FcεRI on antigen-presenting cells

773

FceRI on antigen-presenting cells Thomas Bieber The high-affinity receptor for IgE, FcERI, expressed on antigen-presenting cells such as monocytes and Langerhans' cells exhibits profound differences to its homologue expressed on mast cells and basophils. The lack of the chain, the presence of an intracellular pool of preformed (~ chains, highly variable surface expression, and its function (to provide antigen focusing for T cells) are some of the main issues which have led us to consider the functional role of this receptor in a new light.

Addresses

Department of Dermatology, Ludwig-Maximilians University, FrauenlobstraBe g, 80337 Munich, Germany; e-maih [email protected] Current Opinion in Immunology 1996, 8:7?3-777

© Current Biology Ltd ISSN 0952-7915 Abbreviations APC antigen-presenting cell DC dendriticcell Fc~RI high-affinity IgE receptor IL interleukin

LC PTK TCR

Langerhans' cell protein tyrosine kinase T cell receptor

Introduction Among APCs, one classically distinguishes nonprofessional APCs as being endothelial cells or fibroblasts expressing M H C class II, and professional APCs as being monocytes, B cells and dendritic cells (DCs; in this review, only professional APCs will be considered). While follicular DCs, B cells and monocytes are mainly confined to lymph nodes and blood, other DCs are more widely distributed in the tissues and epithelia at the interface between the body and the environment. Here, they represent the first line in immunosurveillance, that is, the outpost of the immune system in epithelia of the lung, nasal mucosa, gastro-intestinal tract and the skin. It would have been expected that such cells also express Fc receptors for IgE, which by essence are prone to bind parasites or other extracellular agents, such as house dust mites or pollens. Until recently, however, the detailed study of DCs has largely been hampered by the lack of relevant cell lines and the great difficulties in obtaining sufficient amounts of DCs to perform reliable functional, biochemical and molecular biological investigations. Thus, the presence of the high-affinity receptor for IgE (FcERI), known to be expressed on effector cells of anaphylaxis, such as basophils and mast cells, was only recently reported on human dendritic epidermal Langerhans' cells (LCs) [1,2] and subsequently on monocytes [3] and finally on circulating DCs [4]. This unexpected finding has led me

to review FcERI in a new light: when it is expressed on APCs. Molecular structure of FceRI expressed on APes T h e classical Fc•RI, as expressed on mast cells and basophils, is a heterotetrameric receptor complex composed of one 50-60 kDa a chain which includes the IgE-binding site, one 30 kDa 13chain with four transmembrane domains and two disulfide-linked 7 - 9 k D a y chains [5,6]. In contrast, detailed analysis of FcERI on APCs revealed some differences in its structure (Table 1). T h e mRNA transcripts for the c( chain (FcERIet) and the y chain (FcERIT) were detected on highly purified LCs, monocytes and circulating DCs using polymerase chain reaction technology but transcripts for the 13 chain (FceRI13) are found only in a minority of individuals without correlation to an atopic status. It is noteworthy that the gene for FcERI13, a candidate gene for atopy [7] localized on human chromosome llq13, is lacking in APCs. It should also be mentioned that other genes of the same family, those encoding CD20 and Htm4, could not be detected, at least in LCs (T Bieber, unpublished data). Hence, the 13 chain seems to be expressed exclusively in cells containing preformed mediators packed in granules, such as mast cells, basophils and, more recently, eosinophils [8], but not in APCs. This suggests that Fc£RI13 may be involved in special functional duties of effector cells, for example, the activation mechanisms leading to the rapid release of preformed cellular granules. Interestingly, attempts to demonstrate the presence FcERI on LCs in mice remained unsuccessful (at least in the BALB/c strain; H De-la-Salle, D Hanau, T Bieber, unpublished data). Whether this explains the difficulties in generating murine models of atopic dermatitis remains to be verified. Because the gene encoding the 13chain is lacking in APCs, FcERI on human APCs is composed of an IgE-binding (~ chain and two disulfide-linked y chains. This trimeric et, 2y structure retains all the features necessary for a functional receptor on APCs, as will be discussed below. Regulation of the Fc~RI expression on APCs It is well accepted that basophils and mast cells constitutively express a rather high amount of FceRI. In contrast, a striking particularity of FcERI on APCs is its highly variable expression depending on the individual and the pathological circumstances. Regarding monocytes, FcERI has been shown to be mainly expressed in atopic individuals [3] and to a lesser extent also in nonatopics [9"], but it is nearly undetectable on LCs in about 10% of the population [10], and the expression is usually low on LCs isolated from normal skin of nonatopic individuals [11]. FcERI expression is dramatically enhanced on LCs

