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IgE Response and Its Regulation in Allergic Diseases
Pediatric Allergic Disease
0031-3955/88 $0.00
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IgE Response and Its Regulation in Allergic Diseases
Bee Wah Lee, MD,* RaifS. Geha, MD,t and Donald Y. M. Leung, MD, PhDt.
Allergic diseases are among our most common health problems, affecting 12 to 20 per cent of the general population. In 1966, the Ishizakas 28. 29 demonstrated that the skin-sensitizing activity transmitted from the sera of patients with ragweed allergy was due to a distinct class of immunoglobulins designated IgE. Since then it has been established that the main characteristic of the allergic diathesis is the propensity to develop a sustained IgE response following antigenic stimulation. Serum IgE levels are elevated in 60 per cent of patients who suffer from allergic diseases,33 and children who have elevated serum IgE levels in the first year of life have a greater likelihood to develop allergic symptoms later in childhood than children with normal IgE levels. 38 The role of IgE in the pathogenesis of allergic diseases such as allergic rhinoconjunctivitis, allergic asthma, and atopic dermatitis has been well documented. 1, 23, 31 IgE mediates its effects by binding to mast cells, which bear high-affinity Fc receptors for IgE (Fc.R), Mast cells line the respiratory tract and mucosal surfaces and are present in the dermal layer of the skin, Interaction of allergen with IgE bound to mast cells at these anatomic locations results in the release of vasoactive mediators and the characteristic clinical symptoms of wheezing, itching, and sneezing. An understanding of the mechanisms that regulate IgE synthesis is essential for distinguishing the basic differences between allergic and nonallergic individuals. During the past 20 years, there has been substantial progress made in this field. This article focuses on current concepts in the mechanisms responsible for the regulation of IgE synthesis and briefly outlines the responses of IgE and the role of the Fc.R in allergic disease. *Fellow in Allergy, The Children's Hospital, Boston, Massachusetts tProfessor of Pediatrics, Harvard Medical School; Chief of Immunology Program, The Children's Hospital, Boston, Massachusetts :j:Associate Professor of Pediatrics, Harvard Medical School; Chief of Allergy, The Children's Hospital, Boston, Massachusetts
Pediatric Clinics of North America-Vol. 35, No.5, October 1988
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GENETIC DETERMINANTS OF THE IGE ANTmODY RESPONSE Serum IgE levels depend on genetic and environmental factors. Data from family and twin studies have shown that total serum IgE levels have a heritability of greater than 50 per cent.4 The mode of inheritance as yet is not established, but family studies suggest a great deal of genetic heterogeneity. Antigen-specific IgE antibody responses have been associated with certain HLA specificities. Population studies have demonstrated the association of the HLA-B8 antigen to rye-grass pollen sensitivity. 51 Higher levels of IgE frequently are found in atopic patients and family members who may be genetically predisposed to increased IgE production. It is worth noting, however, that a genetically predisposed person can develop an IgE response only after environmental exposure to the offending antigen. Finally, other stimuli such as parasitic or viral infections can induce elevation of serum IgE in normal nonatopic persons.
IGE RESPONSE IN ALLERGIC DISEASE An important feature of the allergic diathesis is a propensity to develop IgE antibody responses to a variety of environmental and food allergens. This tendency may be present in utero, since positive radioallergosorbent test (RAST) results to allergens have been reported even in cord blood. 55 Orgel has demonstrated that serum IgE levels taken at 1 year of age are predictive of the subsequent development of atopic symptoms by the age of 2 years. 58 In atopic dermatitis, serum IgE levels are elevated in about 80 per cent of patients,34 and most children have positive immediate skin test results and RAST directed to a whole spectrum of antigens. Sampson et al. 63 have shown that food hypersensitivity plays a pathogenic role in children with atopic dermatitis. In their study, more than 50 per cent of affected children experienced positive food challenges. Most patients manifested skin symptoms on positive challenge. There also was associated gastrointestinal and respiratory symptomatology in a smaller proportion of patients. Chronic rhinitis and bronchial asthma are a heterogeneous group of diseases with multiple etiologies. In the presence of elevated serum IgE levels, however, an allergic etiology is implicated. Total serum IgE levels are positively correlated with the duration, intensity, and multiplicity of allergic sensitivities. Patients with pollen allergies have been shown to have postseasonal rises in serum IgE. Following immunotherapy with the relevant allergen, there is a blunting of the postseason rise in serum IgE level. 49
CELLS BEARING Fe RECEPTORS FOR IGE Fc.R are present on various cell types and play an important role in the immune effector functions of these cells. These receptors may be classified into two categories by their distribution on various cell types and
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,<±l-Figure 1. Antigen-induced "bridging" of IgE receptors leads to the activation of membrane enzymes, increase in free intracellular Ca'+, and granule-associated release of histamine, (Key: ffi = stimulation; Ptd Ins-P, = phosphatidyl inositol 4,5-bisphosphate; DAG = 1,2 diacylglycerol; PKC = protein kinase C; IP 3 = inositol 1,4,5-trisphosphate,)
their affinity for IgK They are (1) Fc.R type 1, which are present on mast cells and basophils and have a high affinity for monomeric IgE; and (2) Fc.R type 2, which are low-affinity Fc.R present on subpopulations of lymphocytes,23, 77 monocytes,68 platelets,35 and eosinophik 9 IgE is a homocytotropic antibody that by definition is an antibody capable of interacting with target cells of the homologous species, such that these cells would release mediators on contact with specific antigen, IgE therefore mediates its effects by sensitization of mast cells and basophils via its binding to high-affinity Fc.R. Using E heavy-chain fragments, which have been cloned and synthesized in E, coli, it has been shown that fragments containing the CH 2 and CH 3 domains were able to inhibit the Praunitz-Kustner (P-K) reaction, This strongly suggests that the CH 2 and CH 3 region of the E heavy chain is involved in the binding of IgE to Fc.R type 1. 19 The Fab end of the IgE molecule is accessible for combining with antigen, On exposure to antigen, the binding of neighboring molecules of cell bound IgE results in the "bridging" of corresponding Fc.R (Fig, 1), The "bridging" of a few molecules of Fc.R is sufficient to activate the transmembrane enzyme phospholipase C, This enzyme hydrolyzes a distinct membrane-associated inositol phospholipid, resulting in the generation of diacylglycerol and inositol 1,4,5-trisphosphate, These two products act as second messengers in cell activation. These series of biochemical events culminate in the release of granule-associated histamine and other vasoactive mediators, and the generation of other mediators such as leukotrienes and platelet activating factor. 74
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The function(s) of the low-affinity Fc£R is not well understood. It is, however, known that the number of circulating monocytes and lymphocytes bearing Fc£R are abnormally elevated in patients with allergic disorders. 54. 77 Fc£R on monocytes,53 eosinophils,IO, 36, 37 and platelets 12 , 35 have been shown to be involved in the killing of IgE-coated targets such as helminthic parasites and the release of inflammatory mediators following ligand binding. In allergic asthma, the presence of allergen-specific IgE on alveolar macrophages and its activation by receptor bridging with bivalent antigen, results in the release of mediators that cause bronchospasm, and chemotactic factors that attract inflammatory cells. 15 This indicates that in addition to tissue mast cells, Fc£R-bearing alveolar macrophages also may play an important role in the pathogenesis of asthma. Similarly, in atopic dermatitis, the presence of IgE on macrophages and dendritic cells infiltrating into skin lesions has been demonstrated. 6, +4 These cells would therefore be potentially capable of inflammatory mediator release on interaction with allergen. T lymphocytes that bear Fc£R have been shown to secrete factors that enhance IgE synthesis in an isotype specific manner. 80 The biologic significance of Fc£R on B lymphocytes is still uncertain. It has been shown to be upregulated by the T cell-derived lymphokine interleukin 4.78 A 28 kilodalton fragment of the Fc£R on Epstein-Barr virus-transformed B cell line is spontaneously cleaved and shed into culture supernatants. This moiety has recently been shown to a~t as a growth factor for Epstein-Barrinfected B lymphoblasts, and anti-mu-stimulated normal B lymphocytes, suggesting a role in autocrine B cell growth. 69 These findings suggest that the IgE antibody can interact with a variety of Fc£R + immune effector cells to generate hypersensitivity reactions. At present, much of our pharmacologic management of allergic diseases is focused on controlling the symptoms that result from the release of mediators from these immune effector cells. 59 The development of any fundamental changes in the treatment of allergic diseases will require a clear understanding of the mechanisms that regulate the human IgE response. IGE SYNTHESIS AND ITS REGULATION Our current understanding of the regulation of IgE synthesis has been derived from (1) research in experimental animals, especially the rat and mouse models, (2) human in vitro lymphocyte model systems, and (3) the study of human diseases associated with elevations of IgE. These diseases include the hyper-IgE syndrome, a disease characterized by extremely elevated serum IgE, recurrent serious infections, and chronic pruritic dermatitis; severe atopic dermatitis, and acute graft-versus-host (GVH) diseases. In this section, discussion of IgE synthesis and its regulation will be made with reference to these areas of research. B Cell Differentiation and Immunoglobulin Class Switching Immunoglobulins have a four-chain structure comprised of two heavy and two light chains. Isotypic variation in immunoglobulins is determined
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by heavy chains j.L, 8, ,,{, E, and a. Bone marrow stem cells undergo a series of maturational steps to develop into B cells committed to production of Igs of a specific isotype. The maturational process of B cells may be defined in five different cellular stages. 67 Stage I represents immature B cells. These cells express IgM on their cell surface. Stages II and III correspond to the two stages of resting B cells. These cells carry two isotypes on their cell surfaces. In stage II, B cells carry IgM and IgD, and in stage III the cell surface immunoglobulin isotypes are IgM and IgE (lgG or IgA). Stage IV is the stage of the activated B cell. These cells express only IgE (lgG, 19A, IgM, or IgD) on their cell surface. The final stage (V) of B cell maturation involves stimulation of transcription, and corresponds to a plasma cell that secretes IgE, IgG, 19A, IgM, or IgD. All the above stages are known to occur in vivo. Stage II may not be obligatory. Theoretically, the pathways in stages I through II and II through III involve gene splicing and are reversible. The step involving stage III through IV is a phenomenon known as class switching and involves irreversible deletion of the constant heavy chain genes. T cells may have regulatory effects between stages III through IV, and IV through V. Evidence for the role of T Cells in the Regulation of IgE Synthesis The induction of antibody synthesis to most protein antigens requires the collaboration of B and T lymphocytes. This principle also applies to IgE antibody formation. Early evidence for the requirement of T lymphocytes in the regulation of IgE synthesis came from the observations that neonatally thymectomized rats 57 and congenitally athymic nude mice 32 were unable to generate IgE antibody. Furthermore, this defect could be corrected by the infusion of normal thymocytes. Subsequent studies on rodents demonstrated that IgE was regulated by two distinct T cell subpopulations: helper/inducer T cells, which induce and enhance IgE synthesis, and suppressor T cells, which inhibit IgE synthesis. 70. 71 In these studies, the elimination of suppressor T lymphocytes by use of irradiation or cyclophosphamide therapy converted rats from their usual pattern of low-level IgE production to patterns of sustained IgE synthesis. This enhanced IgE response could be terminated by passive transfer of syngeneic thymocytes or spleen cells. These observations provide direct evidence that the low levels of IgE response in untreated rats reflect the dominance of a suppressor T cell regulatory control mechanism that normally serves to minimize antibody production in this Ig class. In humans, evidence that IgE production is subject to T cell regulation is based on the frequent observation of increased serum IgE levels in patients with primary immunodeficiency disorders.7 Patients with WiskottAldrich, ataxia telangiectasia, Nezelof, and DiGeorge syndromes have been reported to have increased levels of serum IgE. It has been postulated that such patients have sufficient number of helper/inducer T cells for the initiation ofIgE antibody synthesis, but an inadequate number of suppressor T cells to inhibit IgE synthesis, resulting in increased IgE production. Several diseases associated with decreased number and function of suppressor T cells have been found to be accompanied by extremely high serum IgE levels. These diseases include the hyper-IgE syndrome20 ; severe
