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Local respiratory allergy (LRA) is defined by the negativity of atopy tests, a clinical history suggestive of airway allergy and a positive response to the nasal and/or bronchial allergen challenge. The clinical spectrum of LRA is comprised of three conditions: local allergic rhinitis (LAR) and local allergic asthma in non-atopic patients, and dual allergic rhinitis (coexistence of allergic rhinitis and LAR) in atopic individuals. LRA is an independent disease phenotype not progressing to atopy over time, but naturally evolving to the clinical worsening and the onset of comorbidities. Published data suggests that LRA is mediated through the mucosal synthesis of allergen-specific (s)IgE, which binds to FcϵRI on resident mast cells, and in >50% of cases traffics to the blood stream to sensitize circulating basophils. To date, 4 clinical trials have demonstrated the capacity of allergen immunotherapy (AIT) to decrease nasal, conjunctival and bronchial symptoms, to improve quality of life, to increase the threshold dose of allergen eliciting respiratory symptoms, and to induce serum sIgG4 in LRA individuals. Collectively, these data indicate that local allergy is a relevant disease mechanisms in both atopic and non-atopic patients with airway diseases. [ABSTRACT FROM AUTHOR]

The increased incidence of allergic diseases and food-induced anaphylaxis overtime demands an urgent development of disease-modifying therapies that reverse the synthesis of IgE and the induction of IgE-mediated allergic reactions. Keywords: allergic sensitization; food allergens; germinal center; IgE synthesis EN allergic sensitization food allergens germinal center IgE synthesis 1545 1549 5 05/17/21 20210501 NES 210501 Understanding the biology of IgE in humans has become a matter of interest that remains incompletely understood due to the rarity of peripheral IgE SP + sp cells. Biology of IgE production: IgE cell differentiation and the memory of IgE responses. [Extracted from the article]

Rationale: Recombinant fragment of human surfactant protein D (rfhSP-D) has been shown to suppress house dust mite- and Aspergillus fumigatus-induced allergic inflammation in murine models.Objectives: We sought to elucidate the effect of rfhSP-D on high-affinity IgE receptor- and CD23-mediated, grass pollen-induced allergic inflammatory responses.Methods: rfhSP-D, containing homotrimeric neck and lectin domains, was expressed in Escherichia coli BL21(λDE3)pLysS cells. Peripheral blood mononuclear cells and sera were obtained from individuals with grass pollen allergy (n = 27). The effect of rfhSP-D on basophil activation and histamine release was measured by flow cytometry. IgE-facilitated allergen binding and presentation were assessed by flow cytometry. T-helper cell type 2 (Th2) cytokines were measured in cell culture supernatants. The effect of rfhSP-D on IgE production by B cells when stimulated with CD40L, IL-4, and IL-21 was also determined.Measurements and Main Results: rfhSP-D bound to Phleum pratense in a dose- and calcium-dependent manner. Allergen-induced basophil responsiveness and histamine release were inhibited in the presence of rfhSP-D, as measured by CD63, CD203c (P = 0.0086, P = 0.04205), and intracellularly labeled diamine oxidase (P = 0.0003, P = 0.0148). The binding of allergen-IgE complexes to B cells was reduced by 51% (P = 0.002) in the presence of rfhSP-D. This decrease was concomitant with reduction in CD23 expression on B cells (P < 0.001). rfhSP-D suppressed allergen-driven CD27-CD4+CRTh2+ T-cell proliferation (P < 0.01), IL-4, and IL-5 levels (all P < 0.01). Moreover, rfhSP-D inhibited CD40L/IL-4- and IL-21-mediated IgE production (77.12%; P = 0.02) by B cells.Conclusions: For the first time, to our knowledge, we show that rfhSP-D inhibited allergen-induced basophil responses at a single-cell level and suppressed CD23-mediated facilitated allergen presentation and Th2 cytokine production. In addition, rfhSP-D inhibited IgE synthesis by B cells, which is also a novel observation. [ABSTRACT FROM AUTHOR]