774

Atopic allergy and other hypersensitivities

Table 1 Comparison of the structural and functional characteristics of Fc~RI expressed on different cells. Mast*

Effector cells Basophils*

Eosinophils*

Structural Molecular structure Existence of soluble form

¢(, ~, 2y +

or, ~, 2y +

c(, 13, 27 ?

(x, 2y ?

Functional src-PTKs

p56/yn

p56/y n

?

?

p56/Yn

? ?

p56~'n p56/ck p72syk +

Fc~RI characteristics

syk/ZAP-PTKs Cytokine synthesis

p 7 2 syk

p 7 2syk

+

+

? ?

Antigen-presenting cells Monocytes ~ Langerhans't (x, 27 -

*Cells that contain granules with preformed mediators, tCells that do not contain granules with preformed mediators but do have antigen-presentation

ability. in lesional skin of atopic dermatitis, however, and seems to be highly specific for this disease [12"]. Interestingly, the amount of receptor expressed on LCs isolated from lesional skin correlates with the serum level of IgE of the patients [13"]. These observations strongly suggest that distinct mediators present in atopic skin may contribute to an important upregulation of FcERI on LCs, thereby increasing the binding sites for IgE on the surface of these APCs and herewith their ability to bind acroallergens. Very recently, first insights into the regulatory mechanisms of FcERI surface expression on LCs revealed new interesting aspects: IL-4 induces the transcription and translation of FcERIot in LCs generated in vitro (M Magerstaedt et a/., unpublished data); normal LCs without detectable surface expression of FcERI contain an intracellular pool of preformed FcERI~ (S Kraft et al., unpublished data); FclzRI7 appears to be the crucial and limiting factor for the surface expression of these intracellularly segregated FceRIc( moieties in LCs; finally, upon in vitro maturation into lymphoid DCs, LCs completely and irreversibly downregulate their transcripts for FceRI subunits, leading to a rapid loss of their intracellular and surface expression of receptor moieties. Thus, in contrast to effector cells of anaphylaxis, the expression of FcERI on APCs is tuned by the microenvironment. Signals emerging from surrounding tissue dictate not only the phenotype but also the function of FcERI-expressing APCs in a way appropriate to control or enhance the physiological/allergic defense reaction against allergens. Activation APCs

cascade

upon

Fc~RI

ligation

on

Fc~RI belongs to the family of so-called multichain immune recognition receptors which includes the TCR, the B cell receptor and receptors for the Fc fragments of IgG (Fc~'R) [14]. All members of this family have in common the presence of one or several cytoplasmic domains containing a conserved amino acid motif including two tyrosine residues (the immunoreceptor tyrosine activation motif, or ITAM) [15]. This motif is crucial for the initiation of the activation cascade

triggered by receptor ligation. Although involving distinct elements in each receptor type of the muhichain immune recognition receptor family, there is substantial evidence that this signal transduction cascade follows a common scheme of events leading to cell activation. In mast cells and basophils, the activation cascade initiated by FceRI ligation is now better understood and, very schematically, includes activation of protein tyrosine kinases (PTKs) of the Src family and subsequently of the Syk/ZAP family, hydrolysis of phosphatidylinositol by phospholipase C, increase in free intracellular CaZ+ and activation of protein kinase C (for more details on the signal transduction pathway in basophils see the review by Beaven and Baumgarmer in this section, pp 766-772). T h e picture is much less clear in APCs than in mast cells and basophils. First insights into the 'black box' of the biochemical pathway downstream of FcERI in LCs suggest that LCs possess a large repertoire of Src kinases, including among others p56/.vn, p59fyn, and most unexpectedly, the so-far T cell specific p56/ck (S Kraft etal., unpublished data) and that as for mast cells and basophils, these PTKs are involved in a mandatory proximal event in the activation cascade. Indeed, ligation of FcERI on LCs initiates the rapid de novo tyrosine phosphorylation of several proteins, including p72 s~'k, p78, p95 ray, p115 and others [16"']. Aggregation of FceRI on normal LCs from nonatopic individuals does not result in Ca 2÷ mobilization (nonresponder LCs), however, whereas LCs isolated from atopic skin clearly respond by increase in free intracellular Ca 2÷ (responder LCs) despite the absence of the 13 chain [16"']. Similarly, monocytes fail to exhibit Ca 2+ mobilization upon receptor ligation unless they are allowed to adhere for a short period of time before the challenge [3]. Whether this difference in responsiveness is due to the low receptor expression on these APCs resulting in an inefficient signalling cascade for the activation of second messengers or whether it is due to the lack of a critical P T K in these cells, or both, remains to be clarified. In the case of monocytes, however, the adhesion step may allow some distinct interactions of FceRI with other accessory molecules and/or the activation of focal

