The Journal of Allergy and Clinical Immunology
Volume 111, Issue 1 , Pages 38-44, January 2003

Unraveling the mission of FcϵRI on antigen-presenting cells☆

Bonn, Germany, and Boston, Mass

From athe Department of Dermatology, Rheinische-Friedrich-Wilhelms-University of Bonn, Bonn, and bthe Laboratory of Allergy and Immunology, Department of Pathology, Beth Israel Deaconess Medical Center, Boston

Received 7 July 2002; received in revised form 3 September 2002; accepted 16 September 2002.

Article Outline

Abstract 

A decade ago, the discovery of the high-affinity receptor for IgE (FcϵRI) on epidermal Langerhans cells documented the end of the dogma that FcϵRI is only expressed on effector cells of anaphylaxis. Since then, the functional significance of this receptor on antigen-presenting cells (APCs) has been an area of intense research work. Scientists have focused on a better understanding of the molecular structure, regulation, and role of FcϵRI on APCs in the human immune system. Insights into the cellular events linked to the activation of APCs on ligation of FcϵRI by IgE and allergens might provide the basis for new aspects in the pathophysiology of allergic diseases and the design of future diagnostic and therapeutic strategies. This review is dedicated to the 10th anniversary of the discovery of FcϵRI on APCs and describes the numerous areas of research in this field. (J Allergy Clin Immunol 2003;111:38-44.)

Keywords:  Antigen-presenting cells, dendritic cells, IgE, IgE receptor, allergy, atopic dermatitis

Abbreviations:  AD , Atopic dermatitis, AEDS , Atopic eczema/dermatitis syndrome, APC , Antigen-presenting cell, DC , Dendritic cell, ER , Endoplasmic reticulum, LC , Langerhans cell, MIIC , MHC class II compartment, NF , Nuclear factor

 

Back to Article Outline

Fc ϵri on antigen-presenting cells: the end of a dogma? 

The molecular structure of the classical human high-affinity receptor for IgE (FcϵRI) on the surface of effector cells of anaphylaxis (ie, mast cells and basophils) was characterized in the mid-1980s. This was followed by significant advances in our understanding of its function on these cells.1, 2 Initially, it was assumed that FcϵRI is exclusively expressed on mast cells and basophils, initiating mechanisms involved in cell activation of immediate-type hypersensitivity reactions. But in 1992, Mudde et al3 provided evidence for an IgE-binding capacity of epidermal Langerhans cells (LCs) in lesional and nonlesional skin of patients with atopic dermatitis (AD). Initial attempts to characterize the relevant IgE-binding structure on LCs suggested the presence of a third IgE-binding structure on these cells in addition to the low-affinity receptor for IgE (FcϵRII/CD23) and the human IgE-binding protein ϵBP/galectin-3.4

In 1992, 2 research groups5, 6 reported the presence of specific transcripts for FcϵRI chains, as well as the surface protein expression of the FcϵRI complex in LCs. The identification of FcϵRI on the surface of LCs in the epidermis of atopic skin lesions resulted in a new view of the cellular distribution and functionality of this structure. It prompted a resurgence of interest in the discovery of other FcϵRI-bearing antigen-presenting cells (APCs) distinct from effector cells. Later, it was reported that human peripheral blood monocytes can bind monomeric IgE through FcϵRI. Receptor expression on these cells was significantly higher in atopic individuals.7 In addition, FcϵRI-bearing monocytes can be directly activated after interactions with multivalent allergens, resulting in enhanced allergen presentation, synthesis, and release of proinflammatory cytokines. FcϵRI could also be detected on perivascularly located dermal dendritic cells (DCs), exhibiting pronounced dendrites, an indented nucleus, numerous mitochondria, and abundant endosomal-lysosomal structures but no LC-specific Birbeck granules.8

Finally, FcϵRI-positive cells with a similar immunophenotype and cell morphology to peripheral blood DCs were identified in a subpopulation of lymphocyte-depleted PBMCs. These FcϵRI-positive DCs were efficient stimulators of primary and secondary FcϵRI/IgE-dependent T-cell responses.9

Demonstrating the presence and functional significance of FcϵRI on human APCs was the major advance in understanding the critical role performed by APCs in IgE-mediated antigen-presentation pathways.

