From parasites to allergy: a second receptor for IgE

Immunology Today, vol. 7, No. 1, 1985

reviewsFrom parasites to allergy: a second receptor for igE

Human allergic responses are triggered when mast cells bind IgE antibodies. IgE production is also a regular feature of helminth infection and parasites can be killed by inflammatory cells such as macrophages, eosinophils and platelets sensitized by reaginic antibody. The IgE receptor they use has been identified only recently. Here Andre Capron and his colleagues discuss how it differs from the IgE receptor present on mast cells.

In the past decade it has become clear that antibody-dependent cellular cytotoxicity (ADCC) is a primary defence mechanism against several helminth parasites 1-3. Strikingly, inflammatory cells, such as macrophages, eosinophils and platelets, rather than lymphoid cells, are the active cellular partners in parasite killing, and isotypes usually associated with immediate-type hypersensitivity reactions appear to be the essential antibodies involved (Fig. 1). Parallel studies on the control of the IgE response also clearly indicated that T and B cells bear receptors for IgE and that these participate in the isotypic regulation of the production of this immunoglobulin 4-6. The ability of IgE-activated cells to kill parasites is all the more remarkable because conventional cytotoxicity reactions appear either ineffective or of low efficiency against helminths 7 . The crucial participation of IgE was clearly shown by a series of experiments in which selective depletion of IgE, inhibition by aggregated myeloma IgE, and the use of an anti-Fc~ receptor antibody dramatically decreased the killing capacity of macrophages, eosinophils and platelets 8 13 More direct evidence was obtained by attempting to induce such cytotoxic reactions with an anti-schistosome IgE monoclonal antibody 13. These experiments have deepened our understanding of immunity to schistosomes, and led to the identification of target antigens on schistosome larvae and to their purification and in-vitro production 14-16. However, these novel interactions between IgE antibodies or anaphylactic subclasses of IgG and non-mast cell populations raised the possibility that hitherto unsuspected receptors for IgE might exist on inflammatory cells. Various experimental procedures, including rosette formation with IgE-coated erythrocytes, binding of labelled IgE, use of polyclonal and, more recently, monoclonal anti-Fq receptor antibodies, have now allowed the unequivocal demonstration of specific receptors for IgE on macrophages, eosinophils and platelets in man and various animal Centre d'lmmunologle et de Biologie Parasitaire, Unit4 Mixte INSERM 167-CNRS624, Institute Pasteurde Lille, France

A. Capron,J.P. Dessaint, M. Capron,M. Joseph, J.C. Ameisenand A.B. Tonnel species6,11,12,17 20 The most striking characteristic of this newly discovered receptor for IgE is that it has a lower affinity (Ka 107 M -1) (Ref. 21) than the classical mast cell or basophil receptor (Ka 10 9 M 1). It also has a distinct antigenicity: antibodies to mast cell receptors and inflammatory cell receptors do not cross react whereas polyclonal and monoclonal antibodies to the latter receptor bind similarly to macrophages, eosinophils and platelets and inhibit their interaction with IgE molecules 12'13'19,2°. Notwithstanding possible structural similarities 6'21'22, these distinctions appear clear enough to justify the demarcation of a second class of receptors for IgE (Fc~R2) expressed by inflammatory cells (Table 1). On occasions it has been argued that the lower affinity of this second receptor could lessen its real biological significance in IgE-dependent reactions. In fact, the affinity observed for monomeric IgE (107 M 1) is by all means comparable with, or even higher than, the affinity generally reported for the IgG receptors 23. On the other hand, the increased extrinisic affinity of Fc~R2 for IgE dimers or complexes (Ka 108 M -1) (Refs 24, 25) gives this class of receptors a particular significance in all situations where IgE complexes are produced, such as parasitic infections,2 26 ,27 and allergic diseases28 ' 3O . In addition, the number of FqR2-bearing cells increases when IgE levels are increased pathologically

MAST CELL

EOSINOPHIL ISCHISTOSOMULUM I

Fig.1.Anaphylacticantibody-dependentcell-mediatedcytotoxicityagainstSchlstosomamansonilarvae(schistosomula)in the rat. These in vitro correlatesof protective immunity proceed by a first step of eosinophil-mediatedkilling by anaphylacticIgG2a antibody, followed by a long-persistingstage whereIgEantibody-dependentcytotoxicityis achievedby mononudearphagocytes,eosinophilsandplatelets. © 1986, ElSevierSciencePublishersB.V.,Amsterdam 0167-4919/86/$02.00