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atopic dermatitis, in which a direct correlation between the decreased number of suppressor T cells and elevation of serum IgE has been foundS, 43, 75; and acute graft versus host disease, 21, 60 From these observations, we may therefore infer that the elevation of IgE levels in the atopic person could result from a decrease in numbers or function of suppressor T cells, In Vitro Synthesis of IgE by Cultured Human Lymphocytes Unlike research on the animal model, in vivo experimentation in humans is not possible. In vitro experiments of IgE synthesis by cultured peripheral blood mononuclear cells (PBMC) has therefore provided us with the greater part of our understanding of the regulation of human IgE synthesis. The study of in vitro human IgE synthesis has been fraught with problems. The amounts of IgE secreted in culture are extremely low (pg to ng per ml range) 103 to 106 times less than the amounts of IgG secreted. In addition, preformed IgE bound to cell membranes of basophils, monocytes, and T and B cells has to be accurately determined and subtracted from the total IgE measured in culture. The use of highly specific monoclonal antibodies to the Fc portion of IgE in the IgE radioimmunoassay has minimized cross-reactivity with IgG. To overcome the problem of preformed IgE bound to cell membranes, techniques such as treatment of cells with protein synthesis inhibitors like cyclohexamide, freeze-thawing of cells, and acid treatment all have been used to assess background IgE secretion. 72 Numerous investigators have reported that PBMC of atopic patients as well as those with diseases characterized by elevated serum IgE levels spontaneously synthesized abnormally large amounts of IgE in vitro, whereas cells from nonatopic donors failed to synthesize detectable levels of IgE. 16. 25. 62. 64, 66 This increase in secretion of IgE was isotype restricted because concurrent IgG secretion was not increased. 20. 64 To examine the role of suppressor T cells in atopic persons more directly, several laboratories have studied the effects of normal T cells on in vitro IgE production by cultured PBMC from patients with severe atopic dermatitis or the hyper-IgE syndrome. Unfractionated T cells from haploidentical or histoincompatible normal T cells suppressed spontaneous de novo IgE production by cultured PBM C from atopic donors. 20. 25, 62, 66 Since patients with hyper-IgE syndrome have a deficiency of circulating Ts + cells, Geha et al. 20 investigated the effects of normal Ts + suppressor/ cytotoxic T cells and T4 + helper/inducer T cells on IgE synthesis by PBMC from these patients, and found that spontaneous de novo IgE synthesis by cultured PBMC from their patients could be suppressed by Ts + T cells but not T4 + T cells from nonatopic parents, Because, however, allogeneic interaction can generate IgE-specific suppressor factors, S1 the possibility that results from such co-culture studies were the result of allogeneic effects could not be excluded, In this regard, we have observed that abnormally elevated IgE synthesis by cultured PBMC from patients with acute GVH could be suppressed by Ts + cells from normal histoidentical siblings. 65 Furthermore, T cells from patients who have recovered from acute GVH disease could effectively suppress IgE synthesis by thawed autologous
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cultured PBMC that had been cryopreserved during acute GVH. More recently, Hemady et al. 26 have demonstrated that T cells from patients with atopic dermatitis were not as effective as T cells from normal controls in their capacity to suppress IgE synthesis by HLA-identical B cells. These results support the hypothesis that the increased production of IgE in severe atopic dermatitis, acute GVH disease, and hyper-IgE syndrome is due in part to a relative deficiency of suppressor T cells. Further in vitro experiments on cultured PBMC have been aimed at studying model systems that could induce or augment IgE synthesis in B cells from nonatopic and atopic subjects respectively. Unlike other isotypes, IgE synthesis is not induced by classic polyclonal activators such as pokeweed mitogen, Staphylococcus aureus (Cowan strain), or anti-mu reagents. 16, 25, 62, 66 This failure to induce IgE synthesis in vitro may relate to the enhanced sensitivity of IgE synthesis to suppressor influences exerted by T cells present among the bulk T-cell population. With the use of helper T-cell clones, the differential requirements for induction of IgE synthesis in B cells from normal and atopic donors have been examined. In this system, B cells may be stimulated via two separate pathways: (1) by cognate interaction between T and B cells, in which the helper Tcell clone recognizes an alloantigen directly on the surface of the B cell; and (2) by "factor dependent stimulation," in which the helper T-cell clone is stimulated by the appropriate monocytes and soluble T-cell products act on the B cells, which act as bystander cells in culture. Using this system, it has been found that normal B cells differ from those of atopic persons in that they require cognate interaction with T-cell clones for the induction of IgE synthesis. In contrast, B cells from atopic persons that spontaneously secrete IgE in vitro can have their IgE secretion augmented both under conditions of cognate interaction with T cells or when they are present as bystander cells in culture. 73 These results suggest that allergic persons have B cells activated in vivo towards IgE secretion and are more sensitive to soluble helper signals from T cells. Cognate T and B cell interactions studied in this in vitro model system may be important in the development of IgE immune responses in the normal host. Alloreactive T cells could underlie the elevation of IgE synthesis during acute GVH disease. 21 It is, however, unlikely that alloreactive T cells playa role in the activation of IgE synthesis in other human diseases. In the murine system, the generation of autoreactive T-cell clones following antigen stimulation has been well documented. 22 We have examined the capacity of autoreactive T-cell clones derived during tetanus toxoid antigen activation of T cells from a nonatopic donor to induce IgE synthesis. Under conditions of cognate stimulation, autoreactive T cell clones were capable of inducing normal B cells to synthesize IgE and IgG.46 Hence autoreactive T cells may contribute to the polyclonal B cell activation, which occurs in diseases characterized by intense antigenic stimulation. 2, 45 The presence of elevated serum IgE levels in the acute phase of some of these diseases, such as the Kawasaki syndrome39 and systemic lupus erythematosus,61 may reflect increased IgE production from such immunologic interactions. In atopic patients, it is possible that sustained antigen stimulation leads to the generation of autoreactive T cells, which, in the
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Table 1. Properties of Human IgE Binding Factors
Molecular weight (kd) Affinity for IgE Affinity for IgG Sensitivity to trypsin Sensitivity to neuraminidase Affinity for lentil lectin Affinity for concanavalin A Affinity for peanut agglutinin
IgE POTENTIATING
IgE SUPPRESSIVE
FACTOR
FACTOR
15;60
15;30;60
+
+
+ +
+
+ +
absence of effective IgE specific suppressors 20 , polyclonal IgE response,
+
26
leads to a sustained
IgE Binding Factors Once B cells are activated to enter the pathway of IgE secretion, IgE synthesis is modulated by T-cell derived factors that have specificity for IgE. These isotype-specific factors have been well characterized in the rodent models as IgE binding factors (IgE BF) and can exert either potentiating or suppressor influences. 2~, 30, 76 These factors have been shown to have a common peptide backbone and their biologic activities determined by a post-translational glycosylation process, 52 The IgE potentiating factor is highly glycosylated, containing an N-linked, mannose-rich oligosaccharide, The IgE suppressive factor is poorly glycosylated, containing an 0linked oligosaccharide with terminal sugar of galactose N -acetylgalactosamine. 76 Under physiologic conditions, the natural and biologic activities of IgE BF are controlled by another two T-cell-derived factors: glycosylation enhancing factor (GEF), and glycosylation inhibiting factor (GIF). These factors enhance or inhibit the N-glycosylation of IgE BF during their biosynthesis. 27 In humans, it has been shown that a subset of human T lymphocytes produces IgE BF. 30, 52, 76 Fc.R + human T cell lines derived from patients with the hyper-IgE syndrome constitutively secrete IgE potentiating factors and enhance IgE but not IgG synthesis by B cells of patients with allergic rhinitis. 80 Physiochemical properties of human IgE BF from these T cell lines have been shown to be similar to those of rodent IgE BF79 and are summarized in Table L Serum from normal nonallergic persons contains low molecular weight IgE binding factors that suppress IgE production. 40 In contrast, a low molecular weight IgE enhancing factor(s) can be detected in the sera of patients with the hyper-IgE syndrome. 42 Plasmapheresis of these patients and replacement with normal serum have resulted in decreased rates of IgE synthesis by their peripheral blood lymphocytes. 40, 41 Experiments with alloreactive T-cell clones have shown that normal resting B cells first have to be activated by certain T-cell clones before they can respond to the IgE potentiating factorY In contrast, B cells from symptomatic atopic patients are able to respond directly to human IgE
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potentiating factor(s) with increased IgE secretion. This suggests that B cells need to reach a certain stage of activation before responding to the IgE potentiating factor. . Role of Interleukin-4 (IL4) and Gamma ("Y) Interferon in IgE Synthesis In recent studies ~n the murine model, helper T cells have been characterized into two subsets according to their pattern of lymphokine production. Type 1 T-helper cells (TH 1) produce interleukin 2 (IL2), "Yinterferon, granulocyte-myelocyte colony stimulating factor, and IL3 in response to antigen presenting cells; and type 2 helper cells (TH 2) produce IL3, IL4, a mast cell growth factor, and a T-cell growth factor distipct from IL2.56 Culture supernatants from TH2 clones have been shown to enhance a lOO-fold increase in IgE production by lipopolysaccharide (LPS)-stimulated B cells. There was a concomitant 10- to IS-fold increase in IgGI and IgA. The enhancement of both IgE and IgA could be completely inhibited by relatively low concentrations of "Y-interferon.13 Furthermore, highly purified IL4 enhanced IgE production to the same extent as the TH2 clone supernatants, and its effect was totally inhibited by a monoclonal antibody directed against IL4.14 Preliminary studies performed in our laboratory using culture supernatant from a human TH2-like clone that contains IL4, very little "Y-interferon, and no IL2 activity, suggest that it could directly activate B cells from normal persons to synthesize IgE. This increase in IgE synthesis could be completely inhibited by "Y-interferon. These findings raise the possibility that some persons with a propensity to high IgE levels may have an imbalance between IL4 and "Y-interferon synthesis. The current models of the human B cell IgE response therefore propose that resting B cells have to undergo a series of stages in cell~lar activation prior to differentiation to IgE-secreting plasma cells. From experimental results discussed in the above sections, the proposed sequential requirements for the activation of human IgE antibody resp,onse may be summarized in Figure 2.
