Regulation Of IgE Synthesis Research Articles

Regulation of IgE synthesis in humans

Regulation of IgE synthesis in humans

IgE, IL4, and soluble FcɛRII in the serum of atopic and nonatopic children

We correlated serum IgE, interleukin 4 (IL4) and soluble low affinity Fc receptor for IgE (sFcɛRII) in atopic and nonatopic children. Serum sFcɛRII was significantly higher in atopic than in nonatopic children (0‐2 yr). Serum sFcɛRII correlated closely with serum IgE in infants, but not in older children. To study further the characteristics of IgE synthesis in infants, we measured the serum level of IL4, which has been demonstrated to enhance the production of both IgE and sFcɛRIIin vitro. Serum IL4 was significantly higher in atopic than in nonatopic infants, but there was no significant difference between atopic and nonatopic older children. These results suggest that IL4 plays an important role in the regulation of IgE synthesis in infants and that IgE synthesis in older children might be modulated by other factors.

The effect of Dermatophagoides pteronyssinus allergens on proliferation and CD23 antigen expression of peripheral blood lymphocytes from atopic patients.

The low affinity IgE receptor (FcεRII/CD23) has been proposed to be involved in the regulation of IgE synthesis.The present study was undertaken to investigate the responses to in vitro stimulation by allergen (Dermatophagoides pteronyssinus; D.p) and/or interleukin-4 (IL-4) of peripheral blood lymphocytes (PBLs) isolated from atopic and non-atopic subjects. IL-4 induced up to 5 fold increase in CD23 expression on PBLs from both atopic patients and normal controls, whereas the D.p extract increased CD23 expression on cells from 7 of 8 atopic donors and from 2 of 8 normal controls. The combination of IL-4 and allergen had an additive effect of CD23 expression. PBLs from 6 of 8 atopic patients but 1 of 8 normal controls showed significant proliferative responses to D.p extract whereas IL-4 did not induce any cell proliferation. The dose of D.p extract required for the maximal CD23 expression was 20 fold higher than that for cell proliferation.These results imply that allergen stimulation, presumably through proliferating allergen specific T cells which secrete IL-4, activates B cells from most atopic donors and a few non-atopic donors resulting in increased CD23 expression. This allergen-mediated CD23 expression may play an important role in specific IgE production.

Regulation of IgE synthesis by cytokines

Regulation of IgE synthesis by cytokines

Restricted Lymphokine Synthesis in CD4+ Helper T Cells: New Insights into the Regulation of IgE Synthesis and the Pathogenesis of Allergic Disease

Over the past 5 years, a greater appreciation has developed regarding the role that IgE plays in the pathogenesis of allergic disease and asthma. Clinical investigators have shown that elevated IgE levels strongly correlate with the presence of asthma. In addition, other investigators have demonstrated that crosslinking of IgE on the surface of mast cells not only results in the release of histamine and other mediators but also produces a cascade of events leading to late phase reactions, bronchial hyperreactivity, and an allergic inflammatory response. Recent studies of the effects of a number of factors produced by CD4+ helper T lymphocytes—in particular, interleukin (IL) 4, IL-5 and IL-3—indicate that a distinct subtype of CD4+ T lymphocytes producing a specific profile of lymphokines greatly increases the secretion of IgE from B cells and enhances the accumulation of eosinophils and mast cells in the allergic inflammatory response. Thus, a complex network of cell types, including B cells producing IgE, mast cells, eosinophils, and subsets of CD4+ T lymphocytes secreting specific profiles of lymphokines, is involved in the development and regulation of allergic inflammation. This new understanding of allergic inflammatory disease and its dependence on IgE and on lymphokine synthesis in subsets of CD4+ T cells will lead to improved strategies in the treatment and control of allergic diseases.

Immunoglobulin-E-specific suppressor factors in primary glomerulonephritis with nephrotic syndrome.

