Immunology Today, vol. 6, No. 4, 1985
130 23 Walker, I. D. and Harris, A. W. (1980) Nature (London) 288, 290-293 24 Schwaber, J., Molgaard, H., Orkin, S. H., Gould, H.J. and Rosen, F. S. (1983) Nature (London) 304, 355-358 25 Watson, M. E. E. (1984)NucleicAcids Res. 12, 5145-5164 26 Patten, P., Yokata, T., Rothbard, J., Chien, Y., Arai, K. and Davis, M. M. (1984) Nature (London) 312, 40-46 27 Sakano, H., Kurosawa, Y., Weigert, M. and Tonegawa, S. (1981) Nature (London) 290, 562 565
28 Yaoita, Y., Matsunami, N., Choi, C. Y., Sugiyama, H., Kishimoto, T. and Honjo, T., (1983) NudeicAcids Res. 11, 7303-7316 29 Bothwell, A. L. M., Paskind, M., Reth, M., Imanishi-~ari, T., Rajewsky, K. and Baltimore, D. (1981) Cell 24, 625-634 30 Kurosawa, Y. and Tonegawa, S. (1982)J. Exp. Med. 155, 201-218 31 Manser, T., Huang, S-Y. and Gefter, M. (1984) Science 226, 1283-1288 32 Near, R. I. K., Juszczak, E. C., Huang, S-Y., Sicari, S. A., Margolies, M. N. and Gefter, M. L. (1984) Proc. NatlAcad. Sci. USA 81, 2t67-2171
Leukocyte activation and the asthmatic response H u m a n asthmatic responses have traditionally been considered the result of the immediate effects of one or more mediators on the bronchial wall, leading to smooth muscle spasm, hypersecretion of mucus, and resultant airway narrowing. However, in recent years it has been recognized that the pathogenesis of asthma is more complex. In patients a prominent accumulation of inflammatory cells in the bronchial wall is common and after environmental exposure or inhalation challenge with antigens to which a subject shows IgE sensitivity there is often not only an immediate bronchospastic response but a similar reaction occurring 6-12 h later. It is also now clear that pharmacotherapeutic agents which are potent inhibitors of the immediate response often exert little if any effect on the delayed reaction. The mechanism underlying the inflammatory cell responses in asthma is not well defined. However, a potential mechanism was suggested by our finding I that bronchospasm induced during antigen inhalation challenge is accompanied by an increased serum level of a high molecular weight neutrophil chemotactic activity ( H M W - N C A ) . This increase in serum H M W - N C A correlated with the degree ofbronchospasm induced and persisted over a period of hours only in those individuals exhibiting late-onset as well as immediate bronchoconstriction 1-3. There was also a correlation between the increase in H M W - N C A and an increased circulating neutrophil leveP. Recently, K a y ' s group at the Brompton Hospital in London reported 5 that increased C3b receptor activity on both neutrophils and monocytes was temporally associated with the increase in serum H M W N C A and bronchoconstriction after antigen inhalation challenge of sensitive subjects. The increase in C3b receptors was found during both the immediate and late phase reactions in subjects who showed dual responses. Neither increased serum H M W - N C A nor increased leukocyte C3b receptors occurred with bronchospasm induced in a nonimmune reaction by methacholine 1'4'5. Two questions are raised by these interesting findings. W h a t is the mechanism underlying the increase in C3b receptors? Although a definite answer is not yet to hand, the most likely explanation is that increased C3b receptors reflect a perturbation of the membrane of the cells following interaction with H M W - N C A . Similar enhancement of C3b receptors on neutrophils follows in-vitro interaction of these cells with other chemoattractants such as F-MetLeu-Phe or leukotriene B4 6. A similar effect of H M W N C A on neutrophils would not be surprising since H M W - N C A is chemotactic for these cells. H M W - N C A has not been shown to be chemotactic for monocytes 1.zbut primary activation of neutrophils could result in secondary elaboration of a chemoattractant'for monocytes 7. This interaction could possibly cause a membrane © 1985;ElsevierSciencePublishersB.V., Amsterdam 0167- 4919/85/$02.00