ANTIGEN-SPECIFIC REGULATION OF IcE ANTIBODIES Role of Anti-idiotypic (Id) Antibodies Idiotypic (I d) antibodies are antibodies that arise from the heterogeneity of the variable domain of the immunoglobulin molecule. These antiboqies can be immunogenic in genetically identical persons, including the individual patient himself, thus giving rise to anti-Id antibodies. There is evid~nce from both animal studies 3 and in vitro human experiments 17 that IgG anti-Id antibodies playa role in the inhibition of antigen-specific IgE responses. Because complexes of antigen and Id antibodies are particularly immunogenic, repeated immunization with antigen appears to be conducive to the production of auto-anti-Id antibodies. 18 Allergic diseases involve repeated stimulation by antigens either naturally or in the course of immunotherapy. Thus, the presence of auto-anti-Id antibodies to allergen-
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j
Cognate interaction
potentiatin~lgE B~F factor
Suppressor factor
R~t-IIE-@Activated IgE bearing B cell
IgE
-< -< -< -< IgE plasma cell
{;'\ Cognate \ - - - - - - - - - ~ --"'"in-te..;r'""a-c"""'ti-on----t
t
IL-4
I
e
~
Y Interferon
<
e
Figure 2 Sequential requirements for the in vitro activation of the human IgE antibody response. Resting B cells are activated by T-B cognate stimulation or the type 2 helper T cell (TH-2) derived lymphokine interleukin 4 (IL-4). The latter effect is inhibited (--) by Type 1 helper T cell (TH-l) derived ,(-interferon. T cell-derived IgE binding factors (IgE-BF) act on activated IgE-bearing B cells to potentiate or suppress (--) further differentiation into IgEsecreting plasma cells.
specific antibodies in humans would be expected. Auto-anti-Id antibodies have been described in isolated allergic patients receiving immunotherapy. 5 In a larger series, Castrane et al,u reported the presence of auto-anti-Id to ragweed antibodies in normal subjects and to a lesser extent in untreated allergic subjects. Furthermore, the level of auto-anti-Id antibodies appeared to go up to normal range in subjects treated with immunotherapy. These results suggest that the decreased production of auto-anti-Id antibody in allergic subjects allows the escape of IgE antibody synthesis from immunoregulatory influences. Other Factors Affecting Antigen-Specific IgE Formation Extraneous factors that playa role in suppressing antigen-specific IgE formation are chemical modifications of the antigen, the dose, and the route of administration of the antigen. The list of chemical modifications include polymerization (e.g., glutaraldehyde treatment of antigen), urea denaturation, binding to tolerogenic carriers (e.g., polY-D-glutamyllysine), and substitution by formaldehyde, acetoacetyl groups, or polyethylene
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glycol. It must be acknowledged, however, that although such manipulations are effective in primary and secondary IgE responses, they may be less effective in late established ones. Such chemical modifications of antigen have been used to improve the efficacy of allergen immunotherapy. Polymerization of ragweed pollen antigen using glutaraldehyde reduces allergenicity but retains the immunogenicity of the antigen. A double-blind placebo-controlled trial of immunotherapy with polymerized ragweed antigen showed that this preparation was safe and efficacious. 24 In this study, patients who received polymerized ragweed antigen had 50 per cent lower symptom scores than did controls receiving either no therapy or a histamine placebo. In experimental animals, large doses of antigen have been found to be IgE suppressive, and the intravenous route is more conducive to suppression than subcutaneous, intradermal, or intramuscular administration. In high responder strains of mice, repeated exposure to low doses of an antigen favors the production of IgE over IgG. This suggests that the threshold of antigen alone for IgE production is lower than for IgG.4B Similarly, in the atopic patient with the propensity to develop a sustained IgE response following antigenic stimulation, exposure to antigens in low doses appears to favor an antigen-specific IgE response. Hence, in ragweed pollenallergic persons, the IgE response to this antigen may be induced by chronic low dose exposure during the pollen season. During a typical ragweed season, the average patient is exposed to less than 1 f,Lg of the predominant ragweed allergens, antigen E. 50 These observations emphasize the importance of environmental factors on the IgE response. The failure of normal persons to develop a sustained antigen-specific IgE response on exposure to similar environmental factors presumably results from dominating IgE suppressive influences.
SUMMARY 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.R) present on mast· cells and basophils (Fc.R type 1) and subpopulations of monocytes, macrophages, eosinophils, and platelets (Fc.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.R type 2 on lymphocytes and monocytes are upregulated in atopic disease and may playa 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 a-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
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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.
ABBREVIATIONS Fc.R, Fc receptor for IgE GEF, Glycosylation enhancing factor GIF, Glycosylation inhibiting factor -y-IFN, Gamma interferon GVH, Graft versus host disease Id, Idiotype Ig, Immunoglobulin IgE BF, IgE binding factors IL2, Interleukin-2 IL4, Interleukin-4 LPS, Lipopolysaccharide PBMC, Peripheral blood mononuclear cells RAST, Radioallergosorbent test TH 1 , Type 1 helper cells TH 2 , Type 2 helper cells ACKNOWLEDGMENTS We wish to thank Mrs. Adrienne B. Sisco and Tony Bonjorno for excellent secretarial assistance in the preparation of this article. Supported by USPHS Grants AI-22058, AI-20373, and HL-37260.
REFERENCES 1. Berg T, Johansson SGO: IgE concentrations in children with atopic diseases. Int Arch Allergy Appl Immunol 36:219, 1969 2. Blaese RM,' Grayson J, Steinberg AD: Increased immunoglobulil). secreting cells in patients with active systemic lupus enythematosus. Am J Med 69:345, 1980 3. Blaser K, Nakagawa T, DeWeek AL: Suppression of the benzyl penicilloyl (BPO)-specific IgE formation with isologous anti-idiotypic antibodies in BALB/c mice. J Immunol 125:24, 1980 4. Blumenthal MN, Yunis E, Mendall N et al: Preventive allergy: Genetics ofIgE-mediated diseases. J Allergy Clin Immunol 78:962, 1986 5. Bose R, Marsh DG, Duchateau JS et al: Demonstration of auto-anti-idiotypic antibody cross-reacting with public idiotypic determinants in the serum of rye-sensitive allergic patients. J ImmunoI133:2474, 1984 6. Bruynzeel-Koomen C, Wichen DF, Toonstra J et aI: The presence of IgE molecules on epidermal Langerhans cells in Patients with Atopic Dermatitis. Arch Dermatol Res 278:199, 1986 7. Buckley RH, Fisus SA: Serum IgD and IgE concentration in immunodeficiency diseases. J Clin Invest 55:157, 1975 8. Butler M, Atherton D, Levinsky RJ: Quantitative and functional deficit of suppressor T cells in children with atopic eczema. Clin Exp Immunol 50:92, 1982
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9. Capron M, Capron A, Dessaint JP et al: Fc receptors for IgE in human and rat eosinophils. J Immunol 126:2087, 1981 10. Capron M, Speigelberg HL, Prin L et al: Role of IgE receptors in effector function of human eosinophil. J Immunol 132:462, 1984 11. Castrane JM, Hall JT, Rocklin RE: Generation of anti-idiotypic antibodies in ragweed sensitive patients undergoing specific immunotherapy. Clin Res 33:608A, 1985 12. Cines DB, Van der Keyl H, Levinson AI: In vitro binding of an IgE protein to human platelets. J Immunol 136:3433, 1986 13. Coffman RL, Carty J: A T cell activity that enhances polyclonal IgE production and its inhibition by interferon--y. J ImmunoI136:949, 1986 14. Coffman RL, Ohara J, Bond MW et al: B cell stimulatory factor-l enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol 136:4538, 1986 15. Dessaint JP, Torpier G, Capron M et al: Cytophilic binding of IgE to the macrophage. Cell Immunol 46:12, 1979 16. Fiser PM, Buckley RH: Human IgE biosynthesis in vitro: Studies with atopic and normal blood mononuclear cells and subpopulations. J Immunol 123: 1788, 1979 17. Geha RS: Detection of autoantiidiotypic antibody during the normal human immune response to tetanus toxoid antigen. J Immunol 129:139, 1982 18. Geha RS: Idiotypic interactions in the treatment of human diseases. Adv ImmunoI39:255, 1986 19. Geha RS, Helm B, Wood N et al: IgE sites relevant for binding type 1 Fc Epsilon (Fc,R) Receptors on mast cells. J Allergy Clin Immunol 79:129 abstr 20, 1987 20. Geha RS, Reinherz EL, Leung DYM et al: Deficiency of suppressor T cells in the hyperimmunoglobulinemia E syndrome. J Clin Invest 68:783, 1981 21. Geha RS, Twarog F, Rappaport J et al: Increased serum IgE levels following allogeneic bone marrow transplantation. J Allergy Clin Immunol 66:78, 1980 22. Glimcher LH, Shevach EM: Production of autoreactive I-region restricted T cell hybridomas. J Exp Med 156:640, 1982 23. Gonzalez-Molina A, Spiegelberg HL: A subpopulation of normal human peripheral B lymphocytes that bind IgE. J Clin Invest 59:616, 1977 24. Grammer LC, Zeiss CR, Suszko 1M et al: A double-blind, placebo controlled trial of polymerized whole ragweed for immunotherapy of ragweed allergy. J Allergy Clin Immunol 69:494, 1982 25. Hemady Z, Blomberg F, Gellis S et al: IgE production in vitro by human blood mononuclear cells: A comparison between atopic and non-atopic subjects. J Allergy Clin Immunol 71:324, 1983 26. Hemady Z, Gellis S, Chambers M et al: Abnormal regulation of in vitro IgE synthesis by T cells obtained from patients with atopic dermatitis. Clin Immunol Immunopathol 35:156, 1985 27. Ishizaka K: Regulation of IgE synthesis. Annu Rev Immunol 2:159, 1984 28. Ishizaka K, Ishizaka T, Hornbrook M: Physio-chemical properties of human reaginIc antibody IV. Presence of unique immunoglobulin as a carrier of reaginic activity. J Immunol 97:75, 1966 29. Ishizaka K, Ishizaka T, Hornbrook M: 'Physio-chemical properties of human reaginic antibody V. Correlation of reaginic activity with E-globulin antibody. J Immunol 97:840, 1966 30. Ishizaka K, Suemura M, Yodoi J, et al: Regulation ofIgE response by IgE binding factors. Fed Proc 40:58, 1981 31. Ishizaka T, Ishizaka K: Activation of mast cells for mediator release through IgE receptors. Progr Allergy 34:188, 1984 32. Ito K, Ogita T, Suko M et al: IgE levels in nude mice. Int Arch Allergy Appl Immun. 58:474, 1979 33. Johansson SGO: Radioimmunoassay of IgE and IgE antibody and its clinical application. In Symposium on Disorders of Protein Metabolism. J Clin Pathol 23 (Suppl):33, 1975 34. Johnson EE, Irons JJ, Patterson Ret al: Serum IgE concentration in atopic dermatitis. J Allergy Clin Immunol 54:94, 1974 35. Joseph M, Auriault C, Capron A et al: A new function for platelets: IgE dependent killing of schistosomes. Nature 303:810, 1983 36. Joseph M, Tonnel AB, Capron A et al: Enzyme release and superoxide anion production
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45. 46. 47.
