the allergic reaction, binding of IgE to CD23 on B cells plays an important role in both IgE regulation and presentation. Furthermore, IgE‐immune complexes (IgE‐ICs) bound by B cells enhance antibody and T cell responses in mice and humans. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are still a matter of debate. Here, we focus on CD23 and discuss several mechanisms related to IgE binding, as well as the impact of the IgE/antigen‐binding on different immune cells expressing CD23. One recent paper has shown that free IgE preferentially binds to FcεRI whereas IgE‐ICs are preferentially captured by CD23. Binding of IgE‐ICs to CD23 on B cells can, on one hand, regulate serum IgE and prevent effector cell activation and on the other hand facilitate antigen presentation by delivering the antigen to dendritic cells. These data argue for a multifunctional role of CD23 for modulating IgE serum levels and immune responses.

Glycan-specific IgG anti-IgE autoantibodies are protective against allergic anaphylaxis in a murine model

IgE causes anaphylaxis in type I hypersensitivity diseases by activating degranulation of effector cells such as mast cells and basophils. The mechanisms that control IgE activity and prevent anaphylaxis under normal conditions are still enigmatic. We aimed to unravel how anti-IgE autoantibodies are induced and we aimed to understand their role in regulating serum IgE level and allergic anaphylaxis. We immunized mice with different forms of IgE and tested anti-IgE autoantibody responses and their specificities. We then analyzed the effect of those antibodies on serum kinetics and their invitro and invivo impact on anaphylaxis. Finally, we investigated anti-IgE autoantibodies in human sera. Immunization of mice with IgE-immune complexes induced glycan-specific anti-IgE autoantibodies. The anti-IgE autoantibodies prevented effector cell sensitization, reduced total IgE serum levels, protected mice from passive and active IgE sensitization, and resulted in cross-protection against different allergens. Furthermore, glycan-specific anti-IgE autoantibodies were present in sera from subjects with allergy and subjects without allergy. In conclusion, this study provided the first evidence that in the murine model, the serum level and anaphylactic activity of IgE may be downregulated by glycan-specific IgG anti-IgE autoantibodies.

Diagnosis of Latent Tuberculosis Infection in Personnel of Various Institutions and Determination of the Risk Group for Tuberculosis

Early diagnosis of tuberculosis remains essential for the prevention of the disease and control of its incidence. The diagnosis of latent tuberculosis infection (LTBI) has significantly improved over the last years due to the use of new immunological tests, including the Diaskintest.The aim of the study was to assess the potential of immunological assays for diagnosis of latent tuberculosis infection and determination of risk groups for tuberculosis among personnel of different institutions.Materials and methods: in 2015–2018, a prospective group-control study was conducted that included employees of various medical centres (n = 154) and healthy individuals (n = 30). There were no significant age differences between the subjects. All the subjects included in the study shared their medical history, underwent general examination, X-ray examination, and were tested with Diaskintest. Multispiral computed tomography (MSCT) of the chest was performed for every subject with a positive Diaskintest result.Results: the comparison of the number of persons with LTBI in general care hospitals, personnel of a manufacturing firm, and among healthy individuals showed that the risk of being infected with Mycobacterium tuberculosis is very similar in all the groups (from 6.8 to 10.0 %). The highest risk of developing LTBI was found in people who worked in an infectious area for more than 5 years (48.4 %). The analysis of the level of immune complexes (ICs) demonstrated that individuals with LTBI did not have isotypes of IgG3 and IgE immune complexes, which are found in patients with tuberculosis. The identification of particular isotypes indicates a borderline state between LTBI and tuberculosis and requires therapeutic intervention.Conclusions: the use of the Diaskintest makes it possible to distinguish groups of employees of various institutions who are at a higher risk of developing tuberculosis. At the same time, determination of the ICs helps to reveal the borderline condition which requires medical intervention.

Le rôle des récepteurs de l’IgE dans le contrôle de la réaction allergique

IgE cross-linking is known to trigger inflammatory reactions to antigens after binding FcɛRI, a high-affinity IgE receptor present on mast cells or basophils. The second receptor engaged by IgE is the low-affinity IgE receptor, CD23/FcɛRII, most prominently expressed in B cells, which is thought to negatively regulate IgE levels. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are not yet understood. We investigated several mechanisms related to the binding of IgE and antigen to both receptors, as well as the influence of such binding on different immune cells expressing the receptors. We showed that free IgE preferentially binds to FcɛRI whereas IgE immune complexes (IgE-ICs) are preferentially captured by CD23. Binding of IgE-ICs to CD23 on B cells can regulate serum IgE and prevent effector cell activation on one hand while on the other hand it can facilitate antigen presentation by delivering antigen to dendritic cells.