Back to Article Outline

What is different in the structure of fcϵri on apcs? 

The classical, tetrameric FcϵRI expressed on effector cells of anaphylaxis consists of 3 distinct protein species (αβ2γ). The heavily N-glycosylated α-chain exhibits 2 Ig-like domains that mediate binding to the Fc portion of IgE. Recently, the basis of this interaction was revealed by the crystal structure of the human IgE-FcϵRIα complex.10 One receptor molecule binds one IgE-Fc molecule asymmetrically through interactions at 2 sites, each involving one Cϵ3 domain of the IgE-Fc molecule in a 1:1 stoichiometry (Fig 1).

  • View full-size image.
  • Fig. 1. 

    Structural characteristics of IgE and the IgE-binding receptors. The structure of the IgE molecule with the constant region (Fc) and the structural characteristics and cellular distributions of the tetrameric and trimeric variants of FcϵRI, FcϵRII, and the soluble form (sFc ϵRII) are summarized.

The β-chain acts as an amplifier of signaling downstream of the receptor. In addition, the β-chain augments the maturation of the α-chain and its intracellular trafficking to the cell surface, thus leading to increased surface expression. This was documented by pulse-chase experiments with stable transfectants expressing either the trimeric or the tetrameric form of FcϵRI. In these experiments the presence of the β-chain accelerated the processing of nascent α-chains and α-β–chain association that occurs early in the process of biosynthesis.11, 12

The γ-chain dimer, which is shared by other Fc receptor complexes, carries 2 immunoreceptor tyrosine-based activation motifs in its cytoplasmic tail for downstream signal propagation. Immunoreceptor tyrosine-based activation motifs are phosphoacceptors through which the β- and γ-chains of FcϵRI interact with signaling proteins. Transfection studies have shown that the γ-chain masks an endoplasmic reticulum (ER)–retention motif in the α-chain, which is located near the cytoplasmic domain and functions as a retrieval-retention signal, leading to export and full maturation of the FcϵRI complex. Coexpression of the γ-chains leads to the formation of the αγ2 complex and represents an essential prerequisite for the FcϵRI surface expression.13 Unexpectedly, in LCs and other APCs only specific transcripts for the α- and γ-chain were pres-ent, whereas the putative β-subunit is completely lacking in these cells. This suggests that FcϵRI shows a modular structure in the human system: the tetrameric form (αβ2γ) on effector cells and the trimeric variant (α2γ) on APCs.

Back to Article Outline

Fcϵri and other ige-binding structures on apcs 

To differentiate FcϵRI-mediated versus FcϵRII-mediated effects on APCs, experiments with blocking antibodies have been performed to show that FcϵRI and not FcϵRII/CD23 represents the main IgE-binding structure on monocytes,7 LCs,14 and monocyte-derived DCs.15 Further on, the interaction of FcϵRI with other IgE-binding structures, such as the low-affinity receptor for IgE, which binds IgE complexes or ϵBP/Galectin-3, a surface structure mediating chemotactic signals and factors involved in cell adhesion, is still a matter of intensive research work. FcϵRII exists in 2 forms: FcϵRIIa is expressed constitutively on B cells, and FcϵRIIb, which could be induced by IL-4, is expressed on the surface of non-B cells, such as monocytes, LCs, DCs, macrophages, platelets, and various other cell types (Fig 1). In addition, surface-bound FcϵRII can be cleaved into a soluble form of FcϵRII (sFcϵRII; Fig 1). The surface expression of these IgE-binding structures shows disease-related and interindividual variations. Interestingly, APCs from patients with allergic-extrinsic forms of atopic diseases going in with increased IgE serum levels display a higher FcϵRI and FcϵRII surface expression than APCs from patients with nonallergic-intrinsic forms of atopic diseases and low IgE serum levels.16

Back to Article Outline

Which factors regulate the surface expression of fcϵri on apcs? 

Cells that express the FcϵRI α2γ trimer and those that express the αβ2γ tetramer are functionally distinct and comprise different compartments. Tetrameric FcϵRI is expressed on mast cells and basophils, which constitute the αβ2γ compartment, whereas trimeric FcϵRI is expressed on professional APCs constituting the α2γ compartment (Fig 2).

