IgE: A molecule in search of a function

VOL,

132 C

N° 1

JANV!ER-FEVR!ER

!98!

ANNALES D'IMMUNOLOGIE

POSITION PAPER

IgE: A M O L E C U L E

IN

SEARCH

OF A F U N C T I O N

by A. Capron and J. P. Dessaint Centre d'lmmunologie el de Biologie Para~;.taire (INSER~,I U-167, CNRS ERA422), Inslilul Pasteur, 15, rue Camille-Gu~rtn, B. P. 245, 59#19 Lille Cedex (France) el Facuiid de Mddecine, Cenlre Hospilalier de Lille, place de Verdun, 59000 Lille (France)

The essential function attributed to immunoglobulin E molecules since the initial description of their isotype in man has been their implication in immunopathological reactions of immediate hypersensitivity [15]. It should be pointed out that besides their deleterious effects du~ng allergic reactions, the mediators released by the degranulation of mast cells can also participate in the regulation of the immune response through H-2 receptor-mediated modulation of cell activation [26]. Mast cell mediators can also have a beneficial role in immunity. Not only do vasoactive amines, in increasing vascular permeability, have an obvious role in allowing a closer contact between the various components of the immune response and the target antigen~ rob+t__+,r,,,+. ~l~.+ in .~ome narasitic, infections vasoactive amines can have a direct participation in the effector phase of the immune response [25]. This focussed concept of IgE in allergy has led to important development concerning the privileged interaction ~f antibodies of the IgE class with their cellular allies, namely mast cells and basophils, but has also led us to underestimate the possible interaction of IgE molecules with other cell populations of the immur:e system. Manuscrit r e c u le 12 juillet 1980, a c c e p t e ie ~ d~cembre 193~.

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A. CAPRON AND J. P. DESSAINT

Interaction with mast cells or basophils. According Z.~ Metzger [22], IgE can be considered as a transducer of cellular stimulation: IgE molecules bound to the surface receptor of mast cells or basophils play a merely passive role, the signal being provided by the aggregation of the receptors themselves, though - - in physiological conditions - - receptors are aggregated by means of the cross-linking of IgE molecules by the corresponding (multivalent) antigen [15, 22]. Once the minimal threshold of receptor aggregation on a given surface area of the V cell is reached, a signal is given to the corresponding cellular compartment. Depending upon the number of eross-linkings, the compartment is turned to either activation, which releases the mediators of anaphylaxis, or to deactivation and the subsequent desensitization to additional stinmli [8, 9]. In this respect, IgE adds to its function of h'ansduction o~ cell activation, a modulatory role on the cellular response at the compartmental level. One of the paradoxes in parasitic d i s e a s e s - specially helminthie infect i o n s - is the massive production of IgE, either parasite-specific or directed against environmental antigens through the mechanism of potentiation (reviewed in [16]), contrasting with the low incidence of allergic manifestations classically reported in endemic areas [28]. Among possible explanations, a preeminent role of antigenic competition or saturation of the mast cell receptors has been suggested, but cannot any longer be accepted as the only explanation since cutaneous reactions are still elieitable [28], eventhough mast cells of different tissues differ in their saturability by IgE [24]. A more recent approach to this problem has been the identification of a pharmacologically active sehistosome-derived inhibitory factor (SDIF) which modulates mast cell degranulation both in Vitro and 2~ L, vioo, leading to a significant decrease in the release of mediators of anaphylaxis [20]. Another classical and striking feature of the immune response to parasites, specially metazoans, is the production of large numbers of eosinophils which can be detected both in blood and in tissues. In addition to the recognized association of eosinophilia and immediate hypersensitivity, and the particular regulatory function of eosinophils in these reactions, the recent demonstration of the effeetor role played by these cells in antibodydependent cell-mediated eytotoxieity (ADCC) to some metazoan parasites [2] requires consideration of the possible interaction between eosinophils and anaphylaetie antibodies. Interaction of IgE with eosinophils and macrophages. It has been shown in rat schistosome infections that not only IgG2a anaphylactic antibodies but also mast cells are essential requirements for eosinophil-mediated cytotoxicity [7]. The existence of an interaction of IgG-antibody classes with the mast cell and eosinophil surface is widely accepted. However, the necessary requirement of mast cell-eosinophil cooperation almost necessarily implies the intervention of IgE in this ADCC

