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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]

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]

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]