A Case of IgG4-Related Mikulicz’s Disease with Chronic Rhinosinusitis and Elevated Levels of IgG4-and IgE-Immune Complexes

A Case of IgG4-Related Mikulicz’s Disease with Chronic Rhinosinusitis and Elevated Levels of IgG4-and IgE-Immune Complexes

A novel recycling mechanism of native IgE-antigen complexes in human B cells facilitates transfer of antigen to dendritic cells for antigen presentation

IgE-immune complexes (IgE-ICs) have been shown to enhance antibody and T-cell responses in mice by targeting CD23 (FcεRII), the low-affinity receptor for IgE on B cells. In humans, the mechanism by which CD23-expressing cells take up IgE-ICs and process them is not well understood. To investigate this question, we compared the fate of IgE-ICs in human B cells and in CD23-expressing monocyte-derived dendritic cells (moDCs) that represent classical antigen-presenting cells and we aimed at studying IgE-dependent antigen presentation in both cell types. B cells and monocytes were isolated from peripheral blood, and monocytes were differentiated into moDCs. Both cell types were stimulated with IgE-ICs consisting of 4-hydroxy-3-iodo-5-nitrophenylacetyl (NIP)-specific IgE JW8 and NIP-BSA to assess binding, uptake, and degradation dynamics. To assess CD23-dependent T-cell proliferation, B cells and moDCs were pulsed with IgE-NIP-tetanus toxoid complexes and cocultured with autologous T cells. IgE-IC binding was CD23-dependent in B cells, and moDCs and CD23 aggregation, as well as IgE-IC internalization, occurred in both cell types. Although IgE-ICs were degraded in moDCs, B cells did not degrade the complexes but recycled them in native form to the cell surface, enabling IgE-IC uptake by moDCs in cocultures. The resulting proliferation of specific T cells was dependent on cell-cell contact between B cells and moDCs, which was explained by increased upregulation of costimulatory molecules CD86 and MHC class II on moDCs induced by B cells. Our findings argue for a novel model in which human B cells promote specific T-cell proliferation on IgE-IC encounter. On one hand, B cells act as carriers transferring antigen to more efficient antigen-presenting cells such as DCs. On the other hand, B cells can directly promote DC maturation and thereby enhance T-cell stimulation.

Distinct Expression and Function of FcεRII in Human B Cells and Monocytes.

FcεRII is a multifunctional low-affinity IgER that is involved in the pathogenesis of allergic, inflammatory, and neoplastic diseases. Although discrepancies in FcεRII-mediated functions are being increasingly recognized, the consequences of FcεRII activation are not completely understood. In this study, we evaluated the expression of FcεRII on human blood cells and found that it was primarily expressed on monocytes and B cells. Although IL-4 promoted expression of the FcεRIIb isoform on B cells and monocytes, the expression of the FcεRIIa isoform was not dependent on IL-4. Furthermore, FcεRII predominantly bound allergen-IgE complexes on B cells but not on monocytes. FcεRII-mediated allergen-IgE complex uptake by B cells directed Ags to MHC class II-rich compartments. FcεRII-bearing monocytes and B cells expressed high levels of the FcεRII sheddase a disintegrin and metalloproteinase 10, which implies that they are important sources of soluble FcεRII. Moreover, we identified that IgE immune complex stimulation of FcεRII activated intracellular tyrosine phosphorylation via Syk in B cells but not in monocytes. Importantly, FcεRII-mediated signaling by allergen-IgE immune complexes increased IFN-γ production in B cells of allergic patients during the build-up phase of allergen-specific immunotherapy. Together, our results demonstrate that FcεRII mediates cell type-dependent function in allergic reactions. In addition, the results identify a novel allergen-IgE complex/FcεRII/Syk/IFN-γ pathway in allergic responses and suggest that FcεRII may play a role in regulating allergic reactions via modulating IFN-γ production in B cells.