Human immunoglobulin (Ig) E synthesis is regulated by T-cell-derived binding factors which include potentiating factors and suppressor factors (IgE-SFs) and B-cell-derived factors. Seventeen cases of primary glomerulonephritis (GN) with nephrotic syndrome and high serum IgE were studied for their serum IgE-SFs. These include 8 cases of minimal-change disease (MCD), 3 cases of IgM nephropathy, 4 cases of focal segmental glomerulosclerosis, and 2 cases of IgA nephropathy, aged between 20 and 60 years (mean: 37.2). A significantly lower activity of these factors was noted in the patient group as shown by a lower overall inhibition rate on in vitro IgE synthesis (median: 22.9 vs. 53.2%, p less than 0.05). Some of them even exhibited an enhancing activity in their serum as shown by a negative inhibition rate. These findings suggest that there is a T cell disorder in some of the primary GNs with high serum IgE, especially in MCD, which causes an abnormal regulation of IgE synthesis.

Regulation of IgE synthesis by cytokines

Considerable progress has been made in our understanding of the mechanisms underlying regulation of human IgE synthesis. Interleukin-4 induces IgE production specifically, but costimulatory signals provided by T cells are required. Other cytokines modulate interleukin-4-induced IgE synthesis. The roles of T cells and cytokines in regulating IgE switching are discussed.

Hydrocortisone and IL-4 induce IgE isotype switching in human B cells.

Induction of IgE synthesis in human B cells requires two signals. The first signal is delivered by the cytokine IL-4. The second signal activates B cells and is delivered by T cells, EBV infection, or engagement of the B cell-specific Ag CD40. Hydrocortisone (HC) has recently been shown to synergize with IL-4 to induce IgE synthesis in CD5+ chronic lymphocytic leukemia B cells. We show herein that a combination of HC and rIL-4 induces IgE synthesis in highly purified normal peripheral blood B cells. HC and IL-4 acted directly on B cells, because T cells and monocytes were not required for IgE synthesis. IgE induction was shown to occur in surface IgE- B cells isolated by cell sorting. These results suggest that IgE synthesis results from isotype switching, rather than from expansion of a precommitted B cell population. Furthermore, IgE synthesis was induced in sorted CD5- B cells, indicating that the ability to produce IgE in response to HC and IL-4 is not constrained by CD5 expression. Endogenous IL-6 was critical for induction of IgE synthesis by HC and IL-4, because an anti-IL-6 antibody strongly inhibited IgE production. These data suggest that hormones may play an important role in the regulation of IgE synthesis.

Regulation of IgE synthesis in humans: A tale of two signals

It is an unambiguous sign of vitality for a field when reviews become rapidly obsolete. After a decade of relatively slow progress, this is happening in the field of IgE regulation. After years of cell and cytokine cocktails, molecular biology is now providing an insight into the IgE system at a deeper, more meaningful level. The study of IgE regulation becomes important now not only because of the role of IgE in allergic disease but also, more generally, as a model to study the signals involved in isotype-specific regulation of immunoglobulin synthesis. In the past 2 to 3 years, evidence from different laboratories has indicated that induction of IgE synthesis requires two signals: One is delivered by a cytokine, IL-4, and is IgE isotype specific. The other signal is a B cell-activating signal.’ The challenge in IgE studies now is to determine what role the two signals play in the induction of IgE synthesis at the level of gene regulation.

Soluble Fc ϵR II levels in normal children and patients with immunodeficiency diseases

CD23 is expressed on mature B cells and is identical to a low-affinity IgE Fc ϵ receptor type II (Fc ϵR II). The C terminal portion of CD23 is released to the serum as soluble Fc ϵR II (sFc ϵR II), which may be involved in regulation of IgE synthesis. We studied sFc ϵR II levels in normal children and in patients with immunodeficiencies, including common variable immunodeficiency (CVI), partial DiGeorge syndrome, and immunodeficiency associated with ectodermal dysplasia to examine the relationship of sFc ϵR II levels to B cell numbers and other immunoparameters. Serum Fc ϵR II levels are higher in younger children (younger than 3 years) and decline gradually with age. In 11 patients with CVI with normal numbers of B cells (>6%), sFc ϵR II levels were comparable to that of control subjects. Five patients with CVI with deficiencies of peripheral B cells had levels of sFc ϵR II similar to levels of control subjects. In all but one patient with partial DiGeorge syndrome, sFc ϵR II levels were not significantly elevated, despite the presence of elevated peripheral B cell numbers. Of six patients with ectodermal dysplasia, four demonstrated increased Fc ϵR II levels, a finding not correlated with serum IgE levels or with peripheral eosinophil or B cell numbers.