  • View full-size image.
  • Fig. 2. 

    Functional characteristics of FcϵRI on effector cells and APCs of atopic and nonatopic donors. The classical tetrameric FcϵRI expressed on effector cells of both a topic and nonatopic donors is shown at the top . In contrast, the trimeric variant of FcϵRI is distinctly expressed on APCs of atopic and nonatopic individuals, as shown at the bottom .

This has important consequences for FcϵRI regulation and function. First, various cells of the α2γ compartment show intracellular accumulation of α-chains, presumably caused by a slower maturation and transport process in the absence of the β-chain. Thus FcϵRI in its trimeric form shows a much lower density of FcϵRI surface expression and reduced stability of the receptor protein complexes. Second, signals mediated by the trimeric receptor are 3 to 5 times weaker than those mediated by the tetrameric form. This was demonstrated by Lin et al12 comparing transfected αβ2γ and α2γ FcϵRI complexes. Ligation of trimeric FcϵRI could induce activation of the protein-tyrosine kinase syk and calcium mobilization, whereas additional expression of the β-chain in tetrameric FcϵRI amplified these signals 5- to 7-fold.

FcϵRI on human APCs has a highly variable range of expression and shows a close correlation to the atopic status. Although LCs from normal donors express low or no FcϵRI on their cell surface, receptor expression is upregulated in atopic donors. It also correlates with serum IgE levels, being maximal on LCs from lesional skin of patients with AD.17 These variable surface levels might result in part from differences in the γ-chain expression of atopic and nonatopic individuals (Fig 2).18 A series of experiments, semiquantitative analyses of PCR products, and immunoblot and FACS analyses of FcϵRIα and FcϵRIγ of enriched LCs from epidermal skin lesions of donors with AD and nonatopic control subjects were done for this purpose. Most interestingly, in the absence of γ-chains in nonatopic subjects, APCs exhibited mainly ER-localized immature α-chains, showing core glycosylation, whereas APCs from atopic subjects coexpressing the γ-chains show mature, terminally glycosylated α-chains associated with γ-chains in the golgi compartment and on the cell surface. Transfection studies have shown that N-linked glycosylation is necessary for efficient folding of FcϵRIα and its ability to leave the ER.19 Surface expression seems also to be dependent on glucosidase trimming of terminal glucose residues as a quality-control mechanism for the intracellular assembly of the α- and γ-chains of FcϵRI.20 Association of α- and γ-chains putatively leads to the masking of a retention signal and export of the receptor complex from the ER to the golgi compartment, where terminal maturation occurs. Mature FcϵRI complexes can then exit to the cell surface.

Recent advances provide evidence for a pivotal role of IgE in the mechanisms regulating the surface expression of the FcϵRI complex: IgE binding to the α-chain seems to be the minimal requirement for the induction of FcϵRI upregulation in the monocytic cell line U937 and NIH3T3 FcϵRI transfectants.21 Recently it could be shown that monomeric IgE regulates the FcϵRI expression on monocyte-derived DCs of atopic individuals in vitro. In addition, a significant upregulation of FcϵRI of monocyte-derived DCs from patients with allergic forms of atopic diseases could be achieved by creating a reducing microenviroment,15 which leads to a significant upregulation of the FcϵRIγ pool. In summary, the mechanism of IgE-mediated upregulation is the result of a combination of the stabilization of the receptor at the cell surface, the use of a preformed intracellular pool, and a continued basal level of protein synthesis.

Back to Article Outline

What is known about the functions of fcϵri-expressing apcs? 

Aggregation of FcϵRI on cells of the αβ2γ compartment is involved in immediate-type hypersensitivity reactions by releasing preformed mediators, such as histamine, prostaglandins, and leukotrienes. In contrast, the main role of the α2γ compartment on APCs is believed to be antigen focusing. Detailed studies with birch and grass pollen allergen, which were recognized by antigen-specific IgE bound to APCs through FcϵRI, showed that FcϵRI is the pivotal structure mediating IgE-dependent antigen presentation to T cells. Additionally, monocyte-enriched PBMCs present allergen to T cells 100- to 1000-fold more effectively if the allergen has been targeted to FcϵRI on these cells through allergen-specific IgE.22 After polyvalent li-gation, FcϵRI-bound IgE is efficiently internalized into acidic proteolytic compartments, degraded, and delivered into organelles containing MHC class II, HLA-DM, and lysosomal proteins. In contrast, this process does not occur in consequence of monovalent ligation of FcϵRI.