Allergen-specific Th2 cells from atopic individuals generally belong to the T helper 2 (Th2) subset producing, among other cytokines, high levels of IL-4, IL-5 and IL-13, but low levels of IL-2 and IFN-γ following activation. Both IL-4 and IL-13 induce IgE synthesis, which is inhibited by IFN-γ. IL-4, but not IL-13, also directs differentiation of naive CD4+ T cells into Th2 cells. Furthermore, IL-5 induces the differentiation of eosinophils and eosinophilia, whereas IL-3, IL-4 and IL-10 produced by Th2 cells, synergize with c-kit ligand in promoting mast cell growth. These observations indicate that allergy is a Th2 cell disease, and that targeting of allergen-specific Th2 cells may provide an efficient way to intervene in allergic inflammation. Three different approaches aimed at inhibiting the function or differentiation of allergen-specific Th2 cells are discussed. It is shown that an IL-4R and IL-13R antagonist inhibits IL-4-driven Th2 cell differentiation and human IgE production both in vitro and in SCID-hu mice. In addition, it is discussed that allergen-specific Th2 cells can be rendered anergic following stimulation with allergen-derived peptides, representing T cell activation inducing epitopes. These anergic Th2 cells fail to produce IL-4, IL-5 and IL-13, to proliferate, and to provide help to B cells for IgE synthesis after rechallenge with allergen- and antigen-presenting cells. Finally, it is shown that IL-4-driven allergen-specific Th2 cell differentiation can be redirected into a Th0 and Thl cell differentiation pathway by stimulating these IL-4-driven allergen-specific Th cell populations in the presence of IL-12, or by co-stimulating these cells via a novel T cell receptor, designated signalling lymphocyte activation molecule (SLAM). The clinical implications of these approaches are discussed.

Background The production of allergen-specific IgE antibodies is a hallmark of IgE-mediated allergy but the contribution of blood cells to allergen-specific IgE production in allergic patients has not been studied in detail. Objective Aim of this study was the characterization of IgE-producing cells in the blood of allergic patients and the determination of the amount of IgE antibodies which are produced by these cells in relation to total amounts of circulating specific IgE. Methods Peripheral blood mononuclear cells ( PBMCs) were isolated from allergic patients and cell populations were purified or depleted using magnetically labelled antibodies directed against specific cell surface markers ( CD19, CD20, CD22, CD27, CD38, CD126, CD138, CD203c). Allergen-specific IgE was measured in serum samples and cell culture supernatants by quantitative Immuno CAP measurements and by ELISA using purified recombinant allergens. IgE transcripts were detected using RT- PCR with primers specific for human IgE. Results We found that allergen-specific IgE levels in PBMC supernatants correlated strongly with specific serum IgE but represented less than 1% of circulating IgE. Depletion of basophils resulted in substantial reduction of allergen-specific IgE levels in PBMC culture supernatants suggesting that an important source of allergen-specific IgE in PBMC supernatants could be IgE derived from the surface of basophils. Newly synthesized IgE was derived from CD138+ plasma cells, but not from B and B memory cells, and accounted for only approximately 0.2% of circulating IgE in blood. Conclusion and Clinical Relevance Our finding that the majority of allergen-specific IgE in the peripheral blood is not derived from IgE-secreting cells in the blood suggests local IgE production in tissues as a major source for allergen-specific IgE and possible target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Exposure to cadmium (Cd) can cause a variety of biological effects including alterations of immune responses in animals and humans. Both immunosuppression and immunoenhancement have been reported. The present study was aimed at investigating the consequences of exposure to Cd on the human immunoglobulin (Ig) E synthesis, using purified peripheral blood B lymphocytes and IL-4 and anti-human CD40 monoclonal antibody (a-CD40 mAb) as stimuli. Low concentrations of Cd (0.1–10 μM) markedly inhibited production of IgE in a concentration-dependent manner. IgG production, in contrast to IgE, showed a tendency towards being enhanced by Cd, although with a certain individual variability; IgM production was not affected. Cd failed to alter immediate surface expression of the activation markers CD69 and CD23 indicating that early activation events were not impaired. However, the portion of activated B cells was diminished by Cd after stimulation for more than 24 h, paralleled by a concomitant decrease in viability and a subsequent reduction in proliferation. These data suggest that the mechanism of Cd action on activated B cells involved pathways that interrupted an effectively initiated cell activation and induced a cytotoxic signal. Results from this study thus provide further evidence for and new information on the immunotoxic and immunomodulatory effects of Cd on human immune responses. [Copyright &y& Elsevier]