FcsRI on APCs Bieber 775

adhesion kinase-related structures which are required for full cell activation. Finally, aggregation of the protein tyrosine phosphatase CD45 by cross-linking with antiCD45 monoclonal antibodies impairs the phosphorylation cascade induced by FcERI ligation and results in a diminution of CaZ÷ mobilization in responder LCs [17"]. This indicates a crucial role for CD45 in the initiation of signal transduction, most probably by dephosphorylating an inhibitory tyrosine residue on a Src family PTK. R o l e o f Fc~RI e x p r e s s e d on A P C s in t h e i m m u n e r e s p o n s e and in allergic reactions It has been proposed that IgE molecules and effector cells such as basophils, mast cells and eosinophils are the evolutionary result of an efficient antiparasitic defense system which has now been redirected toward benign environmental allergens because of the lack of its physiological/pathological partners [18]. Enough data has been gathered to reflect on the role of FcERI-expressing APCs in the network of IgE-mediated immune and allergic reactions. Since APCs are obviously not equipped with any granule or preformed mediator able to kill parasitic invaders, one has to look at new functional duties for FcERI on these cells. Furthermore, since receptor expression is highly dependent on the microenvironment of the APC, a modulation of the function of the cells under these conditions is likely. Antigen uptake, processing and presentation are the main functional characteristics of professional APCs. Of antigen capture methods, which classically include nonspecific adsorption, fluid phase pinocytosis, and cell surface receptor endocytosis, the latter provides the most efficient and specific pathway. This seems to be the case for FcERI. Indeed, the expression of high FclzRI density on LCs of patients with atopic dermatitis implies several important features (Fig. 1). Firstly, LCs extend their ability to react toward allergens by binding many IgE molecules with various specificities. This significantly enhances the probability of cross-linking FcERI by a defined allergen at the cell surface. Secondly, the IgE-FcI~RI complexes allow the capture of rather large allergens which, under normal circumstances, are not engulfed via the usual pathway, that is, by pinocytosis. Thirdly, aggregation of FceRI on LCs is followed by its internalization via receptor-mediated endocytosis involving coated pits, coated vesicles and endosomes [16"']. In analogy to BCRs, in which Igor and Ig13 target different endosomal compartments [19"], however, this IgE-FcERI route used for antigen uptake by LCs may dictate whether the foreign structure will be efficiently processed and targeted to MHC class II rich compartments, ultimately leading to a higher density of specific peptides in the grooves of surface MHC class II molecules. Finally, as mentioned above, LCs expressing high receptor densities display full cell activation upon FcI~RI ligation, most probably inducing the synthesis and release of yet to be defined mediators. Such mediators may have proinflammatory capacities and/or may contribute