Neuronal Fc-epsilon receptor I contributes to antigen-evoked pruritus in a murine model of ocular allergy

Pruritus is the major symptom of ocular allergy but currently available treatments are often ineffective. Previous studies demonstrated that subpopulations of primary sensory neurons express Fc receptors and may contribute to antigen-specific pain. We investigated the role of neuronal Fc-epsilon Receptor I (FcεRI) in allergic ocular pruritus. Ovalbumin (OVA) was used as allergen together with alum adjuvant (OVA+alum) to produce a mouse model of ocular allergy with a significant elevation in the serum levels of both antigen-specific IgE and IgG. Mice sensitized by OVA without alum only induced elevation of serum IgG but not IgE. Scratching behavior toward the eyes with the hindlimb was used as an indicator of ocular itch. Topical OVA challenging to the eye dose-dependently induced scratching toward the eye in the OVA+alum sensitized mice, but not those sensitized by OVA only. The antigen-induced scratching was largely abolished by topical application of the blocking antibody to FcεRIα, but was only partially alleviated by pretreatment of mast cell stabilizer or histamine I receptor antagonist. The expression of FcεRI was detected in subpopulations of trigeminal ganglion (TG) neurons including those expressing pruriceptive markers and innervating the conjunctiva in the naïve mice. Moreover, FcεRI was found significantly upregulated in small-sized TG neurons in the OVA+alum sensitized mice. In acutely dissociated TG neurons, IgE-immune complex (IC), but not the antibody or antigen alone, induced intracellular calcium increase. The neuronal responses to IgE-IC could be specifically blocked by pre-application of a siRNA for FcεRIα. Our results indicate that FcεRI expressed on peripheral nociceptive neurons in the TG may be directly activated by IgE-IC and contribute to allergic ocular pruritus. This study may suggest a novel mechanism for the development of pathological itch in allergic diseases.

CD23 can negatively regulate B-cell receptor signaling.

CD23 has been implicated as a negative regulator of IgE and IgG antibody responses. However, whether CD23 has any role in B-cell activation remains unclear. We examined the expression of CD23 in different subsets of peripheral B cells and the impact of CD23 expression on the early events of B-cell receptor (BCR) activation using CD23 knockout (KO) mice. We found that in addition to marginal zone B cells, mature follicular B cells significantly down regulate the surface expression level of CD23 after undergoing isotype switch and memory B-cell differentiation. Upon stimulation with membrane-associated antigen, CD23 KO causes significant increases in the area of B cells contacting the antigen-presenting membrane and the magnitude of BCR clustering. This enhanced cell spreading and BCR clustering is concurrent with increases in the levels of phosphorylation of tyrosine and Btk, as well as the levels of F-actin and phosphorylated Wiskott Aldrich syndrome protein, an actin nucleation promoting factor, in the contract zone of CD23 KO B cells. These results reveal a role of CD23 in the negative regulation of BCR signaling in the absence of IgE immune complex and suggest that CD23 down-regulates BCR signaling by influencing actin-mediated BCR clustering and B-cell morphological changes.

Evidence that FcRn mediates the transplacental passage of maternal IgE in the form of IgG anti-IgE/IgE immune complexes.

SummaryBackgroundThe mechanism(s) responsible for acquisition of maternal antibody isotypes other than IgG are not fully understood. This uncertainty is a major reason underlying the continued controversy regarding whether cord blood (CB) IgE originates in the mother or fetus.ObjectiveTo investigate the capacity of maternal IgE to be transported across the placenta in the form of IgG anti‐IgE/IgE immune complexes (ICs) and to determine the role of the neonatal Fc receptor (FcRn) in mediating this process.MethodsMaternal and CB serum concentrations of IgE, IgG anti‐IgE, and IgG anti‐IgE/IgE ICs were determined in a cohort of allergic and non‐allergic mother/infant dyads. Madin–Darby canine kidney (MDCK) cells stably transfected with human FcRn were used to study the binding and transcytosis of IgE in the form of IgG anti‐IgE/IgE ICs.ResultsMaternal and CB serum concentrations of IgG anti‐IgE/IgE ICs were highly correlated, regardless of maternal allergic status. IgG anti‐IgE/IgE ICs generated in vitro bound strongly to FcRn‐expressing MDCK cells and were transcytosed in an FcRn‐dependent manner. Conversely, monomeric IgE did not bind to FcRn and was not transcytosed. IgE was detected in solutions of transcytosed IgG anti‐IgE/IgE ICs, even though essentially all the IgE remained in complex form. Similarly, the majority of IgE in CB sera was found to be complexed to IgG.Conclusions and Clinical RelevanceThese data indicate that human FcRn facilitates the transepithelial transport of IgE in the form of IgG anti‐IgE/IgE ICs. They also strongly suggest that the majority of IgE in CB sera is the result of FcRn‐mediated transcytosis of maternal‐derived IgG anti‐IgE/IgE ICs. These findings challenge the widespread perception that maternal IgE does not cross the placenta. Measuring maternal or CB levels of IgG anti‐IgE/IgE ICs may be a more accurate predictor of allergic risk.

