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T-cell r e c o g n i t i o n - perhaps by encoding T-cell receptors - and there is also evidence that genes at this locus play a role in E A M G in the mouse 7, and in myasthenia gravis in m a n s. A striking number of developments in this area have come from work on myasthenia gravis or its animal models; perhaps some of the pipe-dreams puffed in this short article will become reality in the same field in a few years.

NICK

WILl.COX

Deparlment q/'.N?,~ro/ogi~al N'iem e, Royal Free Itos/)ital Me&ca! School, Pond Slreel, l,orldor~,,¥W3 2QG, U.K.

References

1 Hohlfeld, R., Kalies, I., Heinz, F., Kalden, J. R. and Wekerle H. (1981).7. bmmmol. 126, 1355-1359 2 Wekerle, H., Ketelson, P., Hohlfeld, R., Kalies, 1. and Kalden, .J.i. (1981) A,m .V.Y.Acad. &'z.(in press) 3 Watson, J., Mochizuki, D. and Gillis, S. (1980) Immlmo[. TMay 1,113-117 4 Sredni, B., Tse, H. Y. and Schwartz, R. H. (1980) .Vhlz~re (kombm) 283, 581-583 5 Adorini, L., Harvey, M. A,, Miller, A. and Sercarz, E. E. (1979). ,7. E.'cp. Med. 150, 293-306 6 Schwartz, M., Norvick, 1)., Givol, D. and Fuchs, S. (1978) .¥alure ( kondorz ) 273, 543-545 7 Berman, P. W. and Patrick, J. (1980),7. t'2xp. Med. 152, 507-520 8 Nakao, Y., Miyazaki, T., Ota, K., Matsumoto, H., Nishitani, H., Fujita, T. and Tsuki, K. (1980) La~ce! i, 677-680

Emphysema, smoking and the alveolar macrophage P u l m o n a r y e m p h y s e m a , p r i m a r i l y a d i s e a s e of cigarette smokers, is characterized by destruction of alveolar walls, obstruction of the bronchioles and trapping of air. These events lead to a b n o r m a l enlargement of air spaces distal to the terminal bronchiole. The observation that individuals" with inherited antitrypsin deficiency are predisposed to develop p u l m o n a r y e m p h y s e m a j served as the basis for the current view that the destruction of lung alveoli is m e d i a t e d by elastolytic enzymes. Serum as well as alveolar lavage fluid contain protease inhibitors which would normally protect the alveolar connective tissue from attack by elastolytic proteases. Careful studies during the last several years have provided insite into the alterations that occur in protease - antiprotease activity and the role of inflammatory lung cells in mediating these alternations which could result in the generation of emphysematous lesions. Alveolar macrophages and neutrophils have been shown to produce elastase zr~ vitro and are regarded as the major source of this enzyme 2. T h e role of cigarette smoke appears critical to the initiation of the sequence of related events, depicted schematically in Fig. 1, that ultimately produce the disease.

[ ~

~,

Cigarette smoke

Macrophage activation

;

Antiprotease inhibition

t

Secretion of neutrophil

Production of reactive

chemotactic factor

oxygen species

1

Secretion of elastase by macrophages and neutrophils

I

t

Macrophage chemotaxis

m Digestion of elastin

l

to form fragments

Fig.1. Proposed sequence of events underlying the formation of emphysematous lesions.

Exposure of alveolar macrophages to cigarette smoke components resuhs in increased macrophage activity which includes the production of a neutrophil chemotactic factor 3,4. While the m a c r o p h a g e is capable of producing elastase, the neutrophil appears to be the major source of the enzyme. Digestion of elastin produces elastin fragments which a p p e a r to be chemotactic for macrophages, thus amplifying the destructive process. Hunninghake el al. ~ have now shown that elastin fragments produced after digestion of elastin with leucocyte elastase are chemotactic for peripheral blood monocytes. T h e fragments, which ranged in mol. wt from 10,000 to 50,000, attracted monocytes, at concentrations as low as 3 ng mI -I, but not neutrophils. The chemotactic receptors on the monocytes for elastin a p p a r e n t l y diflered from receptors for CSa since deactivation of the chemotactic response to the fragments by incubation with elastin fragments did not alter their chemotactic response to activated serum. T h e failure of the antiproteases to control the elastolytic process has been attributed to the action of cigarette smokea, r. A transient exposure to cigarette smoke by inhalation of six putts of smoke led to inactivation of antiprotease activity in lung lavage fluid. The transient imbalance between hlng proteases a n d antiprotease caused by smoking could be sufficient to account for injury to alveolar walls. Furthermore, repeated cycles of i m b a l a n c e over a long period of time would cause a slow destruction of the alveolar walls that occur in chronic smokers. Recently, Carp and Janoff ~ have reported that human neutrophils, monocytes and pulmonary macrophages, stimulated by phorbol myristate acetate (PMA), released reactive oxygen species that resulted in suppression of antiprotcase inhibitor activity in h u m a n serum. T r e a t m e n t of the serum with the reducing agent dithiothreitol resulted in the restoration of antiprotease activity of the serum. This observation is consistent with earlier studies indicating that inactivation of h u m a n a~-antitrypsin by aqueous extracts of ,e