Multimeric ligands of FcϵRI are channelled efficiently into specialized endosomal MHC class II compartment (MIIC)–like organelles of DCs. In MIIC, cathepsin S–dependent ligand peptide loading of newly synthesized MHC class II molecules occurs. Thus the decision to take up and consequently to present antigens in an IgE-dependent manner is made on the basis of whether antigens or pathogens carry repetitive or multiple distinct IgE epitopes. The observation of a stringent cathepsin S dependency for the presentation of FcϵRI-targeted agents strongly suggests that cathepsin S plays a major role for the maturation and peptide loading of those MHC class II molecules that access MIIC-like organelles of DCs. The cathepsin S–dependent pathway could be of relevance for allergens, such as house dust mite or food allergens, which are resistant to rapid endosomal degradation. In addition, it is assumed that DCs express other proteases than cathepsin S in case of high numbers of peptide copies or at high antigen concentrations. With the help of FcϵRI-mediated antigen presentation of APCs, allergen-specific T-cell activation can occur in the presence of vanishing antigen, even in the absence of IgE-mediated immediate hypersensitivity reactions of mast cells.23 As a proof of concept, the successful application of aeroallergens, such as cat dander, in the atopy patch test shows that it is possible to elicit eczematous skin lesions by solely external application of aeroallergens to the skin.24, 25 This form of test is assumed to evaluate the clinical relevance of IgE-mediated sensitization in patients with AEDS. Patients with positive atopy patch test reactions have a higher number of IgE-bearing DCs in the epidermis and dermis than patients with negative atopy patch test reactions.26, 27 The intermittent or continuous flow of aeroallergens and autoantigens in the process of facilitated antigen presentation might define the pathophysiologic basis of recurrent or self-perpetuating course of AEDS frequently seen in untreated patients. This mechanism supports the hypothesis of AEDS as an IgE-mediated delayed-type hypersensitivity reaction in which APCs serve as the link between aeroallergens penetrating the reduced epidermal skin barrier and antigen-specific immunologic and cellular mechanisms involved in the maintenance of the ongoing proinflammatory reaction induced by this event.28, 29

Back to Article Outline

What happens downstream? 

Thus far, signaling events initiated by FcϵRI have been explored mostly in mast cells and basophils or in in vitro model systems bearing tetrameric FcϵRI. However, studies on FcϵRI signal transduction in APCs, especially the activation of transcription factors responsible for FcϵRI-mediated gene activation, have been initiated recently. There is some evidence that the quality and quantity of the signal transduction events triggered in LCs from normal individuals and individuals with AD differ profoundly. First, it has been shown that cross-linking of FcϵRI on LCs leads to rapid tyrosine phosphorylation of several proteins, including p72, p77, and p95.30 However, significant calcium mobilization could only be detected in LCs from lesional skin of patients with AD. In contrast, LCs from healthy donors, even in the presence of significant FcϵRI expression, show no calcium mobilization. Calcium mobilization is dependent on tyrosine phosphorylation and the activation of phospholipase C γ. This does not occur in LCs from healthy donors but is clearly detectable when LCs from atopic donors are analyzed.31 These data imply that some steps of FcϵRI-mediated signaling cascade might be upregulated in an atopic background. However, there are cell-specific differences in the composition of the nuclear factor (NF) κB complexes of various APC-DC types. Classical p50/66 complexes can be detected in FcϵRI-stimulated monocytes and monocyte-derived DCs, whereas FcϵRI-stimulated LCs show complexes containing p50 and mainly RelB. In contrast, in mast cells and basophilic cell lines, a weak FcϵRI-induced NF-κB activation has been detected. Because the kb element in the murine TNF-α promoter region preferentially binds NF of activated T cells I mast cells, it binds NF-κB in DCs. Therefore a cell-specific regulation of κB sites by different transcription factors could be assumed.