Functional implication for the topographical relationship between MHC class II and the low‐affinity IgE receptor: occupancy of CD23 prevents B lymphocytes from stimulating allogeneic mixed lymphocyte responses

Following the observation of Bonnefoy et al. (J. Exp. Med. 1988. 167:57), that the low-affinity IgE receptor (CD23) on B lymphocytes can be coupled (with the use of chemical cross-linking reagents) to major histocompatibility complex (MHC) class II DR molecules, we now report that ligands binding within the lectin-homology region of CD23 prevent B cells from stimulating allogeneic mixed lymphocyte responses. Ligands capable of blocking mixed lymphocyte responses include the anti-CD23 antibodies MHM6 and EBVCS 4 but not EBVCS 1 and 5. IgE itself, and small peptides representing sequences within the CH3 domain of IgE. The detailed topographical relationship between CD23 and MHC class II on the B lymphocyte surface was examined using dual immuno-fluorescence labeling of cells and direct visualization of the staining by confocal laser scanning microscopy. On transformed B lymphoblasts, the two antigens were seen to co-localize in discrete patches; on normal B cells which had been cultured for 2 days with interleukin 4, CD23 and MHC class II converged at a single pole which exhibited a tendency to pseudopod formation and provided a focus for homotypic cell-cell interactions. The possibility that CD23 could serve as a co-stimulatory-adhesion molecule in antigen presentation by B lymphocytes is discussed with special reference to a potential role in the regulation of IgE synthesis.

Endogenous interleukin 6 plays an obligatory role in interleukin 4-dependent human IgE synthesis.

The lymphokine interleukin (IL) 4 plays a crucial role in the regulation of IgE synthesis. In the present study, the cellular and cytokine requirements for the IL4-dependent induction of IgE synthesis in humans were analyzed. Recombinant IL4 could induce IgE synthesis by peripheral blood mononuclear cells and autologous T/B cell mixtures, but not by highly purified B cells. IgE induction by IL4 was strongly decreased in monocyte-depleted peripheral blood mononuclear cells. These results show that the induction of IgE synthesis by recombinant IL4 is T cell dependent and optimal in the presence of monocytes. IL5 and IL6, but not IL2, IL1 and tumor necrosis factor-alpha, strongly up-regulated the IL4-dependent synthesis of IgE, with modest effects on cell proliferation. An anti-IL6 polyclonal antibody strongly inhibited IL4-driven IgE production. Endogenous IL6 plays, therefore, an obligatory role in the IL4-dependent induction of IgE. However, a combination of IL4, IL5 and IL6 (with or without IL1) at optimal concentrations could not induce IgE synthesis by purified normal B cells, indicating that cytokine-mediated signals, although essential, are not sufficient for the IL4-dependent induction of IgE synthesis.

Induction of Fc epsilon R2/CD23 on human epidermal Langerhans cells by human recombinant interleukin 4 and gamma interferon.

Human rIL-4 and human rIFN-gamma are able to induce the expression of the low affinity receptor for IgE (Fc epsilon R2/CD23) on normal human epidermal Langerhans cells, whereas IL-2 and PMA have no effect. A synergistic effect is observed when both cytokines are combined. These receptors are synthesized de novo by the LC since cycloheximide completely inhibits the appearance of Fc epsilon R2/CD23. Fc epsilon R2/CD23+ LC may have a major role in the pathogenesis of atopic eczema, as well as in the regulation of IgE synthesis.

Regulation of IgE Synthesis

The importance of FceR2/LgE-BF system on the IgE regulation has been clarified in both human as well as rodents. Recent cloning of human low affinity FceR (FceR2) will help us to clarify the dynamic regulatory mechanism of IgE regulation. The unique lectin-like molecular property of human FceR2 and its variable expression on hematopietic cell lineages including T, B lymphocytes, monocytes, and eosinophils may indicate the multiple functions of this receptor system.