Summary Background Kimura's disease (KD) is a chronic inflammatory disorder characterized by tumours in the head and neck region, enlarged lymph nodes, increased eosinophil counts and high serum IgE. Mast cells are known to play a central role in IgE-mediated allergic diseases through the release of inflammatory mediators like IL-4, IL-5 and chemokines. We hypothesized that mast cells may play a role in the pathogenesis of KD by regulating eosinophilic infiltration and IgE synthesis. Objective In order to investigate the role of mast cells in the pathogenesis of KD, we examined the expression of cytokines/chemokines in the lesions of KD. Methods We examined the number of tryptase+ cells, EG2+ cells, CD3+ cells, IL-4+ cells, IL-5+ cells, eotaxin+ cells, RANTES+ cells and CCR3+ cells in five specimens of KD versus normal tissues by immunohistochemistry. The sources of IL-4, IL-5, eotaxin and RANTES and the expression of CCR3 were examined by immunostaining of serial sections with antibodies to IL-4, IL-5, eotaxin, RANTES and CCR3, and antibodies to tryptase, ECP (EG2) and CD3. Results Mast cells, activated eosinophils, T cells, IL-4+ cells, IL-5+ cells, eotaxin+ cells, RANTES+ cells and CCR3+ cells were all increased in the lesions of KD as compared with those in normal tissue. Mast cells and T cells were the major source of IL-4, whereas mast cells, T cells and activated eosinophils were the main source of IL-5. Mast cells, T cells and activated eosinophils were the main source of eotaxin and RANTES. Conclusions The number of IL-4, IL-5, eotaxin and RANTES-expressing mast cells and T cells were increased in the lesions of KD. As mast cells are lesional resident cells, these cells may play an important role in the pathogenesis of KD by regulating IgE synthesis and orchestrating eosinophilic infiltration. [ABSTRACT FROM AUTHOR]

Interleukin-4 (IL-4) is produced by T-helper cells type 2 (TH2) and induces IgE synthesis. T-helper cells type 1 (TH1) produce interferon-gamma (IFN-gamma) which suppresses TH2 and reduces IL-4 induced IgE production. In this :;tudy , we demonstrated that the levels of specific IgE in the serum of atopic children (n=20) were elevated while IL-4 production was increased and IFN-gamma secretion was reduced, compared to those of control group. Inter!eukin-4-induced IgE synthesis by peripheral blood mononuclear cells of atopic children in vitro was blocked in the presence of IFN-gamma. In addition, levels of soluble CD23-which is specifically induced by IL-4 were significantly elevated in our atopic patients. The data indicate that enhanced production of IL-4 and lowered IFN-gamma secretion by T-helper cells correlate with the elevated specific IgE levels in the serum of atopic children.

Corticotropin releasing factor, adrenocorticotropic hormone (ACTH) and alpha-melanocyte stimulating hormone either inhibit or enhance in a dose-dependent fashion an interleukin-4 (IL-4) driven human IgE synthesis in vitro. Here, we show that culture conditions strongly influence the earlier observed dose- and donor-dependent effects of adrenocorticotropic hormone. The effect of ACTH on IgE synthesis became only apparent late during culture periods, suggesting an indirect effect via the cellular microenvironment rather than by acting directly at the level of B-cell isotype switching. Thus, we studied other proopiomelanocortin (POMC) derived peptides and neuropeptides known to influence the cellular microenvironment. Indeed, similar modulatory effects on IgE synthesis were also observed by the addition of other proopiomelanocortin-derived peptides such as α-, β-, and γ-endorphins as well as by the opioid binding pentapeptide Leu-enkephalin. Furthermore the neuropeptide substance P accentuated an IL-4 or an IL-4 and anti-CD40 antibody driven class switch to IgE. In contrast to ACTH, substance P interfered not only with IgE synthesis but also with the synthesis of the other immunoglobulin isotypes. Thus, systemically acting neuroendocrine peptides such as ACTH and locally acting neuropeptides such as the enkephalins and substance P can modulate the magnitude of an IL-4 induced lgE response. [ABSTRACT FROM AUTHOR]