Antigen transfer from exosomes to dendritic cells as an explanation for the immune enhancement seen by IgE immune complexes.

IgE antigen complexes induce increased specific T cell proliferation and increased specific IgG production. Immediately after immunization, CD23+ B cells capture IgE antigen complexes, transport them to the spleen where, via unknown mechanisms, dendritic cells capture the antigen and present it to T cells. CD23, the low affinity IgE receptor, binds IgE antigen complexes and internalizes them. In this study, we show that these complexes are processed onto B-cell derived exosomes (bexosomes) in a CD23 dependent manner. The bexosomes carry CD23, IgE and MHC II and stimulate antigen specific T-cell proliferation in vitro. When IgE antigen complex stimulated bexosomes are incubated with dendritic cells, dendritic cells induce specific T-cell proliferation in vivo, similar to IgE antigen complexes. This suggests that bexosomes can provide the essential transfer mechanism for IgE antigen complexes from B cells to dendritic cells.

IgE enhances B cell-derived exosomal induced T cell proliferation. (P5013)

Abstract The immunostimulatory potential of IgE immune complexes is known to be dependent on CD23, the low affinity IgE receptor. This was originally thought to be due to CD23 mediated uptake and subsequent stimulation of T cells by B cell processed antigen. Recent findings have indicated that dendritic cells (DC) are required in this process and B cells are primarily needed for antigen transportation. This has called into question the role of B cells in this interaction and leaves a gap in the knowledge of how the antigen is transferred to the DC. Given the resurgent interest in exosomes as having the capacity to mediate antigen presentation, we tested whether B cell derived exosomes might provide an explanation for this transfer. B cell derived exosomes express CD23 as well as the costimulatory molecules CD80 and CD86. Exosomes isolated from B cells that had been cultured with anti-TNP-IgE and TNP-OVA were shown to induce proliferation of ova specific DO11 T cells in a dose dependent manner. In the absence of either CD23 or anti-TNP-IgE, specific T cell stimulation was severely reduced. Thus, B cell derived exosomes alone have the capacity to induce antigen specific T cell activation and could represent the mechanism for antigen transfer to DCs. Ongoing testing involves whether injection of exosomes with processed antigen, either iv or intrasplenic will give an enhanced T cell and anti-OVA response in a manner similar to the classical IgE immune complex injection.

In vivo intranasal anti-CD23 treatment inhibits allergic responses in a murine model of allergic rhinitis

Although CD23-dependent transcytosis of IgE and IgE-derived immune complexes across respiratory epithelial cells is likely to play a pivotal role in the initiation and development of airway allergic inflammation, there is currently a lack of physiological support for this phenomena to suggest that the targeting of CD23 could be used as a means of therapeutic intervention. The present study was designed to detect the CD23 expression in the nasal mucosa of allergic rhinitis (AR) murine model by immunohistochemistry and western blotting, and to investigate whether intranasal anti-CD23 treatment could inhibit allergen-induced upper airway inflammation in the AR model. This is the first report to show that CD23 was constitutively expressed in murine nasal epithelial cells, and its expression was significantly up-regulated in the AR murine model. In vivo, the up-regulation of CD23 expression was correlated with increased serum IL-4 levels. Following intranasal anti-CD23 treatment, nasal symptoms were alleviated and histopathologic examination showed a significant decrease in eosinophilic infiltration. Meanwhile, ELISA analysis showed levels of serum leukotriene C4 (LTC4), eosinophil cation protein (ECP), ovalbumin (OVA)-specific IgE and IL-4 also significantly decreased, as were LTC4 and OVA-specific IgE in the nasal lavage fluid. Furthermore, Western blotting analysis showed that ECP expression in the nasal mucosa was down-regulated. Finally, flow cytometric analysis revealed anti-CD23 treatment inhibited Th2 cell responses. These results indicate that intranasal anti-CD23 treatment can reduce allergic responses in a murine model of allergic rhinitis.