IgE: A MOLECULE IN SEARCH OF A FUNCTION

5

system. Recent experiments have shown that not only IgE interacts in this system in inducing mast cell degranulation but also directly activates eosinophils into killer cells through specific receptors [6]. The involvement of IgE has also been shown in an other ADCC system involving mononuclear phagocytes both in humans and in the rat. The first evidence came from experimental rat schistosomiasis where, at the optimal period of immunity to reinfection, a serum factor identified as anti-parasite IgE nntibody was shown to induce macrophage activation and the subsequent in vitro killing of sehistosome larvae [4]. Further studies indicated that IgE antibodies eomplexed with parasite antigens, which are optimally found at that period of infection, were responsible for the development of macrophage cytotoxicity [5, 18]. Monomeric IgE binds transiently to a specific macrophage receptor [11], and IgE dimers appear to be the minimal aggregation requirement to induce the cellular increase in cyclic GMP and the subsequent release of lysosomal enzymes in a calcium-dependent process [ 10, 12]. Whereas the receptor for IgE on mast cells has been described as monovalent and binds IgE at 4o C [22], the IgE receptor on maerophages appears to function multivalently and binds IgE monomers at 37oC only [11]. Once bound and if aggregated, IgE will deliver a triggering signal which is followed by signs of macrophage activation within a shorter period than when aggregated IgG is used [10, 12]. These experiments suggest there may be separate receptors for IgG and IgE on the maerophage, and this view has been strenghthened by competitive inhibition studies with purified IgG or IgE and the recent development of a macrophage activation system using the cross-linking of IgE passively sensitizing maerophages by anti-IgE F(ab')s [10]. The analogy of this system with mast cell degramlULnU~LIjm~lI

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affinity, the receptors expressed by both cells are specific for IgE, distinct from IgG receptors, and deliver the aetivatio~ signal through their dimerization. When mast cell receptors are blocked by excess monomefie IgE, maerophage activation is still obtained by IgE dimers [ 12], which indicates that these aggregated molecules can trigger the maerophage directly. However, this experiment does not exclude that, in vioo, mast cell products could themselves interfere with maerophage activation as suggested by our recent observations. This mechanism of maerophage activation which might initially appear to be restricted to rat schistosomiasis has also been shown to be operative in human sehistosome infections [ 17], and not limited to parasitic diseases. Indeed, evidence has been provided in an in vitro eytotoxieity system of the existence of a receptor for the Fe portion of IgE on human monoeytes [27]. A possible implication of maerophage IgE receptors in atopie reactions of the lung has recently been suggested. A significant secretion of maerophage enzymes and superoxide production could be demonstrated when alveolar maerophages from allergic patients were exposed either to anti-human IgE antibody or to the homologous allergen [19]. It is noticeable that the key role of IgE in the pathophysiology of imme-

6

A. CAPRON AND J. P. DESSAINT

diate hypersensitivity reactions can thus involve not only the classical mast cell degranulation process but also macrophage triggering. Supporting evidence has recently been acquired on the release by macrophages of such mediators as the slow reacting substance [1], the platelet-activating factor [21] and various arachidonic acid metabolites.

Interaction of IgE with lymphoid cells. A receptor for the Fc portion of IgE has been identified on a small percentage of lymphoid cells in man and in the rat. Evidence for a Fc~ receptor has clearly been provided on membrane immunoglobulin-bearing lymphocytes as well as on null cells [13]. The existence of such a receptor on T cells [29] appears more controversial since neither thymus cells nor thoracic duct lymphocytes reportedly seem to bind IgE [14]. The function of these receptors is presently unclear. The participation of IgE in lymphoid cell-dependent ADCC systems has been suggested [14]. But the increase in IgE-binding lymphocytes in situations where serum IgE levels are considerably elevated (atopic diseases, parasitic infections) or when cells are exposed in vitro to high concentrations of IgE, may favour a regulatory role for IgE on its own synthesis [30].

Conclusion. The regulatory function of igE appears more and more to be one of the essential physiological features of this immunoglobulin. The regulation of cell activity by IgE can be achieved either indirectly through vasoactive amines or directly through the modulation of cell activation by the stage of aggregation of IgE molecules on the cell surface. The essential character which governs the selective affinity for the appropriate receptors of various ceil populations, seems to be related to the molecular form in which lgE is presented to the cell. Even when monovalent receptors are present on a given cell surface, only bivalent binding at least of aggregated IgE can deliver the triggering signal [8, 9, 15, 9.2]. The importance and/or the density of separate signals which are received through receptor cross-linking by the membrane area of the corresponding cell compartment, governs the modality of the response, either cell activation or deactivation [8]. The importance of the molecular form in which IgE is on the plasma membrane is such that, even when a process of cell activation has already taken place, the rearrangement of IgE molecules either in larger aggregates [8] or inveisely in monomers [9] can switch off activation and switch on deactivation. The most meaningful lesson which can be drawn from the past five years litterature is certainly the widespread interaction of IgE -with the most important cellular components of the immune response. The exact significance of these diversified interactions is certainly still unclear. But the evidence now accumulated concerning the effect of IgE-binding on cellular function allows us to speculate that IgE might act as a humoral messenger which modulates the activity of its targets cells. At this stage,

IgE: A MOLECULE iN SEARCH OF A FUNCTION

7

one may question whether the classical effector funcLion attributed to IgE in immediate-type hypersensitivity is not a mere side-effect of the general function of this immunoglobulin or whether these various activities are not the reflect of some molecular heterogeneity of this isotype, for which no subclass has so far been described. In any case, from the initial limited role in which IgE was confined, a wider opening on multiple aspects of the immune response is now offered to investigation. KEY-WORDS: IgE, Immunomodulation, tivity; Editorial.