There is evidence that FcϵRI ligation on monocytes and monocyte-derived DCs can induce DNA binding of NF-κB dimers composed solely of the p50 and p65 subunits, despite increased expression of the transcription factor RelB during differentiation. NF-κB activation is preceded by serine phosphorylation and degradation of its inhibitory protein, IκB-α. In this way FcϵRI might induce NF-κB activation, which is known to regulate genes involved in inflammatory responses and, in this way, might contribute to the control of inflammatory reactions in atopic diseases.32 These observations are in line with a recent hypothesis speculating that FcϵRI might play a role in the control of bacterial pathogenicity and intestinal inflammation.33 Transgenic mice expressing a humanized FcϵRI both in the αβ2γ and the α2γ compartment were compared with wild-type mice, which express murine FcϵRI only in the αβ2γ compartment, and with FcϵRα-deficient mice. In the transgenic mice levels of colonic IL-4 were higher, the composition of the fecal flora was modified, and bacterial translocation toward mesenteric lymph nodes was increased. In addition, they showed more pronounced trinitrobenzene sulfonic acid–induced colitis, which supports the idea that the presence of FcϵRI might favor the creation of an inflammatory tissue environment. However, it is not clear whether these observations are due to an additional expression of FcϵRI in the α2γ compartment or other mechanisms (eg, higher overall surface expression of FcϵRI in these mice). Recently, it could be shown that LCs of the oral mucosa bear FcϵRI in high amounts on their cell surface and might play a key role in the unique mucosal immunity (Allam et al, unpublished data, 2002). In an in vitro system using human monocyte-derived LCs, the engagement of FcϵRI on monocyte-derived LC-like DCs increased IL-16 mRNA expression and storage of intracellular IL-16 protein.34 As a consequence, the secretion of mature IL-16 is enhanced in a biphasic manner. IL-16 is assumed to play a major role in the epidermis of atopic skin lesions, and the capacity of LCs to produce IL-16 in vitro might play a substantial role in the recruitment of different T-cell subtypes and DCs in vivo. Additionally, other cytokines and chemokines, such as TNF-α, IL-8, monocyte chemo-attractant protein 1, and macrophage-inflammatory protein 1α, are released in high amounts in consequence of FcϵRI ligation of APCs in vitro.15

In addition to the ability of IgE-bearing APCs to prime naive T cells, recent data support a rather unexpected modulatory role of FcϵRI on the differentiation of APCs. This role is mediated by the release of factors known to be involved in anti-inflammatory pathways and to promote a rather tolerogenic state.35 Engagement of FcϵRI on human monocytes from atopic donors at the beginning of the IL-4/GM-CSF–driven culture induced the production of the tolerogenic cytokine IL-10 and modulated the generation of DCs. In contrast, it resulted in the emergence of rather macrophage-like cells, which were poor stimulators of allogeneic T cells. These data imply a novel pivotal function of this receptor in influencing the differentiation of DCs, which should make efforts to further characterize the precise interactions of this modulation worthwhile. Another scenario in which FcϵRI seems to be involved is the regulation of cell-survival events and apoptosis, which has recently been shown for mast cells.36, 37 Mast cell survival and growth are promoted by monomeric IgE binding to its high-affinity receptor. In this way the ability of IgE to enhance mast cell survival and FcϵRI expression might contribute to amplified allergic reactions. These data correlate with the finding that FcϵRI mediates signals preventing monocyte apoptosis in atopic donors directly by increasing the levels of Bcl-2 and Bcl-xL and indirectly by means of TNF-α in an autocrine and paracrine fashion.38

Back to Article Outline

What are the therapeutic options of the future? 