to enhance/influence the subsequent antigen presentation and/or may recruit inflammatory cells at the site of allergen penetration. This scenario should ultimately lead to a most efficient antigen presentation of even minute amounts of allergens. Indeed, while it has been reported that LCs isolated from atopic skin use IgE for antigen uptake followed by presentation to autologous T cells [20], the formal demonstration that FcERI enables APCs to provide IgE-mediated antigen focusing has been provided only recently for monocytes [21"], circulating DCs [4] and for LCs (T Bieber, unpublished data). One may speculate that FcERI-expressing APCs armed with specific IgE are able to boost the secondary response and to further trigger IgE synthesis by recruiting and activating more antigen-specific Th2 cells. Among APCs, DCs are the most potent stimulators of naive T cells, that is, they are committed to initiate a primary immune response. At first glance, FceRI-mediated antigen uptake and subsequent presentation is rather unlikely in the primary reaction since specific IgE should be present at the very beginning. It cannot be excluded, however, that complex allergenic structures efficiently captured via FcERI on DCs are processed by these cells in a way that leads to the unmasking and presentation of, among others, cryptic peptides/epitopes never encountered by T cells. Presentation would then initiate a primary reaction against these unmasked antigens, thereby contributing to the extension of the IgE repertoire. Whether, as suggested above, simultaneous antigen uptake and FceRI aggregation on APCs leads to the de novo synthesis and release of mediators capable of directing T cells towards a defined phenotype and/or function, that is, towards becoming T h l or Th2 cells, is a very seductive working hypothesis. This striking concept in the field of FcERI-expressing APCs remains to be verified, especially in the light of recent findings suggesting a role for APC-derived IL-12 or prostaglandin E z in driving T cells to be either T h l or Th2 respectively [22]. On the other hand, receptor ligation putatively triggers the synthesis and release of mediators which may initiate a local inflammatory reaction, as has been demonstrated for mast cells [23]. Thus, from a physiopathological point of view, FceRI-expressing APCs, and particularly LCs and related DCs in the epidermis, have been suspected to play a crucial role in atopic dermatitis since they may represent the pivotal link between epidermis-penetrating aeroallergens and antigen-specific T cells infiltrating the skin lesions caused by the allergen. Strongly supporting this concept is the observation that the presence of FcERI-expressing LCs bearing IgE molecules is a prerequisite to provoke eczematous lesions by application of aeroallergens on the skin of atopic patients (FC van Reijsen et al., J lnvest Dermatol Abstr 1995, 105:867). Consequently, atopic dermatitis may represent

776 Atopic allergy and other hypersensitivities

Figure 1

Primary response / t

(a) Crypticlepitope

\

Memory Thl cell J

I g E ~ ;econdary response

~

/,

(d) Fc~RI / / Receptor-mediated endoc_yto_sis_ __

(g) Allergen , , . ~ ~ 0

F~-'~

sponse © 1g96 Current Opinion in Immunology

Functional consequences of Fc~RI-mediated allergen uptake by LCs/DCs (APCs). (a) Cryptic allergen epitopes not directly recognized by the allergen-specific IgE on Fc~.RI may be unmasked and loaded onto MHC class II molecules. This would result in a primary immune response (b) and would ultimately extend the IgE repertoire (broken arrows denote a primary response). (c) As a conseqence of the simultaneous cell activation initiated by Fc~RI ligation, APCs may be driven to synthesize and release inflammatory cytokines, thus causing inflammation, and/or mediators that influence the efficiency and the outcome (Thl or Th2) of the antigen presentation. (d) Receptor-mediated endocytosis of the allergen via FcERI may result not only in a more efficient processing of the allergen but also in the access to MHC class II rich compartments (e) with subsequent antigen presentation at the cell surface resulting in a secondary response (f). (g) Allergen uptake by pinocytosis leads to rather limited processing, carried out in endosomes, and a subsequent loading onto MHC class II molecules.

the paradigm of an IgE-FceRI-mediated delayed-type hypersensitivity reaction (reviewed in [24,25]). A similar role could be attributed to other FcERI-expressing lung DCs which may be responsible for the initiation and/or the regulation of the chronic inflammation in asthma [26]. Hence, since the skin and the lung are very accessible organs, FceRI on these DCs may provide a putative target for new topical therapeutic approaches to managing atopic diseases. On the other hand, systemic approaches similar to that focusing on classical IgE-mediated allergic reactions, for example, preventing the binding of IgE to its receptor by the addition of soluble recombinant receptors, recombinant human anti-IgE antibodies or even highaffinity oligonucleotides, could also represent valuable

alternatives in the management of atopic conditions. Once the mechanisms at the APC level leading to tolerance are better understood, one finally may speculate that in v i t r o generated FcERI-expressing DCs may be used in the future to induce allergen-specific tolerance or anergy in patients exhibiting exaggerated immune responses towards environmental allergens. Conclusions In recent years, the demonstration of the expression of FcERI on human APCs and particularly on LCs has shed new light on the biology of the receptor on these cells, their putative involvement in the regulation of IgE synthesis and their pathophysiological role in atopic diseases. FceRI expressed on APCs differs in terms of