Activin A not only stimulates the synthesis and release of pituitary follicle-stimulating hormone, but exerts various effects on haematopoietic cells, embryos, and fibroblasts. In the present study we have examined effects of activin A on IgE synthesis and cytokine production by peripheral blood mononuclear cells (PBMC) in normal humans. When PBMC were cultured in the presence of IL-4, activin A significantly augmented IgE production induced by IL-4. Activin A did not affect, however, IgE production from highly purified B cells when they were stimulated with anti-CD40 MoAb and IL-4, The fact that in the latter condition IgE synthesis was T cell- and monocyte-independent indicated that activin A docs not directly influence B cells for IgE synthesis. Rather, production as well as gene expression of IL-6, which is known to enhance IgE synthesis by purified monocytes, was induced by activin A alone. In addition, activin A induced other monokines such as IL-l and tumour necrosis factor (TNF)-α from monocytes. In contrast, activin A neither induced nor augmented the production of TNF-β or interferon-gamma (IFN-γ), both of which are known to be exclusively generated by T cells. These data indicate that activin A plays a certain role in physiological functions for monocytes In normal humans. [ABSTRACT FROM AUTHOR]

The role of T cells for IL-4-induced IgE synthesis by peripheral blood mononuclear cells (PBMC) was investigated. The removal of monocytes from PBMC abolished IL-4-induced IgE synthesis. When PBMC were separated into T and non-T cells, non-T cells alone were not able lo secrete significant amounts of IgE in the presence of IL-4. Depending on the separation procedure, the reconstitution of non-T cells with T cells prepared by rosetting did not restore IgE secretion, whereas T cells obtained by the use of anti-CD3 antibodies could co-induce IgE formation. However, when the T cells were first irradiated, large amounts of IgE were produced, which strongly exceeded those found in unseparated PBMC cultures. IL-4-induced IgE synthesis was also obtained in co-cultures of formaldehyde-fixed T cells with non-T cells. Furthermore, not only autologous hut also allogeneic T cells, which have been irradiated or fixed, could provide the costimulatory effect on IgE formation by non-T cells in the presence of IL-4. Mitogenically pre-activated T cells, however, were not able to support IgE synthesis. Hydrocortisone (HC) potentiated the IL-4-induced IgE synthesis by PBMC and enabled non-T cells lo secrete IgE in the presence of IL-4. Adding both HC and T cells led lo a marked synergistic effect on IL-4-induced IgE production. We conclude that monocytes are required for the induction of IgE synthesis in PBMC in addition to T cells and IL-4. Our results support the view that the T cell signal is delivered via cognate and non-cognate T/B cell membrane interaction. Furthermore, active and proliferating T cells rather suppress IgE synthesis. Finally, HC appears to be a potent alternative stimulus, which bypasses the necessity for T cells in IL-4-induced IgE formation. [ABSTRACT FROM AUTHOR]

We measured the in vitro production of interferon-gamma (IFN-γ) in five cases of hyper-IgE syndrome (HIgE), induced by mitogens, calcium ionophores and phorbol ester. The biosynthesis of IFN-γ was severely reduced or undetectable in HIgE, while it was near normal in most atopic patients. The in vitro spontaneous production of IgE was increased overall in HIgE patients, although no correlation was found with serum IgE levels. Recombinant interleukin-4 (IL-4) induced a further increase in IgE synthesis, and its effect was totally antagonized by recombinant IFN-γ; the same pattern of response was also observed in atopic subjects with high production of IgE. IFN-α synergized with IL-4 on IgE synthesis, whereas recombinant IL-6 gave opposite changes in individual cases tested. We propose that IFN-γ deficiency may be responsible for some of the features of HIgE patients, including IgE levels and infections. [ABSTRACT FROM AUTHOR]