perturbation leading to increased expression of C3b receptors. It should be noted that there is no decrease in serum complement levels at the time the C3b receptor activity on these cells would be increased 1. The second question concerns the pathophysiologic implications of these findings. These should be viewed in the light of several recent studies. After in-vitro incubation with a variety of chemoattractants, neutrophils may exhibit decreased mobility, increased release oflysosornal enzymes and other granular contents. There is increased production of several proinflammatory mediators such as superoxide radicals, prostaglandins and leukotrienes 8. Under similar conditions, activated monocytes can release interleukin 1, elastase myeloperoxidase and lysozyme 9. Histologic studies have demonstrated the prominent and prolonged accumulation of granulocytes and mononuclear cells in allergic reactions 10.11. Furthermore, there is in-vitro and in-vivo evidence in animal studies that activation of these cell types leads to tissue damage and increased bronchial liability 12. Thus, the concept of the pathophysiology of asthma must be broadened to include not only ,the smooth muscle spasm and increased mucus production mentioned earlier, but also the recruitment and activation of inflammatory cells. Do these cellular inflammatory responses serve only a proinflammatory role? Do they explain in part the beneficial effects of corticosteroids? These and other questions will need to be answered but the important first step has been taken - the demonstration that the induction of asthma is accompanied by in-vivo activation of circulating leukocytes. ~[] References 1 Atkins, P. C., Norman, M., Weiner, H. and Zweiman, B. (1977) Ann. Intern. Med. 86, 415-418 2 Atkins, P. C., Norman, M. E. and Zweiman, B. (1978)J. AUergy Clin. Immunol. 62, 149-155 3 Nagy, L., Lee, T. H. and Kay, A. B. (1982) N. Engl. J. Med. 306, 497-501 4 Atkins, P. C., Norman, M., Zweiman, B. and Rosenblum, F. (1979)O( Allergy'Clin. Immunol. 64, 251-528 5 Durham, S. R., Carrol, M., Walsh, G. M. and Kay, A. B. (1984) N~ Engl. J. Med. 311, 1398-1402 6 Fearon, D. T. and Collins, L. A. (1983) Clin. Exp. Immunol. 38,294-299 7 Ward, P. A. (1968),]2 Exp. Med. 128, 1201 8 Gallin, J. I. (1984) Clin. Res. 32, 320-328 9 Cohen, A. B., Chenoweth, D. E. and Hugli, T. E. (1982) Am. Rev. Respir. Dis. 126, 241 10 Atkins, P. C., Green, G. R. and Zweiman, B. (1973)J. Allergy Clin. Immunol. 51, 763 11 Soney, G. O., Gleich, G. S., Jordan, R. E. and Schroeter, A. L. (1976) J. Clin. Invest. 58, 408 12 Fabberi, L. M., Aizawa, H., Alpert, S. E., Walters, E. H., Byrne, P. M., Gold, B. D., Nadel, J. A. and Haltzman, M. J. (1984) Am. Rev. Respir. Dis. 129, 288 PAUL. C. ATKINS BURTON ZWEIMAN
Department of Medicine, Allergy and Immunology Section, University of Pennsylvania, Philadelphia, PA 19104, USA
130 23 Walker, I. D. and Harris, A. W. (1980) Nature (London) 288, 290-293 24 Schwaber, J., Molgaard, H., Orkin, S. H., Gould, H.J. and Rosen, F. S. (1983) Nature (London) 304, 355-358 25 Watson, M. E. E. (1984)NucleicAcids Res. 12, 5145-5164 26 Patten, P., Yokata, T., Rothbard, J., Chien, Y., Arai, K. and Davis, M. M. (1984) Nature (London) 312, 40-46 27 Sakano, H., Kurosawa, Y., Weigert, M. and Tonegawa, S. (1981) Nature (London) 290, 562 565
28 Yaoita, Y., Matsunami, N., Choi, C. Y., Sugiyama, H., Kishimoto, T. and Honjo, T., (1983) NudeicAcids Res. 11, 7303-7316 29 Bothwell, A. L. M., Paskind, M., Reth, M., Imanishi-~ari, T., Rajewsky, K. and Baltimore, D. (1981) Cell 24, 625-634 30 Kurosawa, Y. and Tonegawa, S. (1982)J. Exp. Med. 155, 201-218 31 Manser, T., Huang, S-Y. and Gefter, M. (1984) Science 226, 1283-1288 32 Near, R. I. K., Juszczak, E. C., Huang, S-Y., Sicari, S. A., Margolies, M. N. and Gefter, M. L. (1984) Proc. NatlAcad. Sci. USA 81, 2t67-2171
Leukocyte activation and the asthmatic response H u m a n asthmatic responses have traditionally been considered the result of the immediate effects of one or more mediators on the bronchial wall, leading to smooth muscle spasm, hypersecretion of mucus, and resultant airway narrowing. However, in recent years it has been recognized that the pathogenesis of asthma is more complex. In patients a prominent accumulation of inflammatory cells in the bronchial wall is common and after environmental exposure or inhalation challenge with antigens to which a subject shows IgE sensitivity there is often not only an immediate bronchospastic response but a similar reaction occurring 6-12 h later. It is also now clear that pharmacotherapeutic agents which are potent inhibitors of the immediate response often exert little if any effect on the delayed reaction. The mechanism underlying the inflammatory cell responses in asthma is not well defined. However, a potential mechanism was suggested by our finding I that bronchospasm induced during antigen inhalation challenge is accompanied by an increased serum level of a high molecular weight neutrophil chemotactic activity ( H M W - N C A ) . This increase in serum H M W - N C A correlated with the degree ofbronchospasm induced and persisted over a