Fc~RI on APCs Bieber

structure and function from that expressed on effector cells of anaphylaxis, such as mast cells or basophils. It is speculated (by myself) that the highly variable expression of the receptor on APCs allows them to precisely tune their secretory and stimulatory function depending on the microenvironment. Armed with FcERI and specific IgE, APCs may not only initiate and boost the immune response towards allergens but may also contribute to the generation of an inflammatory reaction. Finally, since they arc easily accessible in epithelia such as the skin and the lung, APCs and epidermal LCs in particular may represent potential targets for new therapeutic strategies possibly based on interfering with the receptor itself or with elements of the activation cascade initiated by receptor cross-linking.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • •• 1.

2.

3.

4.

5. 6. 7.

of special interest of outstanding interest Bieber T, De-la-Salle H, Wollenberg A, Hakimi J, Chizzonite R, Ring J, Hanau D, De-la-Saqe C: Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (FcERI). J E_xpMed 1992, 175:1285-1290. Wang B, Rieger A, Kilgus O, Ochial K, Maurer D, Fodinger D, Kinet JP, Stingl G: Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc~RI. J Exp Med 1992, 175:1353-1365. Maurer D, Fiebiger E, Reininger B, Wolffwiniski B, Jouvin MH, Kilgus O, Kinet JP, Stingl G: Expression of functional high affinity immunoglobulin E receptors (Fc~RI) on monocytes of atopic individuals. J Exp Med 1994, 179:745-750. Maurer D, Fiebiger E, Ebner B, Reininger B, Fischer G, Wichlas S, Jouvin MH, Schmitt-Egenolf M, Kraft D, Kinet JP, Stingl G: Peripheral blood dendritic cells express Fc~RI as a complex composed of FccRIc(- and Fc~RIy-chains and can use this receptor for IgE-medlated allergen presentation. J Immunol 1996, 157:607-616. Metzger H: The receptor with high affinity for IgE. Immuno/Ray 1992, 125:3?-48. Ravetch JV, Kinet JP: Fc receptors. Annu Rev/mmuno11991, 9:457-492. Shirakawa T, Li AR, Dubowitz M, Dekker JW, Shaw AE, Faux JA, Ra CS, Cookson WO, Hopkin JM: Association between atopy and variants of the ~ subunit of the high-affinity immunoglobulin E receptor. Nat Genet 1994, 7:125-130.

8.

Gounni AS, Lamkhioued B, Delaporte E, Capron A, Kinet JP, Capron M: High-affinity IgE receptor on eosinophils is involved in defence against parasites. Nature 1994, 367:183-185. 9. Reischl IG, Corvaia N, Effenberger F, Wolff-Winiski B, Kr~mer E, • Mudde GC: Function and regulation of Fc£RI expression on monocytes from non-atopic donors. Clin Exp Allergy 1996, 6:631-641. Monocytes from nonatopic donors express low but significant amounts of Fc~RI without clear correlation to serum IgE level. Binding of IgE and Ca 2+ mobilization, however, are under the control of a sialidase-sensitive structure. 10. 11.

12. •

Bieber T: Fc~RI on human Langerhans cells: a structure in search of new functions. Immunol Today 1994, 15:52-53. Bieber T, Ring J: In vivo modulation of the high affinity receptor for IgE, FcERI, on human epidermal Langerhans cells. Int Arch All C/in Immunol 1992, 99:204-207.