48.
49. 50. 51. 52. 53. 54. 55.
56.
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by human and alveolar macrophages stimulated with immunoglobulin E. Clin Exp Immunol 40:416, 1980 Khalife J, Capron M, Cesbron JY et al: Role of specific IgE antibodies in peroxidase (EPO) release from human eosinophils. J ImmunoI137:1659, 1986 Kjellman NIM: Predictive value of high IgE levels in children. Acta Paediatr Scand 65:465, 1976 Kusakawa S, Heiner DC: Elevated immunoglobulin E in the acute febrile mucocutaneous lymph node syndrome. Pediatr Res 10:108, 1976 Leung DYM, Brozek C, Frankel R et al: IgE specific suppressor factors in normal human serum. Clin Immunol Immunopathol 32:339, 1984 Leung DYM, Brozek L, Frankel Ret al: IgE specific suppressor factors in normal human serum: In vitro and in vivo effects. Clin Res 31:164A, 1983 Leung DYM, Frankel R, Brozek C et al: The biological activity of IgE binding factors in human sera. J Allergy Clin Immunol 73:176, 1984 Leung DYM, Rhodes AR, Geha RS: Enumeration of T cell subsets in atopic dermatitis using monoclonal antibodies. J Allergy Clin Immunol 67:450, 1981 Leung DYM, Schneeberger EE, Siraganian RP et al: The presence ofIgE on macrophages and dendritic cells infiltrating into the skin lesion of atopic dermatitis. Clin Immunol Immunopathol 42:328, 1987 Leung DYM, Siegel RL, Grady S et al: Immunoregulatory abnormalities in mucocutaneous lymph node syndrome. Clin Immunol ImmunopathoI23:100, 1982 Leung DYM, Young MC, Geha RS: Induction ofIgG and IgE synthesis in normal B cells by autoreactive T cell clones. J Immunol 136:2851, 1986 Leung DYM, Young MC, Wood N et al: Induction of IgE synthesis in normal human B cells: Sequential requirements for activation by an alloreactive T cell clone and IgE potentiating factors(s). J Exp Med 163:713, 1986 Levine BB, Vaz NM: Effect of combinations of inbred strain, antigen and antigen dose on immune responsiveness and reagin production in the mouse. Int Arch Allergy Appl Immunol 39:156, 1970 Lichtenstein LM, Ishizaka K, Norman PS et al: IgE antibody measurements in ragweed hayfever: Relationship to clinical severity and the results of immunotherapy. J Clin Invest 52:472, 1973 Marsh DG: Allergens and the Genetics of Allergy. The Antigens, Vol 3. New York, Academic Press, 1975, p 271 Marsh DG, Meyers DA, Freidhoff IR et al: Association of HLA phenotypes AI> Bg, DW3 , and A3 , B7 , DW2 with allergy. Int Arch Allergy Appl Immunol 66 (Suppl 1):48, 1981 Martens CL, Jardieu P, Trounstine ML et al: Potentiating and suppressor factors are expressed by a single cloned gene. Proc Nat! Acad Sci USA 84:809, 1987 Melewics FM, Speigelberg HL: Fc receptors for IgE in a subpopulation of human blood monocytes. J Immunol 125:1026, 1980 Melewicz FM, Zeiger RS, Mellon MH et al: Increased peripheral blood monocytes with Fc receptors for IgE in patients with severe allergic disorders. J Immunol 126:1592, 1981 Michael FB, Bousquet J, Greillier P et al: Comparison of cord blood immunoglobulin E concentrations and maternal allergy for the prediction of atopic diseases in infancy. J Allergy Clin Immunol 65:422, 1980 Mosmann TR, Chewinski H, Bond MW et al: Two types of murine helper T cell clone: 1. Definition according to profiles of Iymphokine activities and secreted proteins. J Immunol 136:2348, 1986 Okurmura K, Tada T: Regulation of homocytotropic antibody formation in the rat. III. Effect of thymectomy and splenectomy. J Immunol 106:1019, 1971 Orgel HA: Genetic and developmental aspects ofIgE. Pediatr Clin North Am 22:17, 1975 Rasmussen JE: Recent developments in the management of patients with atopic dermatitis. J Allergy Clin Immunol 74:771, 1985 Reinherz EL, Parkman R, Rappaport J et al: Aberrations of suppressor T cells in human graft versus host disease. N Engl J Med 300:1061, 1979 Rebhun J, Quismono F, Dubois E et al: Systemic lupus erythematosus activity and IgE. Ann Allergy 50:34, 1983 Romagnani S, Del Prete GF, Maggi E et al: In vitro production of IgE by human peripheral blood mononuclear cells. Clin Exp Immunol 42:579, 1980
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63. Sampson HA, McCaskill CC: Food hypersensitivity and atopic dermatitis: Evaluation of 113 patients. J Paediatr 107:669, 1985 64. Saryan JA, Leung DYM, Ceha RS: Induction of human IgE synthesis by a factor derived from T cells of patients with hyper IgE states. J Immunol 130:242, 1983 65. Saryan JA, Rappaport J, Leung DYM et al: Regulation of human IgE synthesis in acute graft vs host disease. J Clin Invest 71 :558, 1983 66. Saxon A, Morrow L, Steven RH: Subpopulations of circulating B cells and regulation T cells involved in in vitro immunoglobulin E production in atopic patients with elevated serum immunoglobulin E. J Clin Invest 65:1457, 1980 67. Shimizu A, Honjo T: Immunoglobulin class switching. Cell 36:801, 1984 68. Speigelberg HL: Structure and function ofFc receptors for IgE in lymphocytes, monocytes and macrophages. Adv Immunol 35:61, 1984 69. Swendeman S, Thorley-Lawson DA: The activation antigen BLAST-2, when shed, is an autocrine BCCF for normal and transformed B cells. EMBO J 6:1637, 1987 70. Tada T, Taniguchi M, Okumura K: Regulation of homocytotropic antibody formation in the rat. II: Effect of X irradiation. J Immunoll06:1012, 1971 71. Taniguchi M, Tada T: Regulation of homocytotropic antibody formation in the rat. IV. Effects of various immunosuppressive drugs. J Immunol107:579, 1971 72. Turner KJ, Holt PC, Holt BJ et al: In vitro synthesis of IgE by human peripheral blood leucocytes. III. Release of preformed antibody. Clin Exp Immunol 51:387, 1983 73. Umetsu DT, Leung DYM, Siraganian Ret al: Differential requirements of B cells from normal and allergic subjects for the induction of IgE synthesis by an alloreactive T cell clone. J Exp Med 162:202, 1985 74. White JR, Pluznik DH, Ishizaka K et al: Antigen-induced increase in protein kinase C activity in plasma membrane of mast cells. Proc Natl Acad Sci USA 82:8193, 1985 75. Willemze R, DeCraaff-Reitsma CB, Crossen J et al: Characterization of T cell subpopulations in skin and peripheral blood of patients with cutaneous T cell lymphoma and benign inflammatory dermatoses. J Invest Dermatol 80:60, 1983 76. Yodoi J, Hirashima M, Ishizaka K: Regulatory role of IgE binding factors from rat T lymphocytes. The carbohydrate moeities in IgE-potentiating factors and IgE-suppressive factors. J Immunol 128:289, 1982 77. Yodoi J, Ishizaka K: Lymphocytes with Fce receptors for IgE. I. Presence of human and rat lymphocytes with Fee receptors. J ImmunoI122:2577, 1979 78. Yokata T, Otsuka T, Mosmann T et al: Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B cell stimulatory factor,-1 that expresses B cell and T cell stimulating activation. Proc Natl Acad Sci USA 83:5894, 1986 79. Young MC, Ceha RS, Maksad KN et al: Characterization of human T cell derived IgE potentiating factor. Eur J ImmunoI16:985, 1986 80. Young MC, Leung DYM, Ceha RS: Production of IgE potentiating factor in man by T cell lines bearing Fc receptors f<,lr IgE. Eur J ImmunoI14:871, 1984 81. Zuraw BL, Nonaka M, O'Hair C et al: Human IgE antibody synthesis in vitro: Stimulation of IgE responses by pokeweed mitogen and selective inhibition of such responses by human suppressive factor of allergy (SFA). J ImmunoI127:1169, 1981 Division of Allergy The Children's Hospital 300 Longwood Avenue Boston, Massachusetts 02116
0031-3955/88 $0.00
+ .20
IgE Response and Its Regulation in Allergic Diseases
Bee Wah Lee, MD,* RaifS. Geha, MD,t and Donald Y. M. Leung, MD, PhDt.