period of hours only in those individuals exhibiting late-onset as well as immediate bronchoconstriction 1-3. There was also a correlation between the increase in H M W - N C A and an increased circulating neutrophil leveP. Recently, K a y ' s group at the Brompton Hospital in London reported 5 that increased C3b receptor activity on both neutrophils and monocytes was temporally associated with the increase in serum H M W N C A and bronchoconstriction after antigen inhalation challenge of sensitive subjects. The increase in C3b receptors was found during both the immediate and late phase reactions in subjects who showed dual responses. Neither increased serum H M W - N C A nor increased leukocyte C3b receptors occurred with bronchospasm induced in a nonimmune reaction by methacholine 1'4'5. Two questions are raised by these interesting findings. W h a t is the mechanism underlying the increase in C3b receptors? Although a definite answer is not yet to hand, the most likely explanation is that increased C3b receptors reflect a perturbation of the membrane of the cells following interaction with H M W - N C A . Similar enhancement of C3b receptors on neutrophils follows in-vitro interaction of these cells with other chemoattractants such as F-MetLeu-Phe or leukotriene B4 6. A similar effect of H M W N C A on neutrophils would not be surprising since H M W - N C A is chemotactic for these cells. H M W - N C A has not been shown to be chemotactic for monocytes 1.zbut primary activation of neutrophils could result in secondary elaboration of a chemoattractant'for monocytes 7. This interaction could possibly cause a membrane © 1985;ElsevierSciencePublishersB.V., Amsterdam 0167- 4919/85/$02.00
perturbation leading to increased expression of C3b receptors. It should be noted that there is no decrease in serum complement levels at the time the C3b receptor activity on these cells would be increased 1. The second question concerns the pathophysiologic implications of these findings. These should be viewed in the light of several recent studies. After in-vitro incubation with a variety of chemoattractants, neutrophils may exhibit decreased mobility, increased release oflysosornal enzymes and other granular contents. There is increased production of several proinflammatory mediators such as superoxide radicals, prostaglandins and leukotrienes 8. Under similar conditions, activated monocytes can release interleukin 1, elastase myeloperoxidase and lysozyme 9. Histologic studies have demonstrated the prominent and prolonged accumulation of granulocytes and mononuclear cells in allergic reactions 10.11. Furthermore, there is in-vitro and in-vivo evidence in animal studies that activation of these cell types leads to tissue damage and increased bronchial liability 12. Thus, the concept of the pathophysiology of asthma must be broadened to include not only ,the smooth muscle spasm and increased mucus production mentioned earlier, but also the recruitment and activation of inflammatory cells. Do these cellular inflammatory responses serve only a proinflammatory role? Do they explain in part the beneficial effects of corticosteroids? These and other questions will need to be answered but the important first step has been taken - the demonstration that the induction of asthma is accompanied by in-vivo activation of circulating leukocytes. ~[] References 1 Atkins, P. C., Norman, M., Weiner, H. and Zweiman, B. (1977) Ann. Intern. Med. 86, 415-418 2 Atkins, P. C., Norman, M. E. and Zweiman, B. (1978)J. AUergy Clin. Immunol. 62, 149-155 3 Nagy, L., Lee, T. H. and Kay, A. B. (1982) N. Engl. J. Med. 306, 497-501 4 Atkins, P. C., Norman, M., Zweiman, B. and Rosenblum, F. (1979)O( Allergy'Clin. Immunol. 64, 251-528 5 Durham, S. R., Carrol, M., Walsh, G. M. and Kay, A. B. (1984) N~ Engl. J. Med. 311, 1398-1402 6 Fearon, D. T. and Collins, L. A. (1983) Clin. Exp. Immunol. 38,294-299 7 Ward, P. A. (1968),]2 Exp. Med. 128, 1201 8 Gallin, J. I. (1984) Clin. Res. 32, 320-328 9 Cohen, A. B., Chenoweth, D. E. and Hugli, T. E. (1982) Am. Rev. Respir. Dis. 126, 241 10 Atkins, P. C., Green, G. R. and Zweiman, B. (1973)J. Allergy Clin. Immunol. 51, 763 11 Soney, G. O., Gleich, G. S., Jordan, R. E. and Schroeter, A. L. (1976) J. Clin. Invest. 58, 408 12 Fabberi, L. M., Aizawa, H., Alpert, S. E., Walters, E. H., Byrne, P. M., Gold, B. D., Nadel, J. A. and Haltzman, M. J. (1984) Am. Rev. Respir. Dis. 129, 288 PAUL. C. ATKINS BURTON ZWEIMAN
Department of Medicine, Allergy and Immunology Section, University of Pennsylvania, Philadelphia, PA 19104, USA