Elsevier/North-I

III67

h)lland

4919/gl/OI)l)l)

Bimncdical Press 1981

I1f)00/$1)2.51)

156

immt~nology lo@', A~g~.rl 198/

cigarette smoke is due to oxidation reactions 9. The report indicates that inactivation of %-antitrypsin depended in part on O> H 2 0 2 and myeloperoxidase. Monocytes and leucocytes from patients with chronic granulomatous disease, in whom the generation of O 2 and H 2 0 2 are depressed, did not inactivate the antiprotease after exposure to PMA. The effect of cigarette smoke on alveolar macrophage activity suggests that these cells produce reactive oxygen species which should result in enhanced inactivation References 1 Morse, J. O. (1978) .N. Eng/. J. Med. 299, 1045-1048; 1099-1105 2 ,Janoff, A., White, R., Carp, H., tfarel, S., Dearing, R. and Lee, D. (1979) Am.J. l°ntaol. 97, 111-136 3 Merrill, W. W., Naegel, G. P., Matthay, R. A. and Reynolds, tl. Y. (1980),7. C/in. Irtve.~/.65,268-276 4 Gadek, J. E., Hunninghake, G. W., Zimmerman, R. L. and Crystal, R. G. (1980) Am. Re¢~.Re.@r. Dis. 121,723-733

of antiproteases leading to increased destruction of alveolar connective tissue. It appears from these studies that alveolar macrophages and leucocytes are largely responsible for the generation of emphysema. Exposure to cigarette smoke has a profound effect on t h e hemostatic mechanisms of the lung leading to emphysema. BRUCE

S. Z ' W 1 L L I N G

Depar/ment ~!fMicrobiology, Od/ege ~!/"Biologica! Sciences and Comprehens'iz,e Caneer (>,let, The Ohir; S/ale University, Odumbus, OH d3210, U.S.A.

5 Hunninghake, G. W., Davidson,j. M., Rennard, S., Szapiel, S., Gadek,.J.E. and Crystal, R. G. (19811 Science 212, 925-927 6 Janoff, A., Carp. H., Lee, 1). K. and Drew, R. T. (19791 Science 206, 1313-1314 7 Gadek, J. E., Fellis, G. A. and Crystal, R. G. (1979) &ience 206, 1315 1316 8 Carp, It. andJanoff, A. (19801,7. (Yi,. I, vesl. 66, 987-995 9 Carp, H. andJanoff, A. (1978) Am. Rev. Respir. Dis 118,617-621

) The regulation of gastrointestinal immune responses Warren Strober, Lee K. Richman and Charles O. Elson hnmunophysiology Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20205, U.S.A. The antigenic environment of the mucosal i m m u n e system differs from that of the systemic i m m u n e system. The mucosae are in constant contact with a myriad of substances that have readily demonstrable i m m u n o s t i m u l a t o r y or i m m u n o m o d u l a t o r y properties and within such an environment lymphoid tissue could conceivably undergo excessive stimulation. As a result responses to potentially pathogenic stimuli might be pre-empted by responses to an overwhelming array of inconsequential materials. For this reason it would not be surprising to find that the mucosal i m m u n e system had regulatory mechanisms allowing it to react selectively to m a n y or most substances found in the mucosal environment. It is reasonable to suppose that such mechanisms would be mediated by cellular components that differ qualitatively a n d / o r quantitatively from those found elsewhere in the i m m u n e system (see Fig. i ). In the following review, we will discuss mucosal i m m u n e responses from an i m m u n o r e g u l a t o r y viewpoint. We shall first consider studies ,in which ¢ Else~i(J/North I lolland Biomcdica~ Press 1981 0167

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antigen feeding fails to result in i m m u n i z a t i o n and, instead, induces unresponsiveness (tolerance) to subsequent challenge with the antigen. We shall then consider studies in which antigen feeding results in immunization as well as priming of the animal for secondary antibody responses. Finally, we will discuss studies of a mechanism by which the mucosal i m m u n e system can compartmentalize its regulation of a response, so that simultaneous e n h a n c e m e n t and suppression can be obtained, depending on the Ig class of the induced responses. Such a mechanism is indicative of the complexity of mucosal i m m u n o r e g u l a t i o n and provides evidence that regulation in this area may have several unique features. M e c h a n i s m s of oral u n r e s p o n s i v e n e s s (tolerance) Suppre.rsiorz of oral res~Jm~.sesby 13 cells or B-cell products

Oral unresponsiveness was first studied within the context of modern immunology by Chase in 1946, although related observations were made as early as the mid-nineteenth century ~. Chase showed that after

Emphysema, smoking and the alveolar macrophage.

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