Altogether, we now have more information concerning the regulation of FcϵRI expression on APCs. In addition, significant progress has been made in elucidating the role of FcϵRI on different APC types and IgE-mediated signals in immunologic pathways of allergic disease. An important and as yet unsolved question is whether mechanisms that control and modulate allergic and inflammatory hypersensitivity reactions through FcϵRI on APCs might be used as new routes to control these events in therapeutic approaches. Recently, it could be shown that topical treatment with the macrolide FK 506 leads to the reduction of FcϵRI-bearing APCs in the epidermal skin lesions of patients with AEDS.39, 40 A straightforward therapeutic strategy might be to interfere with the binding of IgE to FcϵRI by using recombinant or synthetic peptides comprising structural elements of IgE as competitive inhibitors of the IgE-FcϵRI interactions. Another approach are anti-IgE antibodies, which block the binding of IgE to its respective receptor. These antibodies did not bind receptor-bound IgE-FcϵRI complexes to avoid any unrequested cross-linking of the cells.41, 42 Alternatively, mimotope peptides coupled to carrier protein might be used to develop a peptide-based antiallergy vaccine. Unraveling the downstream events of FcϵRI signaling on APCs might suggest additional methods of controlling allergic responses through the inhibition of specific steps of the signal transduction cascade.43, 44, 45 We suggest that intervening with the activation of FcϵRI-bearing APCs will likely be an important component of therapeutic strategies in the future.

Back to Article Outline

What is left to be learned about fcϵri-bearing apcs? 

Although much has been learned about the structure, regulation, and function of FcϵRI on APCs, numerous questions have been left open.

In particular, the function of the FcϵRI-bearing APCs in the peripheral tissue, such as LCs and inflammatory dendritic epidermal cells, and in the epidermal skin lesions of AD is still a matter of debate because it is not clear in which way each of these DC subtypes contributes to the pathophysiologic puzzle of AD (ie, the recruitment of other cell types at the site of inflammation, the maintenance of the inflammatory reactions, and finally the switch of the TH2 immune response into an immune response of the TH1 type). Additionally, the capability of FcϵRI on APCs to initiate tolerogenic signals, such as the anti-inflammatory cytokine IL-10, which is known to be involved in the induction of T-regulatory cells or the induction of indoleamine 2,3-dioxygenase by FcϵRI, which is the rate-limiting enzyme in the catabolism of the essential amino acid tryptophan and involved in the regulation of T-cell responses,23, 46, 47 open new perspectives in this field. In regard to the current concept of immunotherapeutic strategies of allergic-atopic diseases, in which the induction of anergy of TH2 cells and the conversion of TH2 cells into regulatory T cells represents a major task, the tolerogenic properties of FcϵRI-bearing APCs gain rising interest. Together, this links to a putative role of these cells in tolerance induction pathways, which might be of major interest in self-limiting mechanisms of allergic-inflammatory diseases, such as AD, and must be elucidated in the future.