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Immunology Today, voL ~No. 1, 1986

-reviews Table I Properties of the two types of receptors for IgE Fc~R1

Fc~R2

Distribution

Mast cells Basophils P cells

Subpopulations of: Macrophages, monocytes Eosinophils Platelets T and B lymphocytes

Number/cell

From 104 (basophils) to 106 (mast cells)

From 103 (platelets) to 5 x 10s (macrophages)

Affinity range a

109 M q

For IgE monomers: ~ 1 0 7 M -1 For IgE dimers: - 108 M -1

Structure

Trypsin-sensitive dimer: o~chain 45-50 kDa 13chain 25-33 kDa b

Antigenicity

Tetramer: 1 c~chain 45 kDa 1 13chain 33 kDa 2 3' chains 9 kDa Common to all Fc~R1+ cell types

Modulation Cell activation by

Unknown Aggregated/complexed IgEd

Expression increased by IgE Aggregated/complexed IgEd

Consequences of Fc,Rdependent activation

Mediator release

Secretion of various inflammatory mediators: inflammatory cells Isotypic regulation of IgE response by IgE binding factors: lymphocytes

Common to all Fc~R2+ celt types c

associationequilibriumconstant b13chainpossiblyanalogousto thatof theFqR~onbasophils/mastcells24 casshownbypolyclonal6'~~,42ormonoclonal2°anti-Fc~R2antibody.Antigenicitydistinctfromthatof theFqR1onbasophils/mastcells dminimalactivatingform:IgEdimers21'33 a

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or experimentally 6'~1. Finally, ex-vivo flow cytometry analyses of cell populations from parasitized or allergic individuals indicate the existence of surfacebound IgE on a large proportion of inflammatory cells3~. These last observations are supported by the ability to transfer immunity to schistosomes by IgE antibody-bearing cells from immune donors as well as by monoclonal IgE antibodies. Therefore one can accept that, both in vitro and in vivo, inflammatory cells can, like mast cells or basophils, selectively bind IgE molecules. The important question is thus whether or not these cells participate in IgE-dependent reactions (either protective immunity against parasites or adverse allergic manifestations). Soon after the binding of IgE of the appropriate molecular form - i.e. at least dimers 33 - signs of cell activation can be detected in the various populations concerned (Table 2). As well as the oxygen metabolites that are commonly generated by inflammatory cells, more specialized mediators are released, depending on the particular cell population. In the case of macrophages, IgE triggers the secretion of lysosomal enzymes, sulphidopeptide leukotrienes, prostaglandins, platelet activating factor (PAF) and of interleukin 16'34-39. With eosinophils, PAF and eosinophil peroxidase (EPO)

predominate 4°. The case of platelets demonstrates the selectivity of signals delivered through IgE binding: whereas upon IgG-dependent activation there is a significant release of serotonin but no production of oxygen metabolites, the reverse is observed after triggering by IgE4~. Similarly, in IgGdependent reactions, eosinophils liberate significant amounts of cationic proteins (major basic protein, MBP; eosinophil cationic protein, ECP)42'43, whereas, upon IgE activation, cationic proteins are barely detectable and the predominant substance released is EPO4°. -It should also be stressed that IgE antibodies but not IgG can induce schistosome killing by macrophages or platelets 8'9'12. Even in the case of rat eosinophils, which can damageparasite targets in the presence of IgG antibodies 4 4 .,4 5 , it is the anaphylactic IgG2a subclass that triggers eosinophil cytotoxicity 4~. It is presently difficult to assess whether this selectivity relies on cell compartmentalization or on differences in activation pathways. It should be remembered in this respect that IgE binding to macrophages is followed by a rapid increase in cellular cyclic GMP 33, while in mast cells an increase in cyclic AMP is one of the major initial events 47. Furthermore, this apparent selectivity might be related to the existence of specialized cell sub-

Immunology Today, voL 7, No. 1, 1986

reviews-

Table 2 Functional consequencesof inflammatory cell activation via Fc~R2 Cell type

Releaseof

References

Mononuclear phagocytes

Lysosomalenzymes Plasminogen activator Oxygen metabolites Interleukin 1 Sulphidopeptide leukotrienes Prostaglandins PAF