Allergic diseases are among our most common health problems, affecting 12 to 20 per cent of the general population. In 1966, the Ishizakas 28. 29 demonstrated that the skin-sensitizing activity transmitted from the sera of patients with ragweed allergy was due to a distinct class of immunoglobulins designated IgE. Since then it has been established that the main characteristic of the allergic diathesis is the propensity to develop a sustained IgE response following antigenic stimulation. Serum IgE levels are elevated in 60 per cent of patients who suffer from allergic diseases,33 and children who have elevated serum IgE levels in the first year of life have a greater likelihood to develop allergic symptoms later in childhood than children with normal IgE levels. 38 The role of IgE in the pathogenesis of allergic diseases such as allergic rhinoconjunctivitis, allergic asthma, and atopic dermatitis has been well documented. 1, 23, 31 IgE mediates its effects by binding to mast cells, which bear high-affinity Fc receptors for IgE (Fc.R), Mast cells line the respiratory tract and mucosal surfaces and are present in the dermal layer of the skin, Interaction of allergen with IgE bound to mast cells at these anatomic locations results in the release of vasoactive mediators and the characteristic clinical symptoms of wheezing, itching, and sneezing. An understanding of the mechanisms that regulate IgE synthesis is essential for distinguishing the basic differences between allergic and nonallergic individuals. During the past 20 years, there has been substantial progress made in this field. This article focuses on current concepts in the mechanisms responsible for the regulation of IgE synthesis and briefly outlines the responses of IgE and the role of the Fc.R in allergic disease. *Fellow in Allergy, The Children's Hospital, Boston, Massachusetts tProfessor of Pediatrics, Harvard Medical School; Chief of Immunology Program, The Children's Hospital, Boston, Massachusetts :j:Associate Professor of Pediatrics, Harvard Medical School; Chief of Allergy, The Children's Hospital, Boston, Massachusetts
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GENETIC DETERMINANTS OF THE IGE ANTmODY RESPONSE Serum IgE levels depend on genetic and environmental factors. Data from family and twin studies have shown that total serum IgE levels have a heritability of greater than 50 per cent.4 The mode of inheritance as yet is not established, but family studies suggest a great deal of genetic heterogeneity. Antigen-specific IgE antibody responses have been associated with certain HLA specificities. Population studies have demonstrated the association of the HLA-B8 antigen to rye-grass pollen sensitivity. 51 Higher levels of IgE frequently are found in atopic patients and family members who may be genetically predisposed to increased IgE production. It is worth noting, however, that a genetically predisposed person can develop an IgE response only after environmental exposure to the offending antigen. Finally, other stimuli such as parasitic or viral infections can induce elevation of serum IgE in normal nonatopic persons.
IGE RESPONSE IN ALLERGIC DISEASE An important feature of the allergic diathesis is a propensity to develop IgE antibody responses to a variety of environmental and food allergens. This tendency may be present in utero, since positive radioallergosorbent test (RAST) results to allergens have been reported even in cord blood. 55 Orgel has demonstrated that serum IgE levels taken at 1 year of age are predictive of the subsequent development of atopic symptoms by the age of 2 years. 58 In atopic dermatitis, serum IgE levels are elevated in about 80 per cent of patients,34 and most children have positive immediate skin test results and RAST directed to a whole spectrum of antigens. Sampson et al. 63 have shown that food hypersensitivity plays a pathogenic role in children with atopic dermatitis. In their study, more than 50 per cent of affected children experienced positive food challenges. Most patients manifested skin symptoms on positive challenge. There also was associated gastrointestinal and respiratory symptomatology in a smaller proportion of patients. Chronic rhinitis and bronchial asthma are a heterogeneous group of diseases with multiple etiologies. In the presence of elevated serum IgE levels, however, an allergic etiology is implicated. Total serum IgE levels are positively correlated with the duration, intensity, and multiplicity of allergic sensitivities. Patients with pollen allergies have been shown to have postseasonal rises in serum IgE. Following immunotherapy with the relevant allergen, there is a blunting of the postseason rise in serum IgE level. 49
CELLS BEARING Fe RECEPTORS FOR IGE Fc.R are present on various cell types and play an important role in the immune effector functions of these cells. These receptors may be classified into two categories by their distribution on various cell types and
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,<±l-Figure 1. Antigen-induced "bridging" of IgE receptors leads to the activation of membrane enzymes, increase in free intracellular Ca'+, and granule-associated release of histamine, (Key: ffi = stimulation; Ptd Ins-P, = phosphatidyl inositol 4,5-bisphosphate; DAG = 1,2 diacylglycerol; PKC = protein kinase C; IP 3 = inositol 1,4,5-trisphosphate,)
their affinity for IgK They are (1) Fc.R type 1, which are present on mast cells and basophils and have a high affinity for monomeric IgE; and (2) Fc.R type 2, which are low-affinity Fc.R present on subpopulations of lymphocytes,23, 77 monocytes,68 platelets,35 and eosinophik 9 IgE is a homocytotropic antibody that by definition is an antibody capable of interacting with target cells of the homologous species, such that these cells would release mediators on contact with specific antigen, IgE therefore mediates its effects by sensitization of mast cells and basophils via its binding to high-affinity Fc.R. Using E heavy-chain fragments, which have been cloned and synthesized in E, coli, it has been shown that fragments containing the CH 2 and CH 3 domains were able to inhibit the Praunitz-Kustner (P-K) reaction, This strongly suggests that the CH 2 and CH 3 region of the E heavy chain is involved in the binding of IgE to Fc.R type 1. 19 The Fab end of the IgE molecule is accessible for combining with antigen, On exposure to antigen, the binding of neighboring molecules of cell bound IgE results in the "bridging" of corresponding Fc.R (Fig, 1), The "bridging" of a few molecules of Fc.R is sufficient to activate the transmembrane enzyme phospholipase C, This enzyme hydrolyzes a distinct membrane-associated inositol phospholipid, resulting in the generation of diacylglycerol and inositol 1,4,5-trisphosphate, These two products act as second messengers in cell activation. These series of biochemical events culminate in the release of granule-associated histamine and other vasoactive mediators, and the generation of other mediators such as leukotrienes and platelet activating factor. 74
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The function(s) of the low-affinity Fc£R is not well understood. It is, however, known that the number of circulating monocytes and lymphocytes bearing Fc£R are abnormally elevated in patients with allergic disorders. 54. 77 Fc£R on monocytes,53 eosinophils,IO, 36, 37 and platelets 12 , 35 have been shown to be involved in the killing of IgE-coated targets such as helminthic parasites and the release of inflammatory mediators following ligand binding. In allergic asthma, the presence of allergen-specific IgE on alveolar macrophages and its activation by receptor bridging with bivalent antigen, results in the release of mediators that cause bronchospasm, and chemotactic factors that attract inflammatory cells. 15 This indicates that in addition to tissue mast cells, Fc£R-bearing alveolar macrophages also may play an important role in the pathogenesis of asthma. Similarly, in atopic dermatitis, the presence of IgE on macrophages and dendritic cells infiltrating into skin lesions has been demonstrated. 6, +4 These cells would therefore be potentially capable of inflammatory mediator release on interaction with allergen. T lymphocytes that bear Fc£R have been shown to secrete factors that enhance IgE synthesis in an isotype specific manner. 80 The biologic significance of Fc£R on B lymphocytes is still uncertain. It has been shown to be upregulated by the T cell-derived lymphokine interleukin 4.78 A 28 kilodalton fragment of the Fc£R on Epstein-Barr virus-transformed B cell line is spontaneously cleaved and shed into culture supernatants. This moiety has recently been shown to a~t as a growth factor for Epstein-Barrinfected B lymphoblasts, and anti-mu-stimulated normal B lymphocytes, suggesting a role in autocrine B cell growth. 69 These findings suggest that the IgE antibody can interact with a variety of Fc£R + immune effector cells to generate hypersensitivity reactions. At present, much of our pharmacologic management of allergic diseases is focused on controlling the symptoms that result from the release of mediators from these immune effector cells. 59 The development of any fundamental changes in the treatment of allergic diseases will require a clear understanding of the mechanisms that regulate the human IgE response. IGE SYNTHESIS AND ITS REGULATION Our current understanding of the regulation of IgE synthesis has been derived from (1) research in experimental animals, especially the rat and mouse models, (2) human in vitro lymphocyte model systems, and (3) the study of human diseases associated with elevations of IgE. These diseases include the hyper-IgE syndrome, a disease characterized by extremely elevated serum IgE, recurrent serious infections, and chronic pruritic dermatitis; severe atopic dermatitis, and acute graft-versus-host (GVH) diseases. In this section, discussion of IgE synthesis and its regulation will be made with reference to these areas of research. B Cell Differentiation and Immunoglobulin Class Switching Immunoglobulins have a four-chain structure comprised of two heavy and two light chains. Isotypic variation in immunoglobulins is determined
f IGE RESPONSE AND ITS REGULATION IN ALLERGIC DISEASES
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by heavy chains j.L, 8, ,,{, E, and a. Bone marrow stem cells undergo a series of maturational steps to develop into B cells committed to production of Igs of a specific isotype. The maturational process of B cells may be defined in five different cellular stages. 67 Stage I represents immature B cells. These cells express IgM on their cell surface. Stages II and III correspond to the two stages of resting B cells. These cells carry two isotypes on their cell surfaces. In stage II, B cells carry IgM and IgD, and in stage III the cell surface immunoglobulin isotypes are IgM and IgE (lgG or IgA). Stage IV is the stage of the activated B cell. These cells express only IgE (lgG, 19A, IgM, or IgD) on their cell surface. The final stage (V) of B cell maturation involves stimulation of transcription, and corresponds to a plasma cell that secretes IgE, IgG, 19A, IgM, or IgD. All the above stages are known to occur in vivo. Stage II may not be obligatory. Theoretically, the pathways in stages I through II and II through III involve gene splicing and are reversible. The step involving stage III through IV is a phenomenon known as class switching and involves irreversible deletion of the constant heavy chain genes. T cells may have regulatory effects between stages III through IV, and IV through V. Evidence for the role of T Cells in the Regulation of IgE Synthesis The induction of antibody synthesis to most protein antigens requires the collaboration of B and T lymphocytes. This principle also applies to IgE antibody formation. Early evidence for the requirement of T lymphocytes in the regulation of IgE synthesis came from the observations that neonatally thymectomized rats 57 and congenitally athymic nude mice 32 were unable to generate IgE antibody. Furthermore, this defect could be corrected by the infusion of normal thymocytes. Subsequent studies on rodents demonstrated that IgE was regulated by two distinct T cell subpopulations: helper/inducer T cells, which induce and enhance IgE synthesis, and suppressor T cells, which inhibit IgE synthesis. 70. 71 In these studies, the elimination of suppressor T lymphocytes by use of irradiation or cyclophosphamide therapy converted rats from their usual pattern of low-level IgE production to patterns of sustained IgE synthesis. This enhanced IgE response could be terminated by passive transfer of syngeneic thymocytes or spleen cells. These observations provide direct evidence that the low levels of IgE response in untreated rats reflect the dominance of a suppressor T cell regulatory control mechanism that normally serves to minimize antibody production in this Ig class. In humans, evidence that IgE production is subject to T cell regulation is based on the frequent observation of increased serum IgE levels in patients with primary immunodeficiency disorders.7 Patients with WiskottAldrich, ataxia telangiectasia, Nezelof, and DiGeorge syndromes have been reported to have increased levels of serum IgE. It has been postulated that such patients have sufficient number of helper/inducer T cells for the initiation ofIgE antibody synthesis, but an inadequate number of suppressor T cells to inhibit IgE synthesis, resulting in increased IgE production. Several diseases associated with decreased number and function of suppressor T cells have been found to be accompanied by extremely high serum IgE levels. These diseases include the hyper-IgE syndrome20 ; severe