Back to Article Outline

References 

  1. Kinet JP. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol. 1999;17:931–972
  2. Hanifin JM. Diagnostic criteria for atopic dermatitis: consider the context. Arch Dermatol. 1999;135:1551
  3. Mudde GC, van Reijsen FC, Bruijnzeel-Koomen CA. IgE-positive Langerhans cells and Th2 allergen-specific T cells in atopic dermatitis. J Invest Dermatol. 1992;99:103S
  4. Wollenberg A, de la SH, Hanau D, Liu FT, Bieber T. Human kera-tinocytes release the endogenous beta-galactoside-binding soluble lectin immunoglobulin E (IgE-binding protein) which binds to Langerhans cells where it modulates their binding capacity for IgE glycoforms. J Exp Med. 1993;178:777–785
  5. Bieber T, de la Salle H, Wollenberg A, Hakimi J, Chizzonite R, Ring J, et al.  Human epidermal langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J Exp Med. 1992;175:1285–1290
  6. Wang B, Rieger A, Kilgus O, Ochiai K, Maurer D, Fodinger D, et al.  Epidermal langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med. 1992;175:1353–1365
  7. Maurer D, Fiebiger E, Reininger B, Wolff-Winiski B, Jouvin MH, Kilgus O, et al.  Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J Exp Med. 1994;179:745–750
  8. Osterhoff B, Rappersberger K, Wang B, Koszik F, Ochiai K, Kinet JP, et al.  Immunomorphologic characterization of Fc epsilon RI-bearing cells within the human dermis. J Invest Dermatol. 1994;102:315–320
  9. Maurer D, Fiebiger S, Ebner C, Reininger B, Fischer GF, Wichlas S, et al.  Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation. J Immunol. 1996;157:607–616
  10. Wurzburg BA, Garman SC, Jardetzky TS. Structure of the human IgE-Fc C epsilon 3-C epsilon 4 reveals conformational flexibility in the antibody effector domains. Immunity. 2000;13:375–385
  11. Donnadieu E, Jouvin MH, Kinet JP. A second amplifier function for the allergy-associated Fc(epsilon)RI-beta subunit. Immunity. 2000;12:515–523
  12. Lin S, Cicala C, Scharenberg AM, Kinet JP. The Fc(epsilon)RIbeta subunit functions as an amplifier of Fc(epsilon)RIgamma-mediated cell activation signals. Cell. 1996;85:985–995
  13. Miller L, Blank U, Metzger H, Kinet JP. Expression of high-affinity binding of human immunoglobulin E by transfected cells. Science. 1989;244:334–337
  14. Rieger A, Wang B, Kilgus O, Ochiai K, Mauerer D, Fodinger D, et al.  Fc epsilon RI mediates IgE binding to human epidermal langerhans cells. J Invest Dermatol. 1992;99:30S–32S
  15. Novak N, Kraft S, Haberstok J, Geiger E, Allam P, Bieber T. A reducing microenvironment leads to the generation of FcϵRI high inflammatory dendritic epidermal cells (IDEC). J Invest Dermatol. 2002; In press
  16. Oppel T, Schuller E, Gunther S, Moderer M, Haberstok J, Bieber T, et al.  Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis. Br J Dermatol. 2000;143:1193–1198
  17. Wollenberg A, Wen S, Bieber T. Langerhans cell phenotyping: a new tool for differential diagnosis of inflammatory skin diseases. Lancet. 1995;346:1626–1627
  18. Kraft S, Wessendorf JH, Hanau D, Bieber T. Regulation of the high affinity receptor for IgE on human epidermal langerhans cells. J Immunol. 1998;161:1000–1006
  19. Letourneur O, Sechi S, Willette-Brown J, Robertson MW, Kinet JP. Glycosylation of human truncated Fc epsilon RI alpha chain is necessary for efficient folding in the endoplasmic reticulum. J Biol Chem. 1995;270:8249–8256
  20. Albrecht B, Woisetschlager M, Robertson MW. Export of the high affinity IgE receptor from the endoplasmic reticulum depends on a glycosylation-mediated quality control mechanism. J Immunol. 2000;165:5686–5694
  21. Borkowski TA, Jouvin MH, Lin SY, Kinet JP. Minimal requirements for IgE-mediated regulation of surface Fc epsilon RI. J Immunol. 2001;167:1290–1296
  22. Maurer D, Fiebiger E, Reininger B, Ebner C, Petzelbauer P, Shi GP, et al.  Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation. J Immunol. 1998;161:2731–2739
  23. Oldfield WL, Kay AB, Larche M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects. J Immunol. 2001;167:1734–1739
  24. Ring J, Darsow U, Behrendt H. Role of aeroallergens in atopic eczema: proof of concept with the atopy patch test. J Am Acad Dermatol. 2001;45(suppl 1):S49–S52
  25. Niggemann B. The role of the atopy patch test (APT) in diagnosis of food allergy in infants and children with atopic dermatitis. Pediatr Allergy Immunol. 2001;12(suppl 14):37–40