33-35 1 34, 35 Dessaint etal., unpublished 36-39 37 35

Eosinophilsa

Oxygen metabolites Peroxydase(FPO) PAF

40

Oxygen metabolites Cytocidal mediators

41 41

Plateletsb apredominantlybyhypodensecells bdefectiveinthr0mbasthenicplatelets

populations, a case which is illustrated by the study of eosinophil heterogeneity. A particular subset of human eosinophils, characterized by low density on metrizamide gradients, preferentially expresses IgE .receptors and can release EPO and PAF by anaphylactic antibody challenge; this is associated with the ability to kill parasite targets ~1'4°'48'49. This sequence of activation might also involve the association of the Fc~R2 with other molecules of the cell membrane. Platelets from thrombasthenic patients, for instance, known to be specifically lacking lib-ilia glycoproteins, do not express receptors for IgE and cannot be activated by IgE molecules. Interestingly, monoclonal antibodies to group lib-Ilia glycoproreins dramatically inhibit IgE binding and IgEdependent activation of normal platelets 41 . Along the same line, the hypodense subset of eosinophils also bear complement receptors 1 and 3, and Fc~ R2 (Ref. 50). The selective activation of inflammatory cell subpopulations through their Fc, R2 does not exclude a role for mast cells bearing the Fc~ R~. In this respect, eosinophil-mediated cytotoxicity in the rat requires accessory mast cells or their mediators, among which eosinophil chemotactic factor of anaphylaxis (ECF-A) plays an essential role 46. ECF-A tetrapeptides enhance the expression of Fc{ R2 on rat and human eosinophils 48. All these observations, which have mainly been made during our studies of parasite models, have a particular significance in the context of allergic reactions. Macrophages 34,3s, eosinophils 31 and platelets 4~ from allergic individuals bear IgE antibodies on their surfaces and upon activation by specific allergens or anti-lgE, release an array of inflammatory mediators in vitro and in vivo s~.

Fc~R2 and allergy These results might have a particular importance for the predictive diagnosis and possibly therapy of allergic reactions. One example is provided by

platelets from people sensitized to Hymenoptera (bee) venom. In these people platelets can be triggered directly by the purified allergen to produce cytocidal factors and oxygen metabolites which are a consequence of activation by IgE. This reactivity significantly decreases during efficient desensitization treatment. Also of interest is the observation that disodium cromoglycate, which inhibits mast cell or basophil degranulation, strongly reduces IgE-dependent activation of macrophages 52, eosinophils and platelets (M. Joseph et a/., unpublished). Taken together, this series of observations clearly indicates that mast ceils and basophils can no longer be considered the only cell population involved in IgE-dependent reactions. Inflammatory cells, through the expression of Fc~ R2 and the presence of cytophilic IgE, can directly (and not accessoriiy as previously supposed) participate as effector ceils in the pathology of allergic reactions and particularly in their inflammatory components. Although it appears that Fc~ receptors behave as an important signalling structure on inflammatory cell populations, they are obviously not the only one. There is evidence that tissue eosinophils belong to the hypodense Fc~ R2+ subset, and that this particular subpopulation has a prominent role in tissue lesions observed in hypereosinophilic syndromes 49, but there is as yet no direct indication of the involvement of the Fc~ receptors in the activation of these cells. Another example is provided by aspirin-sensitive asthma, a disease of unknown mechanism, in which IgE-dependent reactions have been clearly ruled out~52 . Our recent studies have shown that aspirin and other cyclooxygenase inhibiting drugs which induce asthmatic attacks in these patients abnormally activate their platelets through a non IgE-dependent mechanism, to release cytocidal factors and generate oxygen metabolites. This abnormal platelet response is

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-reviews directly related to the inhibitory effect of these drugs on ptatelet prostagtandin synthesis and involves the generation of lipoxygenase metabolites of arachidonate s3. These findings suggest that the existence of Fq R2 on inflammatory cells reflects selective activation capacities which might be abnormally triggered in pseudo-allergic diseases through IgE-independent mechanisms.

Conclusion

We have shown here that a receptor for IgE is an important functional structure for macrophages, eosinophils and platelets. In parasitic disease or immediate-type hypersensitivity, where there is an increased production of IgE and the formation of IgE complexes, Fq R2 is an essential initiator of the cellular activation pathway. In defence against parasites, this structure appears to be highly beneficial and of considerable evolutionary significance. In allergy, the existence of Fq R2 points to a specialized function, so far unsuspected in specific immunological reactions, for cell populations previously thought confined to nonspecific inflammatory responses.