Neonatal B cells have been considered immature because of their impaired capacity to produce immunoglobulins in response to polyclonal activators in vitro. Here we demonstrate (hat cord blood mononuclear cells (MNC) produce normal levels of IgE in vitro when cultured in the presence of interleukin-4 (IL-4), indicating that the B cells are mature in their capacity to switch lo IgE-producing cells. However, in contrast to adult peripheral blood T cells, cord blood T cells failed to produce detectable levels of IL-4 upon activation by phytohaemagglutinin (PHA) concanavalin A (Con A) or combinations of PHA and the phorbol ester TPA. Interferon-gamma (IFN-γ) production by cord blood T cells following activation by Con A or PHA was also strongly reduced. However, high levels of IFN-γ, significantly higher than those produced by adult T cells, were synthesized in response to combinations of PHA and TPA, indicating that IFN-γ production by cord blood T cells is not intrinsically defective. In contrast, cord blood T cells produced levels of IL-2 that were significantly higher than those obtained by adult T cells tested in parallel. Collectively, our data indicate that the minimal levels of IgE production measured in cord blood (< 1 U/ml) are not due to immaturity of the cord blood B cells, but may be associated with the failure of cord blood T cells to produce detectable levels of IL-4, which has been shown to be responsible for induction of IgE synthesis both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The role of T cells In the regulation of IgE synthesis by human PBMC was studied. PBMC or separated and recombined populations of T and B cells from both normal and atopic donors were cultured for 10 days with and without cycloheximide. IgE and IgG synthesis were determined by specific RIA. IgE synthesis was detected in 0/30 non-atopic. 6/34 mildly atopic and 25/31 severely atopic subjecls. Autologous T cells from 10/26 atopic donors, whose B cells synthesised IgE, significantly suppressed this IgE synthesis. The addition of allogeneic T cells from atopic or non-atopic subjects to atopic B cells resulted in greater suppression of IgE synthesis than the addition of autologous T cells. These data support the notion that atopic subjects have naturally occurring IgE isotype-specific suppressor T cells as well as suppressor T cells which can be activated during incubation with alloantigen. [ABSTRACT FROM AUTHOR]

CHO cells permanently transfected with mouse FcΥRI αchain were prepared and used as a model to polyclonally activate murine B cells. The transfected CHO cells were treated with mitomycin C and placed into culture with varying quantities of anti-IgD. Using this model, murine splenic B cells (from BALB/c or C57Bl/6) were activated by mouse IgG2a-anti-IgD (10.4.22 or AF3.33) in a manner that is analogous to the activation of B cells seen with highly polyvalent anti-IgD (HΥa/1) prepared by chemical cross-linking to dextran. Efficient B cell activation was seen with nanogram quantities of anti-IgD. In the presence of IL-4 and IL-5, IgG1 production levels were equivalent to or better than seen when stimulation was with Hda/1-dextran; however, Ig;E induction was not seen in either situation. The Ig production capacity was compared to that seen when B cells were activated with CD40L, using either CD40L-transfected CHO or a soluble CD40L construct. In the presence of IL-4 and IL-5, once a critical threshold of B cells was present, IgE and to a lesser extent IgG1 production was inversely proportional to B cell number when CD40L was the activating agent. In contrast, with FcgRI-anti-IgD, IgM and IgG1 production was directly proportional to B cell number, while IgE production was never seen. Finally, when B cells were co-activated with immobilized anti- IgD and CD40L simultaneously, the IgE production from B cells induced by CD40L was strongly inhibited, while IgG1 and IgM production were not affected. Since B cell co-activation via sIg; and CD40L would be a common scenario in secondary follicles, this inhibition of IgE production may be one of the reasons why serum IgE levels are much below IgG in normal immune situations. [ABSTRACT FROM AUTHOR]