  26. Bruijnzeel PL, Kuijper PH, Kapp A, Warringa RA, Betz S, Bruijnzeel-Koomen CA. The involvement of eosinophils in the patch test reaction to aeroallergens in atopic dermatitis: its relevance for the pathogenesis of atopic dermatitis. Clin Exp Allergy. 1993;23:97–109
  27. Langeveld-Wildschut EG, Bruijnzeel PL, Mudde GC, Versluis C, Van Ieperen-Van Dijk AG, Bihari IC, et al.  Clinical and immunologic variables in skin of patients with atopic eczema and either positive or negative atopy patch test reactions. J Allergy Clin Immunol. 2000;105:1008–1016
  28. Wistokat-Wulfing A, Schmidt P, Darsow U, Ring J, Kapp A, Werfel T. Atopy patch test reactions are associated with T lymphocyte-mediated allergen-specific immune responses in atopic dermatitis. Clin Exp Allergy. 1999;29:513–521
  29. Darsow U, Vieluf D, Ring J. Evaluating the relevance of aeroallergen sensitization in atopic eczema with the atopy patch test: a randomized, double-blind multicenter study. Atopy Patch Test Study Group J Am Acad Dermatol. 1999;40:187–193
  30. Jurgens M, Wollenberg A, Hanau D, de la Salle H, Bieber T. Activation of human epidermal langerhans cells by engagement of the high affinity receptor for IgE, Fc epsilon RI. J Immunol. 1995;155:5184–5189
  31. Kraft S, Weßendorf JHM, Haberstok J, Novak N, Wollenberg A, Bieber T. Enhanced expression and activity of protein-tyrosine kinase establishes a functional signaling pathway in FcϵRI Langerhans cells. J Invest Dermatol. 2002; In press
  32. Kraft S, Novak N, Katoh N, Bieber T, Rupec RA. Aggregation of the high-affinity IgE receptor Fc(epsilon)RI on human monocytes and dendritic cells induces NF-kappaB activation. J Invest Dermatol. 2002;118:830–837
  33. Dombrowicz D, Nutten S, Desreumaux P, Neut C, Torpier G, Peeters M, et al.  Role of the high affinity immunoglobulin E receptor in bacterial translocation and intestinal inflammation. J Exp Med. 2001;193:25–34
  34. Reich K, Heine A, Hugo S, Blaschke V, Middel P, Kaser A, et al.  Engagement of the Fc epsilon RI stimulates the production of IL-16 in Langerhans cell-like dendritic cells. J Immunol. 2001;167:6321–6329
  35. Novak N, Bieber T, Katoh N. Engagement of FcepsilonRI on human monocytes induces the production of IL-10 and prevents their differentiation in dendritic cells. J Immunol. 2001;167:797–804
  36. Asai K, Kitaura J, Kawakami Y, Yamagata N, Tsai M, Carbone DP, et al.  Regulation of mast cell survival by IgE. Immunity. 2001;14:791–800
  37. Kalesnikoff J, Huber M, Lam V, Damen JE, Zhang J, Siraganian RP, et al.  Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity. 2001;14:801–811
  38. Katoh N, Kraft S, Wessendorf JH, Bieber T. The high-affinity IgE receptor (FcepsilonRI) blocks apoptosis in normal human monocytes. J Clin Invest. 2000;105:183–190
  39. Wollenberg A, Sharma S, Von Bubnoff D, Geiger E, Haberstok J, Bieber T. Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol. 2001;107:519–525
  40. Panhans-GroB A, Novak N, Kraft S, Bieber T. Human epidermal Langerhans' cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol. 2001;107:345–352
  41. Novak N, Bieber T. To bend or not to bend. Nat Immunol. 2002;3:607–608
  42. Babu KS, Arshad SH, Holgate ST. Anti-IgE treatment: an update. Allergy. 2001;56:1121–1128
  43. Lin SY, Kinet JP. Immunology. Giving inhibitory receptors a boost. Science. 2001;291:445–446
  44. Tuner H, Kinet JP. Signaling through the high-affinity IgE receptor Fc epsilon RI. Nature. 1999;402:B24–B30
  45. Oliver JM, Kepley CL, Ortega E, Wilson BS. Immunologically mediated signaling in basophils and mast cells: finding therapeutic targets for allergic diseases in the human FcvarepsilonR1 signaling pathway. Immunopharmacology. 2000;48:269–281
  46. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196:459–468
  47. Von Bubnoff D, Matz H, Frahnert C, Rao ML, Hanau D, De La Salle H, et al.  FcespilonRI induces the tryptophan degradation pathway involved in the regulation of T-cell responses. J Immunol. 2002;169:1810–1816

☆ Reprint requests: Natalija Novak, MD, Department of Dermatology, Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany.

PII: S0091-6749(02)91264-9

doi:10.1067/mai.2003.2

The Journal of Allergy and Clinical Immunology
Volume 111, Issue 1 , Pages 38-44, January 2003

Article Tools

* Image Usage & Resolution