Wollenberg A, Wen SP, Bieber T: Langerhans cells phenotyping: a new tool for the differential diagnosis of eczematous skin diseases. Lancet 1995, 346:1626-1627. A new diagnostic test for atopic eczema is proposed based on the finding that LCs and DCs specifically express high amounts of FcERI in lesional skin

777

of this disease. The LCs and DCs are isolated from small skin biopsies and analyzed by flow cytometry. 13. Wollenberg A, Kraft S, Hanau D, Bieber T: Immunomorphological • and ultrastructural characterization of Langerhens cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol 1996, 106:446-453. Beside classical LCs, the presence of another CDla + (specific marker for LCs and DCs) cell population with strong expression of FcERI is described and characterized. Since they are not present in normal skin, it is suggested that these cells are migrating de novo in the lesional skin as the inflammatory reaction has started. Depending on the conditions, these inflammatory dendritic epidermal cells can account for more than 900/0 of the epidermal CDla + cells. 14. Keegan AD, Paul WE: The multichain immune recognition receptors: similarities in structure and signalling pathways. Immunol Today 1992, 13:63-68. 15. Cambier JC, Daeron M, Fridman W, Gergely J, Kinet JP, Klausner R, Lynch R, Malissen B, Pecht I, Reinherz E et al.: New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL). /mmuno/Today 1995, 16:110. 16. JurgensM, 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~RI. J Immuno/1995, 155:5184-5189. LCs isolated from normal skin and from skin of patients with atopic dermatitis exhibited several profound differences in terms of density of Fc~RI expression and most importantly in terms of activation profile. Only LCs from individuals with atopic dermatitis were fully activated and display Ca2+ mobilization upon receptor ligation. The authors speculate that this could have important consequences for the initiation of the inflammatory reaction and/or for the costimulatory signals delivered by LCs during antigen presentation. 17. Bieber T, J(Jrgens M, Wollenberg A, Sander E, Hanau D, De-la• Salle H: Characterization of the protein tyrosine phosphatase CD45 on human epidermal Langerhans cells. Eur J Immunol 1995, 25:317-321. As for other receptors of the multichain immune recognition receptor family, the protein tyrosine phosphatase CD45 seems to be crucial in the initiation of the signal transduction cascade triggered by Fc~RI ligation on LCs. 18. Capron A, Dessalnt JP, Capron M, Joseph M, Ameisen JC, Tonnel AB: From parasites to allergy: a second receptor for IgE. /mmunol Today 1986, 7:15-18. 19. Bonnerot C, Lamkar D, Hanau D, Spehner D, Davoust J, Salamero •• J, Fridman WH: Role of B cell receptor Igc( and Ig~ subunits in MHC class II restricted antigen presentation. Immunity 1995, 3:335-34?. Although not dealing with FccRI, this paper is crucial for the understanding of the mechanisms leading to IgE-FcERI-dependent antigen focusing provided by APCs. The structures involved in the pathway of antigen uptake from the ceil surface dictate the route that the allergen will follow in order to be efficiently processed and loaded onto MHC class II molecules. 20. Mudde GC, Van-Reijsen FC, Boland GJ, De Gast GC, Bruijnzeel PL, Bruijnzeal-Kooman CA: Allergen presentation by epidermal Langerhans' cells from patients with atopic dermatitis is mediated by igl= Immunology1990, 69:335-341. 21. Maurer D, Ebner C, Reininger B, Fiebiger E, Kraft D, Kinet JP, •Stingl G: The high affinity IgE receptor (FcERI) mediates IgE-dependent allergen presentation. J Immunol 1995, 154:6285-6290. This excellent work is the first report on the role of FcERI in antigen focusing provided by monocytes armed with IgE. It also demonstrates that, in contrast to B cells, the low-affinity receptor for IgE (CD23) is not involved in antigen uptake by monocytes. 22. Hilkens CM, Snijders A, Vermuelen H, Van der Meide PH, Wiarenga EA, Kapsenberg ML: Accessory cell-derived IL-12 and prostaglandin E2 determine the IFNy level of activated human CD4+ T cells. J Immuno/1996, 156:1722-1 727. 23. Galli SJ, Costa JJ: Mast cell leukocyte cytokine cascades in allergic inflammation. Allergy 1995, 50:851-862. 24. Bieber T: Role of Langerhans cells in the physiopathology of atopic dermatitis. Pathol Biol 1995, 43:871-875. 25. Leung DYM: Atopic dermatitis: the skin as a window into the pathogenesis of chronic allergic diseases. J Allergy C/in Immunol 1995, 96:302-318. 26. Semper AE, Hartley JA, Tunon de Lara JM, Bradding P, Redington AE, Church MK, Holgate ST: Expression of the high affinity receptor for immunoglobulin E (IgE) by dendritic cells in normals and asthmatics. Adv E_xpMed Biol 1995, 378:135-138.