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atopic dermatitis, in which a direct correlation between the decreased number of suppressor T cells and elevation of serum IgE has been foundS, 43, 75; and acute graft versus host disease, 21, 60 From these observations, we may therefore infer that the elevation of IgE levels in the atopic person could result from a decrease in numbers or function of suppressor T cells, In Vitro Synthesis of IgE by Cultured Human Lymphocytes Unlike research on the animal model, in vivo experimentation in humans is not possible. In vitro experiments of IgE synthesis by cultured peripheral blood mononuclear cells (PBMC) has therefore provided us with the greater part of our understanding of the regulation of human IgE synthesis. The study of in vitro human IgE synthesis has been fraught with problems. The amounts of IgE secreted in culture are extremely low (pg to ng per ml range) 103 to 106 times less than the amounts of IgG secreted. In addition, preformed IgE bound to cell membranes of basophils, monocytes, and T and B cells has to be accurately determined and subtracted from the total IgE measured in culture. The use of highly specific monoclonal antibodies to the Fc portion of IgE in the IgE radioimmunoassay has minimized cross-reactivity with IgG. To overcome the problem of preformed IgE bound to cell membranes, techniques such as treatment of cells with protein synthesis inhibitors like cyclohexamide, freeze-thawing of cells, and acid treatment all have been used to assess background IgE secretion. 72 Numerous investigators have reported that PBMC of atopic patients as well as those with diseases characterized by elevated serum IgE levels spontaneously synthesized abnormally large amounts of IgE in vitro, whereas cells from nonatopic donors failed to synthesize detectable levels of IgE. 16. 25. 62. 64, 66 This increase in secretion of IgE was isotype restricted because concurrent IgG secretion was not increased. 20. 64 To examine the role of suppressor T cells in atopic persons more directly, several laboratories have studied the effects of normal T cells on in vitro IgE production by cultured PBMC from patients with severe atopic dermatitis or the hyper-IgE syndrome. Unfractionated T cells from haploidentical or histoincompatible normal T cells suppressed spontaneous de novo IgE production by cultured PBM C from atopic donors. 20. 25, 62, 66 Since patients with hyper-IgE syndrome have a deficiency of circulating Ts + cells, Geha et al. 20 investigated the effects of normal Ts + suppressor/ cytotoxic T cells and T4 + helper/inducer T cells on IgE synthesis by PBMC from these patients, and found that spontaneous de novo IgE synthesis by cultured PBMC from their patients could be suppressed by Ts + T cells but not T4 + T cells from nonatopic parents, Because, however, allogeneic interaction can generate IgE-specific suppressor factors, S1 the possibility that results from such co-culture studies were the result of allogeneic effects could not be excluded, In this regard, we have observed that abnormally elevated IgE synthesis by cultured PBMC from patients with acute GVH could be suppressed by Ts + cells from normal histoidentical siblings. 65 Furthermore, T cells from patients who have recovered from acute GVH disease could effectively suppress IgE synthesis by thawed autologous
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cultured PBMC that had been cryopreserved during acute GVH. More recently, Hemady et al. 26 have demonstrated that T cells from patients with atopic dermatitis were not as effective as T cells from normal controls in their capacity to suppress IgE synthesis by HLA-identical B cells. These results support the hypothesis that the increased production of IgE in severe atopic dermatitis, acute GVH disease, and hyper-IgE syndrome is due in part to a relative deficiency of suppressor T cells. Further in vitro experiments on cultured PBMC have been aimed at studying model systems that could induce or augment IgE synthesis in B cells from nonatopic and atopic subjects respectively. Unlike other isotypes, IgE synthesis is not induced by classic polyclonal activators such as pokeweed mitogen, Staphylococcus aureus (Cowan strain), or anti-mu reagents. 16, 25, 62, 66 This failure to induce IgE synthesis in vitro may relate to the enhanced sensitivity of IgE synthesis to suppressor influences exerted by T cells present among the bulk T-cell population. With the use of helper T-cell clones, the differential requirements for induction of IgE synthesis in B cells from normal and atopic donors have been examined. In this system, B cells may be stimulated via two separate pathways: (1) by cognate interaction between T and B cells, in which the helper Tcell clone recognizes an alloantigen directly on the surface of the B cell; and (2) by "factor dependent stimulation," in which the helper T-cell clone is stimulated by the appropriate monocytes and soluble T-cell products act on the B cells, which act as bystander cells in culture. Using this system, it has been found that normal B cells differ from those of atopic persons in that they require cognate interaction with T-cell clones for the induction of IgE synthesis. In contrast, B cells from atopic persons that spontaneously secrete IgE in vitro can have their IgE secretion augmented both under conditions of cognate interaction with T cells or when they are present as bystander cells in culture. 73 These results suggest that allergic persons have B cells activated in vivo towards IgE secretion and are more sensitive to soluble helper signals from T cells. Cognate T and B cell interactions studied in this in vitro model system may be important in the development of IgE immune responses in the normal host. Alloreactive T cells could underlie the elevation of IgE synthesis during acute GVH disease. 21 It is, however, unlikely that alloreactive T cells playa role in the activation of IgE synthesis in other human diseases. In the murine system, the generation of autoreactive T-cell clones following antigen stimulation has been well documented. 22 We have examined the capacity of autoreactive T-cell clones derived during tetanus toxoid antigen activation of T cells from a nonatopic donor to induce IgE synthesis. Under conditions of cognate stimulation, autoreactive T cell clones were capable of inducing normal B cells to synthesize IgE and IgG.46 Hence autoreactive T cells may contribute to the polyclonal B cell activation, which occurs in diseases characterized by intense antigenic stimulation. 2, 45 The presence of elevated serum IgE levels in the acute phase of some of these diseases, such as the Kawasaki syndrome39 and systemic lupus erythematosus,61 may reflect increased IgE production from such immunologic interactions. In atopic patients, it is possible that sustained antigen stimulation leads to the generation of autoreactive T cells, which, in the
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Table 1. Properties of Human IgE Binding Factors
Molecular weight (kd) Affinity for IgE Affinity for IgG Sensitivity to trypsin Sensitivity to neuraminidase Affinity for lentil lectin Affinity for concanavalin A Affinity for peanut agglutinin
IgE POTENTIATING
IgE SUPPRESSIVE
FACTOR
FACTOR
15;60
15;30;60
+
+
+ +
+
+ +
absence of effective IgE specific suppressors 20 , polyclonal IgE response,
+
26
leads to a sustained
IgE Binding Factors Once B cells are activated to enter the pathway of IgE secretion, IgE synthesis is modulated by T-cell derived factors that have specificity for IgE. These isotype-specific factors have been well characterized in the rodent models as IgE binding factors (IgE BF) and can exert either potentiating or suppressor influences. 2~, 30, 76 These factors have been shown to have a common peptide backbone and their biologic activities determined by a post-translational glycosylation process, 52 The IgE potentiating factor is highly glycosylated, containing an N-linked, mannose-rich oligosaccharide, The IgE suppressive factor is poorly glycosylated, containing an 0linked oligosaccharide with terminal sugar of galactose N -acetylgalactosamine. 76 Under physiologic conditions, the natural and biologic activities of IgE BF are controlled by another two T-cell-derived factors: glycosylation enhancing factor (GEF), and glycosylation inhibiting factor (GIF). These factors enhance or inhibit the N-glycosylation of IgE BF during their biosynthesis. 27 In humans, it has been shown that a subset of human T lymphocytes produces IgE BF. 30, 52, 76 Fc.R + human T cell lines derived from patients with the hyper-IgE syndrome constitutively secrete IgE potentiating factors and enhance IgE but not IgG synthesis by B cells of patients with allergic rhinitis. 80 Physiochemical properties of human IgE BF from these T cell lines have been shown to be similar to those of rodent IgE BF79 and are summarized in Table L Serum from normal nonallergic persons contains low molecular weight IgE binding factors that suppress IgE production. 40 In contrast, a low molecular weight IgE enhancing factor(s) can be detected in the sera of patients with the hyper-IgE syndrome. 42 Plasmapheresis of these patients and replacement with normal serum have resulted in decreased rates of IgE synthesis by their peripheral blood lymphocytes. 40, 41 Experiments with alloreactive T-cell clones have shown that normal resting B cells first have to be activated by certain T-cell clones before they can respond to the IgE potentiating factorY In contrast, B cells from symptomatic atopic patients are able to respond directly to human IgE
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potentiating factor(s) with increased IgE secretion. This suggests that B cells need to reach a certain stage of activation before responding to the IgE potentiating factor. . Role of Interleukin-4 (IL4) and Gamma ("Y) Interferon in IgE Synthesis In recent studies ~n the murine model, helper T cells have been characterized into two subsets according to their pattern of lymphokine production. Type 1 T-helper cells (TH 1) produce interleukin 2 (IL2), "Yinterferon, granulocyte-myelocyte colony stimulating factor, and IL3 in response to antigen presenting cells; and type 2 helper cells (TH 2) produce IL3, IL4, a mast cell growth factor, and a T-cell growth factor distipct from IL2.56 Culture supernatants from TH2 clones have been shown to enhance a lOO-fold increase in IgE production by lipopolysaccharide (LPS)-stimulated B cells. There was a concomitant 10- to IS-fold increase in IgGI and IgA. The enhancement of both IgE and IgA could be completely inhibited by relatively low concentrations of "Y-interferon.13 Furthermore, highly purified IL4 enhanced IgE production to the same extent as the TH2 clone supernatants, and its effect was totally inhibited by a monoclonal antibody directed against IL4.14 Preliminary studies performed in our laboratory using culture supernatant from a human TH2-like clone that contains IL4, very little "Y-interferon, and no IL2 activity, suggest that it could directly activate B cells from normal persons to synthesize IgE. This increase in IgE synthesis could be completely inhibited by "Y-interferon. These findings raise the possibility that some persons with a propensity to high IgE levels may have an imbalance between IL4 and "Y-interferon synthesis. The current models of the human B cell IgE response therefore propose that resting B cells have to undergo a series of stages in cell~lar activation prior to differentiation to IgE-secreting plasma cells. From experimental results discussed in the above sections, the proposed sequential requirements for the activation of human IgE antibody resp,onse may be summarized in Figure 2.