Regulation of IgE synthesis in humans.

Regulation of IgE synthesis in humans.

New Perspectives in the Modulation of Allergic Inflammation

Studies on the regulation of IgE synthesis by IgE cellular receptors or fragments thereof, the so-called IgE-binding factors, are currently attracting much attention. Even more important may be some lymphokines such as interleukin 4 and interferon gamma which have been shown to have opposite influences on IgE synthesis, both in vitro and in vivo. However, the role of anti-isotypic anti-IgE antibodies, which have been shown to occur frequently during an IgE response, also deserves to be further investigated. At the effector level, namely the development of immediate and late allergic reactions following renewed encounter with allergen, new concepts such as variable releasability and priming of effector cells by lymphokines have opened new investigative pathways. Indeed, pretreatment of neutrophils by granulocyte/monocyte colony-stimulating factor or basophils by interleukin 3 appears essential for production or optimal release of inflammatory mediators such as histamine, leukotrienes, or platelet-activating factor. Even the successive impact of purified lymphokines such as interleukins 3 and 8 on basophils may suffice to initiate mediator release. These phenomena may explain, at the molecular level, the induction of a state of hyperreactivity characteristic of the late-phase allergic reaction. They also suggest new immunopharmacological approaches for the treatment of allergy.

IgE Response and Its Regulation in Allergic Diseases

The distinguishing feature of the allergic person is his or her elevation of serum IgE. This propensity to develop a sustained IgE response is determined genetically. The biologic effects of IgE are mediated via Fc receptors (Fc epsilon R) present on mast cells and basophils (Fc epsilon R type 1) and subpopulations of monocytes, macrophages, eosinophils, and platelets (Fc epsilon R type 2). Interaction of allergen with IgE on these cells results in receptor "bridging" and the release of histamine and other inflammatory mediators. Fc epsilon R type 2 on lymphocytes and monocytes are upregulated in atopic disease and may play a role in the allergic inflammatory reaction. The activation of B cells to synthesize IgE requires several stages (see Fig. 2). T cells play an important role in the regulation of IgE synthesis. In vitro activation of resting B cells to synthesize IgE requires direct cellular interaction with T cells or the presence of IL4 for activation. The latter effect is inhibited by alpha-interferon. Preactivated B cells are influenced in an isotype-specific manner by T-cell-derived IgE binding factors (IgE-BF), which may act as IgE-potentiating or IgE-suppressive factors, depending on their degree of glycosylation. The regulation of IgE synthesis is an important area of investigation. It provides us with an understanding of the basis of the human allergic response and ultimately may provide the basis for novel strategies in the treatment of allergic diseases.

IgE-binding factors: their possible role in the regulation of IgE synthesis.

B cell-derived IgE-BFs (sCD23) are cleavage fragments of surface Fc epsilon R II. Their production is increased by IL4 and suppressed by IFN-gamma and IFN-alpha. 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 Fc epsilon R II also display BCGF-like activity although the exact structure of these fragments is not yet identified. The cDNA coding for Fc epsilon R 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.

Regulation of IgE synthesis in atopic disease.

Regulation of IgE synthesis in atopic disease.

Properties of serine proteases of Schistosoma mansoni schistosomula involved in the regulation of IgE synthesis.

The regulation of IgE synthesis in vitro and in vivo by schistosomula-released products (SRP) has been shown to be dependent on the presence of serine proteases. The present paper concerns the characterization of the enzymes involved. The labelling of SRP with [3H]diisopropyl phosphofluoridate revealed two molecules, one major with an MW of 27,500 and one minor with an MW of 29,000. The same pattern was obtained by labelling of schistosomula or cercariae surfaces as well as of the total schistosomulum homogenate. The properties of these enzymes were studied by means of various specific substrates or inhibitors of serine proteases. The specificity was relatively narrow, but had some similarity with trypsin. When added to lymphoid rat cells in culture, SRP induced an increased expression of receptors for the Fc fragment of IgE (Fc epsilon RII). This suggests that the IgE-enhancing property of SRP was due to serine protease activity which may act by enhancing the lymphocyte Fc epsilon RII.