Immediate-type hypersensi-

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and calct~un in macrophage activation by dimeric or aggregated rat myeioma IgE. Cell. Immunol., 1980, 51, 280-292. [!3] GONZALES-MOLINA,A. & SPIEGELBERG, H. L., A subpopulation of normal human peripheral B lymphocytes that bind IgE. J. clin. Invest., 1977, 59, 616-624. [14] HELLSTRiJM, U. & SPIEGELBERG,H. L., Characterization of human lymphocytes bearing Fc receptors for IgE isolated from blood and lymphoid organs. Scand. J. Immunol., 1979, 9, 75-86. [15] ISHIZAKA, K. & ISHIZAKA, T., Mechanisms of reaginic hypersensitivity. Immunol. Rev., 1978, 41, 109-148. [16] JARRETT, E. E. E., Stimuli for the production and control of IgE in rats. Immunol. Rev., 1978, 41, 52-76. [17] JOSEPH,M., CAPRON,A., BUTTER'~VORTH,A. E., STURROCK,R. F. • HOUBA,V., Cytotoxicity of human and baboon mononuclear phagocytes against schistosomula in pilro: induction by immune complexes containing IgE and Schislosoma mansoni antigens. Clin. exp. lmmup.ol., 1978, 33, 45-56. [!81 JOSEPH, M., DESSAINT, J. P. & 4APRON, A., Characteristics of rr_aerophage cytotoxicity induced by IgE immune complexes. Cell. Immunol., 1977, 34, 247-258. [19] JOSEPH, M., TONNEL, A. B., CAPRON, A. & VOISIN, C., Enzyme release and superoxide anion production by human alveolar macrophages stimulated with immunoglobulin E. Clin. exp. Immunol., 1980, 40, 416-422. [20] MAZINGUE,4., DESSAINT,J. P. & 4APRON,A., Modulation de la d~granulation mastocytaire dans la schistosomiase exp6rimentale du rat. Ann. Immunol. (Inst. Pasteur), 1978, 129 C, 754. [21] MENCIA-HUERTA, J. M. & BENVENISTE, J., Platelet-activating factor and macrophages, m I. Evidence for the release from rat and mouse peritoneal macrophages and not from mastocytes. Europ. J. Immunol., 1979, 9, 409-415. [22] METZGER, H., The IgE-mast cell system as a paradigm for the study of antibody mechanisms. Immunol. Hey., 1978, 41, 186-199. [23] M~aRAY, M., Secretory antibody and local immunity: effector mechanism of immediate hypersensitivity at mqcosal interfaces. Proc. roy. Soc. Med., 1Q79 at g=,Q_g~9 [24] PROUVOST-DANON,A. &; ABADIE, A., Competitive inhibition of passive sensitization of mouse mast cells by IgE. A bioassay for mouse and rat IgE. Immunology, 1976, 31, 689-696. [9.5] BOTHWELL,T. L. W., LOVE, R. J. & EVANS, D. P., Studies on the role of histamine and 5-hydroxytryptamine in immunity against the nematode Trichoslrongglus colubri/ormis. ~ IV. Inhibition of the expulsion of worms transplanted into the duodenum of immune guinea-pigs. Int. Arch. Allergy, 1978, 56, 457-462. [26] SAxoN, A., MORLEDGE, V. D. & BONAVIDA, B., Histamine-receptor leucocytes (HRL). Organ and lymphoid subpopulation distribution in mouse. Clin. exp. Immunol., 1977, 28, 394-399. [27] SPIEGELBERG, H. L. & MELEVdICZ,F. M., Fc receptors specific for IgE on subpopulations of human lymphocytes and monocytes. Cliu. Immuuol. Immunopath., 1980, 15, 424-433. [28] TURNER, K. J., QUINN, E. H. & ANDERSON,H. R., Regulation of asthma by intestinal parasites. Investigation of possible mechanisms. Immunology, 1978, 35, 281-288. [29] YODOI, J. & ISHIZAKA,K., Lymphocyte bearing Fc receptors for IgE. - - I. Presence of human and rat T lymphocytes with Fct receptors. J. Immunol., 1979, 122, 2577-2583. [30] YODOI, J. & ISttlZAKA, K., Lymphocyte bearing receptors for IgE. ~ III. Transition of FcyR(-F-) cells to FceR(+) cells by IgE. J. 1mmuuol., 1979, 123, 2004-2010. aLvaad,

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