IgG Immune Complex Induces the Recruitment of Inflammatory Cells into the Airway and TNF-Mediated Late Airway Hyperresponsiveness via NF-κB Activation in Mice

Background. Many of the inflammatory proteins that are expressed in asthmatic airways are regulated, at least partially, by nuclear factor (NF)-κB. Blockade of NF-κB activity has resulted in attenuation of the cardinal features of asthma. Thus, delineating the mechanisms involved in NF-κB activation in asthma might provide an interesting approach to improving the management of asthma. However, despite its importance, the mechanism for NF-κB activation in asthma has not yet been determined. Objective. To examine the role of IgE and IgG antibodies (Abs) in the activation of NF-κB in mouse lungs. Methods. To examine the effect of IgE, mice underwent intratracheal (i.t.) instillation of an IgE immune complex (IgE-IC) (anti-2,4-dinitrophenyl hapten (DNP) IgE + DNP-BSA or DNP-OVA) and anaphylactogenic anti-IgE (LO-ME-2). For IgG, mice underwent i.t. instillation with a complex of anti-chicken gamma globulin (CGG) IgG1 mAb + CGG. NF-κB activation was determined by gel shift assay. Small interfering RNA was used for blockade of p50 expression. The effect of tumor necrosis factor (TNF) blockade was determined using anti-TNF Ab. A previously established murine model of asthma was used to assess airway hyperresponsiveness (AHR). Results. A single i.t. instillation of either IgE-IC or LO-ME-2 failed to induce activation of NF-κB in the lungs. In contrast, single i.t. instillation of IgG-IC was capable of inducing NF-κB activation, as well as NF-κB-dependent proinflammatory molecules, such as TNF and CXC chemokines. Pretreatment of p50 small interfering RNA decreased bronchoalveolar lavage fluid levels of TNF and macrophage inflammatory protein-2 induced by IgG-IC instillation. Single i.t. instillation of IgG-IC caused the recruitment of neutrophils and macrophages into the airway and TNF-mediated late AHR, but failed to induce Th2 cell-mediated asthmatic phenotypes. Conclusion. IgG, but not IgE, is the major Ab that induces not only NF-κB activation and NF-κB-dependent proinflammatory molecules in the lungs but also subsequent recruitment of inflammatory cells into the airway and TNF-mediated late AHR.

IgE Immune Complexes Stimulate an Increase in Lung Mast Cell Progenitors in a Mouse Model of Allergic Airway Inflammation

Mast cell numbers and allergen specific IgE are increased in the lungs of patients with allergic asthma and this can be reproduced in mouse models. The increased number of mast cells is likely due to recruitment of mast cell progenitors that mature in situ. We hypothesized that formation of IgE immune complexes in the lungs of sensitized mice increase the migration of mast cell progenitors to this organ. To study this, a model of allergic airway inflammation where mice were immunized with ovalbumin (OVA) in alum twice followed by three daily intranasal challenges of either OVA coupled to trinitrophenyl (TNP) alone or as immune complexes with IgE-anti-TNP, was used. Mast cell progenitors were quantified by a limiting dilution assay. IgE immune complex challenge of sensitized mice elicited three times more mast cell progenitors per lung than challenge with the same dose of antigen alone. This dose of antigen challenge alone did not increase the levels of mast cell progenitors compared to unchallenged mice. IgE immune complex challenge of sensitized mice also enhanced the frequency of mast cell progenitors per 106 mononuclear cells by 2.1-fold. The enhancement of lung mast cell progenitors by IgE immune complex challenge was lost in FcRγ deficient mice but not in CD23 deficient mice. Our data show that IgE immune complex challenge enhances the number of mast cell progenitors in the lung through activation of an Fc receptor associated with the FcRγ chain. This most likely takes place via activation of FcεRI, although activation via FcγRIV or a combination of the two receptors cannot be excluded. IgE immune complex-mediated enhancement of lung MCp numbers is a new reason to target IgE in therapies against allergic asthma.