ANTIGEN-SPECIFIC REGULATION OF IcE ANTIBODIES Role of Anti-idiotypic (Id) Antibodies Idiotypic (I d) antibodies are antibodies that arise from the heterogeneity of the variable domain of the immunoglobulin molecule. These antiboqies can be immunogenic in genetically identical persons, including the individual patient himself, thus giving rise to anti-Id antibodies. There is evid~nce from both animal studies 3 and in vitro human experiments 17 that IgG anti-Id antibodies playa role in the inhibition of antigen-specific IgE responses. Because complexes of antigen and Id antibodies are particularly immunogenic, repeated immunization with antigen appears to be conducive to the production of auto-anti-Id antibodies. 18 Allergic diseases involve repeated stimulation by antigens either naturally or in the course of immunotherapy. Thus, the presence of auto-anti-Id antibodies to allergen-
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j
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potentiatin~lgE B~F factor
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Figure 2 Sequential requirements for the in vitro activation of the human IgE antibody response. Resting B cells are activated by T-B cognate stimulation or the type 2 helper T cell (TH-2) derived lymphokine interleukin 4 (IL-4). The latter effect is inhibited (--) by Type 1 helper T cell (TH-l) derived ,(-interferon. T cell-derived IgE binding factors (IgE-BF) act on activated IgE-bearing B cells to potentiate or suppress (--) further differentiation into IgEsecreting plasma cells.
specific antibodies in humans would be expected. Auto-anti-Id antibodies have been described in isolated allergic patients receiving immunotherapy. 5 In a larger series, Castrane et al,u reported the presence of auto-anti-Id to ragweed antibodies in normal subjects and to a lesser extent in untreated allergic subjects. Furthermore, the level of auto-anti-Id antibodies appeared to go up to normal range in subjects treated with immunotherapy. These results suggest that the decreased production of auto-anti-Id antibody in allergic subjects allows the escape of IgE antibody synthesis from immunoregulatory influences. Other Factors Affecting Antigen-Specific IgE Formation Extraneous factors that playa role in suppressing antigen-specific IgE formation are chemical modifications of the antigen, the dose, and the route of administration of the antigen. The list of chemical modifications include polymerization (e.g., glutaraldehyde treatment of antigen), urea denaturation, binding to tolerogenic carriers (e.g., polY-D-glutamyllysine), and substitution by formaldehyde, acetoacetyl groups, or polyethylene
IGE RESPONSE AND ITS REGULATION IN ALLERGIC DISEASES
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glycol. It must be acknowledged, however, that although such manipulations are effective in primary and secondary IgE responses, they may be less effective in late established ones. Such chemical modifications of antigen have been used to improve the efficacy of allergen immunotherapy. Polymerization of ragweed pollen antigen using glutaraldehyde reduces allergenicity but retains the immunogenicity of the antigen. A double-blind placebo-controlled trial of immunotherapy with polymerized ragweed antigen showed that this preparation was safe and efficacious. 24 In this study, patients who received polymerized ragweed antigen had 50 per cent lower symptom scores than did controls receiving either no therapy or a histamine placebo. In experimental animals, large doses of antigen have been found to be IgE suppressive, and the intravenous route is more conducive to suppression than subcutaneous, intradermal, or intramuscular administration. In high responder strains of mice, repeated exposure to low doses of an antigen favors the production of IgE over IgG. This suggests that the threshold of antigen alone for IgE production is lower than for IgG.4B Similarly, in the atopic patient with the propensity to develop a sustained IgE response following antigenic stimulation, exposure to antigens in low doses appears to favor an antigen-specific IgE response. Hence, in ragweed pollenallergic persons, the IgE response to this antigen may be induced by chronic low dose exposure during the pollen season. During a typical ragweed season, the average patient is exposed to less than 1 f,Lg of the predominant ragweed allergens, antigen E. 50 These observations emphasize the importance of environmental factors on the IgE response. The failure of normal persons to develop a sustained antigen-specific IgE response on exposure to similar environmental factors presumably results from dominating IgE suppressive influences.
SUMMARY 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.R) present on mast· cells and basophils (Fc.R type 1) and subpopulations of monocytes, macrophages, eosinophils, and platelets (Fc.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.R type 2 on lymphocytes and monocytes are upregulated in atopic disease and may playa 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 a-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
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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.
ABBREVIATIONS Fc.R, Fc receptor for IgE GEF, Glycosylation enhancing factor GIF, Glycosylation inhibiting factor -y-IFN, Gamma interferon GVH, Graft versus host disease Id, Idiotype Ig, Immunoglobulin IgE BF, IgE binding factors IL2, Interleukin-2 IL4, Interleukin-4 LPS, Lipopolysaccharide PBMC, Peripheral blood mononuclear cells RAST, Radioallergosorbent test TH 1 , Type 1 helper cells TH 2 , Type 2 helper cells ACKNOWLEDGMENTS We wish to thank Mrs. Adrienne B. Sisco and Tony Bonjorno for excellent secretarial assistance in the preparation of this article. Supported by USPHS Grants AI-22058, AI-20373, and HL-37260.
REFERENCES 1. Berg T, Johansson SGO: IgE concentrations in children with atopic diseases. Int Arch Allergy Appl Immunol 36:219, 1969 2. Blaese RM,' Grayson J, Steinberg AD: Increased immunoglobulil). secreting cells in patients with active systemic lupus enythematosus. Am J Med 69:345, 1980 3. Blaser K, Nakagawa T, DeWeek AL: Suppression of the benzyl penicilloyl (BPO)-specific IgE formation with isologous anti-idiotypic antibodies in BALB/c mice. J Immunol 125:24, 1980 4. Blumenthal MN, Yunis E, Mendall N et al: Preventive allergy: Genetics ofIgE-mediated diseases. J Allergy Clin Immunol 78:962, 1986 5. Bose R, Marsh DG, Duchateau JS et al: Demonstration of auto-anti-idiotypic antibody cross-reacting with public idiotypic determinants in the serum of rye-sensitive allergic patients. J ImmunoI133:2474, 1984 6. Bruynzeel-Koomen C, Wichen DF, Toonstra J et aI: The presence of IgE molecules on epidermal Langerhans cells in Patients with Atopic Dermatitis. Arch Dermatol Res 278:199, 1986 7. Buckley RH, Fisus SA: Serum IgD and IgE concentration in immunodeficiency diseases. J Clin Invest 55:157, 1975 8. Butler M, Atherton D, Levinsky RJ: Quantitative and functional deficit of suppressor T cells in children with atopic eczema. Clin Exp Immunol 50:92, 1982
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9. Capron M, Capron A, Dessaint JP et al: Fc receptors for IgE in human and rat eosinophils. J Immunol 126:2087, 1981 10. Capron M, Speigelberg HL, Prin L et al: Role of IgE receptors in effector function of human eosinophil. J Immunol 132:462, 1984 11. Castrane JM, Hall JT, Rocklin RE: Generation of anti-idiotypic antibodies in ragweed sensitive patients undergoing specific immunotherapy. Clin Res 33:608A, 1985 12. Cines DB, Van der Keyl H, Levinson AI: In vitro binding of an IgE protein to human platelets. J Immunol 136:3433, 1986 13. Coffman RL, Carty J: A T cell activity that enhances polyclonal IgE production and its inhibition by interferon--y. J ImmunoI136:949, 1986 14. Coffman RL, Ohara J, Bond MW et al: B cell stimulatory factor-l enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol 136:4538, 1986 15. Dessaint JP, Torpier G, Capron M et al: Cytophilic binding of IgE to the macrophage. Cell Immunol 46:12, 1979 16. Fiser PM, Buckley RH: Human IgE biosynthesis in vitro: Studies with atopic and normal blood mononuclear cells and subpopulations. J Immunol 123: 1788, 1979 17. Geha RS: Detection of autoantiidiotypic antibody during the normal human immune response to tetanus toxoid antigen. J Immunol 129:139, 1982 18. Geha RS: Idiotypic interactions in the treatment of human diseases. Adv ImmunoI39:255, 1986 19. Geha RS, Helm B, Wood N et al: IgE sites relevant for binding type 1 Fc Epsilon (Fc,R) Receptors on mast cells. J Allergy Clin Immunol 79:129 abstr 20, 1987 20. Geha RS, Reinherz EL, Leung DYM et al: Deficiency of suppressor T cells in the hyperimmunoglobulinemia E syndrome. J Clin Invest 68:783, 1981 21. Geha RS, Twarog F, Rappaport J et al: Increased serum IgE levels following allogeneic bone marrow transplantation. J Allergy Clin Immunol 66:78, 1980 22. Glimcher LH, Shevach EM: Production of autoreactive I-region restricted T cell hybridomas. J Exp Med 156:640, 1982 23. Gonzalez-Molina A, Spiegelberg HL: A subpopulation of normal human peripheral B lymphocytes that bind IgE. J Clin Invest 59:616, 1977 24. Grammer LC, Zeiss CR, Suszko 1M et al: A double-blind, placebo controlled trial of polymerized whole ragweed for immunotherapy of ragweed allergy. J Allergy Clin Immunol 69:494, 1982 25. Hemady Z, Blomberg F, Gellis S et al: IgE production in vitro by human blood mononuclear cells: A comparison between atopic and non-atopic subjects. J Allergy Clin Immunol 71:324, 1983 26. Hemady Z, Gellis S, Chambers M et al: Abnormal regulation of in vitro IgE synthesis by T cells obtained from patients with atopic dermatitis. Clin Immunol Immunopathol 35:156, 1985 27. Ishizaka K: Regulation of IgE synthesis. Annu Rev Immunol 2:159, 1984 28. Ishizaka K, Ishizaka T, Hornbrook M: Physio-chemical properties of human reaginIc antibody IV. Presence of unique immunoglobulin as a carrier of reaginic activity. J Immunol 97:75, 1966 29. Ishizaka K, Ishizaka T, Hornbrook M: 'Physio-chemical properties of human reaginic antibody V. Correlation of reaginic activity with E-globulin antibody. J Immunol 97:840, 1966 30. Ishizaka K, Suemura M, Yodoi J, et al: Regulation ofIgE response by IgE binding factors. Fed Proc 40:58, 1981 31. Ishizaka T, Ishizaka K: Activation of mast cells for mediator release through IgE receptors. Progr Allergy 34:188, 1984 32. Ito K, Ogita T, Suko M et al: IgE levels in nude mice. Int Arch Allergy Appl Immun. 58:474, 1979 33. Johansson SGO: Radioimmunoassay of IgE and IgE antibody and its clinical application. In Symposium on Disorders of Protein Metabolism. J Clin Pathol 23 (Suppl):33, 1975 34. Johnson EE, Irons JJ, Patterson Ret al: Serum IgE concentration in atopic dermatitis. J Allergy Clin Immunol 54:94, 1974 35. Joseph M, Auriault C, Capron A et al: A new function for platelets: IgE dependent killing of schistosomes. Nature 303:810, 1983 36. Joseph M, Tonnel AB, Capron A et al: Enzyme release and superoxide anion production
966
37. 38. 39. 40. 41. 42. 43. 44.