To determine the role of germline ∈ transcription in IgE synthesis, the effects of cytokines on germline ∈ RNA synthesis in IL-4 dependent ∈ switching in B cells was investigated. Induction of germline ∈ transcription in highly purified B cells seems to be a specific property of IL-4, since none of the other cytokines tested [IL-1α, β, IL-2, IL-3, IL-5, IL-6, IL-7, IL-9, IL-10, G-CSF, GM-CSF, M-CSF, IFN-γ, IFN-α, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β] were effective. TGF-β, IFN-γ, and IFN-α inhibit IL-4 dependent IgE synthesis, but only TGF-β blocked germline ∈ RNA synthesis in purified B cells, indicating that this may be the mechanism by which TGF-β inhibits IgE synthesis, and that IFN-γ and IFN-α act on other stages of the regulatory process resulting In IgE production. IL-5, IL-6, and TNF-α enhance IL-4 dependent IgE synthesis, but only TNF-α enhanced IL-4 induced germline ∈ RNA synthesis. Finally, anti-CD40 mAbs and the non-IL-4 producing CD4 T cell clone A3, which in the presence of IL-4 induce IgE synthesis by purified B cells, both strongly enhanced germline ∈ transcription. These data, together with the observation that ∈ switching in cultures initiated with single slgM, slgE B cells in all instances was preceded by germline ∈ RNA synthesis, indicate that there is a strong relationship between germline ∈ transcription and IgE synthesis. [ABSTRACT FROM PUBLISHER]

Recently, hydrocortisone (HC) has been shown significantly to enhance interleukin-4 (IL-4)-induced in vitro IgE synthesis. For investigation of possible effects of synthetic corticosteroids hut also of effects of other important human hormones, peripheral blood mononuclear cells (PBMC) were incubated with IL-4 and various concentrations of the hormones IgE secreted in the supernatant was determined after a 14-d culture period. Like HC, all synthetic corticosteroids potentiated IgE secretion A minor effect was noted for the mineralocorticoid aldosterone. No modulating effect on IL-4-induced IgE formation was observed for adrenocorticotropic hormone (ACTH), somatotropin (STH), thyroid-stimulating hormone (TSH), triiodothyronine, thyroxine, epinephrine, noradrenaline, insulin, and glucagon. [ABSTRACT FROM AUTHOR]

The effects of indomethacin or macrophage-depletion on the in vitro unstimulated and pokeweed mitogen (PWM)-induced synthesis of IgG and IgE were compared. The effect on the unstimulated synthesis of IgG and IgE was similar, namely, no effect due to indomethacin and enhancement due to macrophage depletion. In contrast, the effect on PWM-induced synthesis was dissimilar. Macrophage depletion enhanced IgG but inhibited IgE production. The effect of indomethacin paralleled that of macrophage depletion suggesting the involvement of prostaglandins. It seems that the regulatory effect of macrophages is different in the IgE system compared with the IgG system. [ABSTRACT FROM AUTHOR]

Peripheral blood lymphocytes from patients with atopy were studied for IgE production in vitro. Addition of a beta-receptor blocking agent (propranolol) to lymphocytes from 9 of 10 patients with low spontaneous IgE production in vitro caused increased IgE production. In 10 tests with lymphocytes from patients, who were undergoing hyposensitization treatment for cat epithelium and/or birch pollen allergy, no spontaneous in vitro production of the relevant antigen-specific IgE antibodies was detected. However, when propranolol was added to the lymphocyte cultures in vitro, production of antigen-specific IgE antibodies was found. No such production was found when lymphocytes from patients who were not allergic to either of these antigens were studied, Szentivanyi's theory of a partial blockade of beta-adrenergic receptors in atopy and a possible linkage between this theory and the hypotheses of disturbed regulatory functions in the immune system of patients with atopy is discussed. [ABSTRACT FROM AUTHOR]

B cell-derived IgE-BFs (sCD23) are cleavage fragments of surface FcɛR II. Their production is increased by IL4 and suppressed by IFN-γ and IFN-α. IgE-BFs are likely to play a role in the regulation of human IgE synthesis as shown by the following two observations: i. MabER specifically blocks both the spontaneous IgE by synthesis by atopic B cells and the IL4-induced IgE synthesis by normal lymphocytes, ii. purified IgE-BFs enhance the IL4-induced and the spontaneous IgE synthesis. Soluble fragments of FcɛR II also display BCGF-Iike activity although the exact structure of these fragments is not yet identified. The cDNA coding for FcɛR II has been cloned and functionally expressed. The predicted amino acid sequence reveals no homology between human and rodent IgE-BFs indicating that they are unrelated molecules. [ABSTRACT FROM AUTHOR]