CD23-Dependent Transcytosis of IgE and Immune Complex across the Polarized Human Respiratory Epithelial Cells

IgE-mediated allergic inflammation occurs when allergens cross-link IgE on the surface of immune cells, thereby triggering the release of inflammatory mediators as well as enhancing Ag presentations. IgE is frequently present in airway secretions, and its level can be enhanced in human patients with allergic rhinitis and bronchial asthma. However, it remains completely unknown how IgE appears in the airway secretions. In this study, we show that CD23 (FcεRII) is constitutively expressed in established or primary human airway epithelial cells, and its expression is significantly upregulated when airway epithelial cells were subjected to IL-4 stimulation. In a transcytosis assay, human IgE or IgE-derived immune complex (IC) was transported across a polarized Calu-3 monolayer. Exposure of the Calu-3 monolayer to IL-4 stimulation also enhanced the transcytosis of either human IgE or the IC. A CD23-specific Ab or soluble CD23 significantly reduced the efficiency of IgE or IC transcytosis, suggesting a specific receptor-mediated transport by CD23. Transcytosis of both IgE and the IC was further verified in primary human airway epithelial cell monolayers. Furthermore, the transcytosed Ag-IgE complexes were competent in inducing degranulation of the cultured human mast cells. Because airway epithelial cells are the first cell layer to come into contact with inhaled allergens, our study implies CD23-mediated IgE transcytosis in human airway epithelial cells may play a critical role in initiating and contributing to the perpetuation of airway allergic inflammation.

The absence of VPAC 2 leads to aberrant antibody production in Aspergillus fumigatus sensitized and challenged mice

Vasoactive intestinal peptide (VIP) facilitates a “pro-allergy” phenotype when signaling through its G protein-coupled receptor, VPAC 2. We have shown that VPAC 2 knock-out (KO) mice developed an allergic phenotype marked by eosinophilia and elevated serum IgE. Therefore, we hypothesized that the humoral response to allergen challenge in these mice was T H2 dominant similar to wild-type (WT) C57BL/6 mice. Antibody responses in WT and KO mice were measured after Aspergillus fumigatus conidia inhalation. In contrast to previous reports, basal levels of serum IgG 2a and IgA were significantly higher in naïve VPAC 2 KO animals. Antibody availability in the serum as well as the bronchoalveolar lavage fluid after fungal challenge was dominated by the pro-inflammatory isotype IgG 2a and the mucosal isotype, IgA. IgA localizing cells dominated in the peribronchovascular areas of allergic KO mice while IgE immune complexes were found in WT allergic lungs. This research shows for the first time that VPAC 2 has a significant effect on antibody regulation, in the context of allergy.

Antigen-Specific IgG and IgA, but Not IgE, Activate the Effector Functions of Eosinophils in the Presence of Antigen

Background: Activated eosinophils are thought to play an important role in allergic inflammation. Prior reports suggest that eosinophils have receptors recognizing IgA, IgG and IgE; however, little is known regarding the direct effects of antigens and antigen-specific immunoglobulins on the functions of eosinophils. Methods: To investigate eosinophil activation by antigens mediated by the various antigen-specific immunoglobulins, we used dansyl-conjugated bovine serum albumin (DNS-BSA) and recombinant dansyl-specific antibodies (human IgG 1–4, IgA and IgE). Eosinophils from healthy donors were incubated in the wells coated with dansyl-specific immunoglobulins with or without DNS-BSA. Eosinophil activation was monitored by superoxide production and eosinophil-derived neurotoxin (EDN) release. Results: Superoxide production and EDN release by eosinophils were induced by the dansyl-specific reaction via all IgG subclasses (IgG 1–4) and IgA in the presence of DNS-BSA; the responses were not observed in the absence of antigen, DNS-BSA. The immune complexes (ICs) of DNS-BSA and dansyl-specific IgE did not induce these responses. Furthermore, IgE ICs did not enhance eosinophil activation stimulated with various immunoglobulins, IL-5 or platelet-activating factor. Conclusion: These data suggest that ICs of antigens and antigen-specific IgGs and IgA, but not IgE, in inflamed tissues may activate eosinophils and play an important role in allergic inflammation.

Basophils and the T helper 2 environment can promote the development of lupus nephritis

SummaryIn systemic lupus erythematosus (SLE) self-reactive antibodies can target the kidney (lupus nephritis) leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE, causes their homing to lymph nodes, promoting TH2 cell differentiation, and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in Lyn−/− mice. SLE patients also have elevated serum IgE, self-reactive IgE's, and activated basophils that express CD62L and the MHC Class II molecule, HLA-DR; parameters that were found to be associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of SLE patients. Thus, in Lyn−/− mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in SLE patients, the presence of IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.