45. 46. 47.
48.
49. 50. 51. 52. 53. 54. 55.
56.
57. 58. 59. 60. 61. 62.
BEE WAH LEE ET AL.
by human and alveolar macrophages stimulated with immunoglobulin E. Clin Exp Immunol 40:416, 1980 Khalife J, Capron M, Cesbron JY et al: Role of specific IgE antibodies in peroxidase (EPO) release from human eosinophils. J ImmunoI137:1659, 1986 Kjellman NIM: Predictive value of high IgE levels in children. Acta Paediatr Scand 65:465, 1976 Kusakawa S, Heiner DC: Elevated immunoglobulin E in the acute febrile mucocutaneous lymph node syndrome. Pediatr Res 10:108, 1976 Leung DYM, Brozek C, Frankel R et al: IgE specific suppressor factors in normal human serum. Clin Immunol Immunopathol 32:339, 1984 Leung DYM, Brozek L, Frankel Ret al: IgE specific suppressor factors in normal human serum: In vitro and in vivo effects. Clin Res 31:164A, 1983 Leung DYM, Frankel R, Brozek C et al: The biological activity of IgE binding factors in human sera. J Allergy Clin Immunol 73:176, 1984 Leung DYM, Rhodes AR, Geha RS: Enumeration of T cell subsets in atopic dermatitis using monoclonal antibodies. J Allergy Clin Immunol 67:450, 1981 Leung DYM, Schneeberger EE, Siraganian RP et al: The presence ofIgE on macrophages and dendritic cells infiltrating into the skin lesion of atopic dermatitis. Clin Immunol Immunopathol 42:328, 1987 Leung DYM, Siegel RL, Grady S et al: Immunoregulatory abnormalities in mucocutaneous lymph node syndrome. Clin Immunol ImmunopathoI23:100, 1982 Leung DYM, Young MC, Geha RS: Induction ofIgG and IgE synthesis in normal B cells by autoreactive T cell clones. J Immunol 136:2851, 1986 Leung DYM, Young MC, Wood N et al: Induction of IgE synthesis in normal human B cells: Sequential requirements for activation by an alloreactive T cell clone and IgE potentiating factors(s). J Exp Med 163:713, 1986 Levine BB, Vaz NM: Effect of combinations of inbred strain, antigen and antigen dose on immune responsiveness and reagin production in the mouse. Int Arch Allergy Appl Immunol 39:156, 1970 Lichtenstein LM, Ishizaka K, Norman PS et al: IgE antibody measurements in ragweed hayfever: Relationship to clinical severity and the results of immunotherapy. J Clin Invest 52:472, 1973 Marsh DG: Allergens and the Genetics of Allergy. The Antigens, Vol 3. New York, Academic Press, 1975, p 271 Marsh DG, Meyers DA, Freidhoff IR et al: Association of HLA phenotypes AI> Bg, DW3 , and A3 , B7 , DW2 with allergy. Int Arch Allergy Appl Immunol 66 (Suppl 1):48, 1981 Martens CL, Jardieu P, Trounstine ML et al: Potentiating and suppressor factors are expressed by a single cloned gene. Proc Nat! Acad Sci USA 84:809, 1987 Melewics FM, Speigelberg HL: Fc receptors for IgE in a subpopulation of human blood monocytes. J Immunol 125:1026, 1980 Melewicz FM, Zeiger RS, Mellon MH et al: Increased peripheral blood monocytes with Fc receptors for IgE in patients with severe allergic disorders. J Immunol 126:1592, 1981 Michael FB, Bousquet J, Greillier P et al: Comparison of cord blood immunoglobulin E concentrations and maternal allergy for the prediction of atopic diseases in infancy. J Allergy Clin Immunol 65:422, 1980 Mosmann TR, Chewinski H, Bond MW et al: Two types of murine helper T cell clone: 1. Definition according to profiles of Iymphokine activities and secreted proteins. J Immunol 136:2348, 1986 Okurmura K, Tada T: Regulation of homocytotropic antibody formation in the rat. III. Effect of thymectomy and splenectomy. J Immunol 106:1019, 1971 Orgel HA: Genetic and developmental aspects ofIgE. Pediatr Clin North Am 22:17, 1975 Rasmussen JE: Recent developments in the management of patients with atopic dermatitis. J Allergy Clin Immunol 74:771, 1985 Reinherz EL, Parkman R, Rappaport J et al: Aberrations of suppressor T cells in human graft versus host disease. N Engl J Med 300:1061, 1979 Rebhun J, Quismono F, Dubois E et al: Systemic lupus erythematosus activity and IgE. Ann Allergy 50:34, 1983 Romagnani S, Del Prete GF, Maggi E et al: In vitro production of IgE by human peripheral blood mononuclear cells. Clin Exp Immunol 42:579, 1980
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63. Sampson HA, McCaskill CC: Food hypersensitivity and atopic dermatitis: Evaluation of 113 patients. J Paediatr 107:669, 1985 64. Saryan JA, Leung DYM, Ceha RS: Induction of human IgE synthesis by a factor derived from T cells of patients with hyper IgE states. J Immunol 130:242, 1983 65. Saryan JA, Rappaport J, Leung DYM et al: Regulation of human IgE synthesis in acute graft vs host disease. J Clin Invest 71 :558, 1983 66. Saxon A, Morrow L, Steven RH: Subpopulations of circulating B cells and regulation T cells involved in in vitro immunoglobulin E production in atopic patients with elevated serum immunoglobulin E. J Clin Invest 65:1457, 1980 67. Shimizu A, Honjo T: Immunoglobulin class switching. Cell 36:801, 1984 68. Speigelberg HL: Structure and function ofFc receptors for IgE in lymphocytes, monocytes and macrophages. Adv Immunol 35:61, 1984 69. Swendeman S, Thorley-Lawson DA: The activation antigen BLAST-2, when shed, is an autocrine BCCF for normal and transformed B cells. EMBO J 6:1637, 1987 70. Tada T, Taniguchi M, Okumura K: Regulation of homocytotropic antibody formation in the rat. II: Effect of X irradiation. J Immunoll06:1012, 1971 71. Taniguchi M, Tada T: Regulation of homocytotropic antibody formation in the rat. IV. Effects of various immunosuppressive drugs. J Immunol107:579, 1971 72. Turner KJ, Holt PC, Holt BJ et al: In vitro synthesis of IgE by human peripheral blood leucocytes. III. Release of preformed antibody. Clin Exp Immunol 51:387, 1983 73. Umetsu DT, Leung DYM, Siraganian Ret al: Differential requirements of B cells from normal and allergic subjects for the induction of IgE synthesis by an alloreactive T cell clone. J Exp Med 162:202, 1985 74. White JR, Pluznik DH, Ishizaka K et al: Antigen-induced increase in protein kinase C activity in plasma membrane of mast cells. Proc Natl Acad Sci USA 82:8193, 1985 75. Willemze R, DeCraaff-Reitsma CB, Crossen J et al: Characterization of T cell subpopulations in skin and peripheral blood of patients with cutaneous T cell lymphoma and benign inflammatory dermatoses. J Invest Dermatol 80:60, 1983 76. Yodoi J, Hirashima M, Ishizaka K: Regulatory role of IgE binding factors from rat T lymphocytes. The carbohydrate moeities in IgE-potentiating factors and IgE-suppressive factors. J Immunol 128:289, 1982 77. Yodoi J, Ishizaka K: Lymphocytes with Fce receptors for IgE. I. Presence of human and rat lymphocytes with Fee receptors. J ImmunoI122:2577, 1979 78. Yokata T, Otsuka T, Mosmann T et al: Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B cell stimulatory factor,-1 that expresses B cell and T cell stimulating activation. Proc Natl Acad Sci USA 83:5894, 1986 79. Young MC, Ceha RS, Maksad KN et al: Characterization of human T cell derived IgE potentiating factor. Eur J ImmunoI16:985, 1986 80. Young MC, Leung DYM, Ceha RS: Production of IgE potentiating factor in man by T cell lines bearing Fc receptors f<,lr IgE. Eur J ImmunoI14:871, 1984 81. Zuraw BL, Nonaka M, O'Hair C et al: Human IgE antibody synthesis in vitro: Stimulation of IgE responses by pokeweed mitogen and selective inhibition of such responses by human suppressive factor of allergy (SFA). J ImmunoI127:1169, 1981 Division of Allergy The Children's Hospital 300 Longwood Avenue Boston, Massachusetts 02116