References

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Immunology Today, voL 7, No. 1, 1986

19 Melewicz, F.M., Plummer, J.M. and Spiegelberg, H.L. (1982) J. ImmunoL 129, 563 569 20 Capron, M., Joseph, M., Prin, L. etal. in Proceedings of the Annual Meeting of the European Academy of Allergy and Clinicallmmunology, Stockholm, 2 5 June 1985 (in press) 21 Metzger, H., Kinet, J.P. and Perez-Montfort, R. (1983)Progr. ImmunologyV(Yamamura, Y. and Tada, T. eds), pp. 493 501, Academic Press, Tokyo 22 Finbloom, D.S. and Metzger, H. (1983) J. ImmunoL 30, 1489-1491 23 Unkeless, J.C., Fleit, H. and Hellman, I.S. (1981)Adv. Immunol. 31,247-270 24 Finbloom, D.S. and Metzger, H. (1982)J. Immunol. 129, 2004-2008 25 Dessaint, J.P., Capron, A., Joseph, M.L. etal. (1983)in Macrophage-Mediated Antibody-Dependent Cellular Cytotoxicty(Koren, H.S., ed.), pp. 315-338, Marcel Dekker, New York 26 Santoro, F., Capron, M., Joseph, M. etal. (1978) Clin. Exp, ImmunoL 32,435-442 27 Stevens, W.J., Feldmeir, H., Bridts, C.H. etaL (1983) Olin. Exp. Immunol. 52, 142-152 28 Brostoff, J., Johns, P. and Stanworth, D.R. (1977)Lancet i i, 741 29 Stevens, W.J. and Bridts, C.A. (1984)J. Allergy Clin. ImmunoL 73,276-282 30 Manger, B.J., Kraft, F.E., Gramatzki, M. etal. (1985) Scand. J. ImmunoL 21,369-373 31 Capron, M., Kusnierz, J.P., Prin, L. etal. (1985) J. Imrnunol. 134, 3013-3018 32 Capron, M. Noguiera-Querioz, J.A., Papin, J.P. etaL (1984) Cell. ImmunoL 83, 60-72 33 Dessaint, J.P., Waksman, B.H., Metzger, H. etal. (1980) Cell. ImmunoL 51,280-292 34 Joseph, M., Tonnel, A.B., Capron, A. etaL (1980) Clin. Exp.. Immunol. 40, 416-422 35 Joseph, M., Tonnel, A.B., Capron, A. etal. (1983) J. Clin. Invest. 71,221-230 36 Rouzer, C.A., Scott, W.A., Hamill, A.L. etal. (1982) Proc. Natl Acad. Sci. USA 79, 5656-5660 37 Rouzer, C.A., Scott, W.A., Hamill, A.L. etal. (1982) J. Exp. Med. 156, 1077-1086 38 Rankin, J.A., Hitchcock, M., Merrill, W.W. etal. (1982) Nature (London) 297, 329-331 39 Rankin, J.A., Hitchcock, M., Merrill, W.W. etal. (1984) J. ImmunoL 132, 1993-1999 40 Khalife, J., Capron, M., Grzych, J.M. etaL (1985) J. Immunol. 134, 1968-1974 41 Capron, A., Ameisen, J.C., Joseph, M. et aL (1985) Int. Archs. Allergy AppL Immunol. 77, 107-114 42 Butterworth, A.E., Wassom, D.L., Gleich, GJ. et aL (1979) J. ImmunoL 122, 221-229 43 McLaren, D.J., McKean, J.R., Olsson, I. etal. (1981) Parasite Immunol. 3,359-373 44 Butterworth, A.E., Sturrock, R.F., Houba, V. etaL (1974) Nature (London) 252, 503-505 45 Butterworth, A.E. Remold, H.G., Houba, V. etal. (1977) J. ImmunoL 118, 2230-2236 46 Capron, M., Capron, A., Torpier, G. etaL (1978) Eur. J. Immunol. 8, 127 133 47 Ishizaka, T. (1983) in Progress in Immunology 1 (Yamamura, Y. and Tada, T. eds), pp. ;503 512, Academic Press, Tokyo 48 Capron, M., Capron, A., Joseph, M. etal. (1983) Monogr. Allergy 18, 33-44 49 Prin, L., Charon, J., Capron, M. etal. (1984) Clin. Exp. Immunol. 57,735 742 50 Tonnel, A.B., Joseph, M., Gosset, Ph. etal. (1983) Lancetl, 1406-1408 51 Joseph, M, Tonnel, A.B., Capron, A. etaL (1981)Agents

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