Hypothesis on the Role of Complement Activation in type I Allergy Reactions

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Results summarized in the chapter clearly indicate that allergens can activate the complement system both in RW-allergic and non-allergic individuals that is both in the absence and presence of IgE antibodies in the serum and/or on the IgE-receptors of basophils, mast cells and other cell types.

According to this hypothesis summarized in Figure 4, there are several types of interactions between complement activation products and the IgE mediated type 1 hypersensitivity reaction. Allergen-induced complement activation results in generation C5a and C3a that affect sensitization stage of the type 1 hypersensitivity reactions to opposite direction: C3a facilitates while C5a inhibits formation of Th2 type cytokines and IgE antibodies. On the other hand in the effector phase of allergic reaction both C3a and C5a (and maybe other complement activation products such as C5b-9), which are generated on the allergen-exposed mucosa, may affect the basic IgE-mediated processes of the type 1 hypersensitivity reactions. These findings are in accordance with the results of the animal experiments. The very potent inflammatory mediators that are formed from the complement proteins can amplify several processes mostly degranulation triggered by the interaction of allergen with IgE antibodies attached to the IgE receptors of different cells. In addition, complement activation products were found to exert their effect in a concerted action with some lymphokines. E.g. presentation of the human basophilic granulocytes with IL-3 significantly increased the sensitivity of the cells to C3a (38). Furthermore, TNFa was found to efficiently prime neutrophils to the response to C5a (39). According to the studies of Carlson et al. (40) IL-5 selectively primes human eosinophils and neutrophils for C3b-induced degranulation.

Neutrophils Fcr C3b

Figure 4. Interactions between the basic IgE-mediated processes and the allergen-induced complement activation products in the development and effector stage of type 1 hypersensitivity reaction. C5a has a dual effect: inhibits sensitisation and production of IgE antibodies and binds to IgE-FcR and inhibits in this way allergen-induced degranulation of the mast cells. C3a has only enhancing effects: facilitates sensitisation and production of IgE type antibodies, and in the effector phase may bind to C3aR on mast cells and basophil leukocytes and increases degranulation of these cells.

Figure 4. Interactions between the basic IgE-mediated processes and the allergen-induced complement activation products in the development and effector stage of type 1 hypersensitivity reaction. C5a has a dual effect: inhibits sensitisation and production of IgE antibodies and binds to IgE-FcR and inhibits in this way allergen-induced degranulation of the mast cells. C3a has only enhancing effects: facilitates sensitisation and production of IgE type antibodies, and in the effector phase may bind to C3aR on mast cells and basophil leukocytes and increases degranulation of these cells.

In persons not allergic to RW, complement activation alone does not result in inflammatory symptoms. Binding of allergens to IgE fixed to IgE-Fc receptors of basophils and mast cells and the consequential degranulation of these cells is an absolute prerequisite of the development of the symptoms. On pollen-exposed mucosa of the RW-allergic individuals interactions depicted in Figure 4 occur. According to the findings detailed above, the severity of the allergic symptoms is related to the extent of complement activation that is the extent of complement activation acts as a fine-tuner of IgE-mediated type 1 hypersensitivity reaction. Complement activation products may enhance the basic, IgE-dependent early and/or late pathological mechanisms e.g. degranulation of mast cells or the chemotaxis and activation of eosinophil leukocytes. Therefore in RW-allergic subjects with a high individual reactivity of complement to RWA the symptoms will be more frequent and/or severe than in the allergic subjects with low complement reactivity. The intensity of this activation, that is the individual reactivity of complement to RWA and possibly to other allergens, is regulated by some yet unidentified factors, with probable involvement of natural antibodies. It would be most important to disclose the factors that are responsible for the low and high complement reactivity of different allergic and non-allergic individuals.

Both animal experiments and observations obtained in patients support the important modulating role of complement activation in the allergy and asthma. Most recently Nakano et al (41) detected elevated C3a in plasma from patients with severe asthma. These findings may have clinical implications and open new avenues for the treatment of allergic patients. According to the very recent results of Taube et al. (42) inhibition of complement activation decreases, indeed, airway inflammation and hyperresponsiveness in mice. Since the development of complement inhibitors is in progress and several of these substances are in phase I or even phase II clinical trials, the first attempts to apply these drugs in the clinical practice may be expected in the near future. Only the results of these experimental trials may decide if the hypothesis on the essential modulating effect of the complement system is correct.

1. Walker, I.C. Complement fixation and precipitin reactions with the serum of broncial asthmatics who are sensitive to the proteins of wheat, horse dandruff, cat hair, and bacteria, using these proteins as antigens, and the cutaneous reaction as an index of sensitization. J Med Res 1917; 36:243-246

2. Albus, G. Beinflussung der Antikorperkonzentration durch spezifische Desensibilierung bei Pollenallergie. Z Ges Exp Med 1935; 95:703-707

3. Cavelti, P.A. Complement fixation studies in allergy. J Allergy 1950; 21:532-544

4. Berrens, L., Van Rijswijk-Verbeek, J., Guikers, C.L.H. Characteristics of complement consumption by atopic allergens. Immunochemistry 1976; 13:367-372

5. Berrens, L., Guikers, C.L.H., van Dijk, A.G. Studies in serum factors mediating complement consumption by house dust allergens Monographs in Allergy. 1979; 14:150-154

6. Nagata, S., Glovsky, M. 1987. Activation of human serum complement with allergens I. Generation of C3a, C4a, and C5a and induction of human neutrophil aggregation. J Allergy Clin Immunol 1987; 80:24-32

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