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HYPERSENSITIVITY
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PNEUMONITIS: CURRENT CONCEPTS OF ETIOLOGY AND PATHOGENESIS M
Lopez, MD. and J. Salvaggio, MD.
Department of Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112
INTRODUCTION Hypersensitivity pneumonitis or extrinsic allergic alveolitis can be defined as a group
of diffuse interstitial and/or alveolar-filling "granulomatous" pulmonary diseases,
associated with intense respiratory exposure to finely dispersed organic dusts of appropriate particle size. These diseases are characterized by symptoms and signs
attributable to a reaction in the peripheral part of the bronchial system giving rise
to defects in gas exchange
(1). Clinically, affected patients have episodes of fever,
cough, and dyspnea 4 to 6 hours following exposure to an organic dust (hay, bagasse,
pigeon droppings, etc). These acute symptoms are frequently mistaken for those of
bacterial or viral pneumonia. In more insidious cases associated with long-term
exposure to small quantities of antigen, an afebrile, chronic form of the disease may occur, often associated with dyspnea, malaise, weakness, and weight loss. Func
tional abnormalities in classic cases consist of defects in alveolar gas exchange, arterial oxygen unsaturation, and decreased pulmonary compliance. Mild but per
sistent airway obstruction has been reported, and changes similar to those found in
emphysema, including irreversible obstructive and restrictive defects with severe disturbances in diffusion capacity may be seen in some chronic cases.
The basic pathology in these diseases consists of inflammation of the alveoli and interstitial pulmonary tissue, plus some involvement of bronchioles. In acute stages,
there is thickening of alveolar septi with predominant lymphocyte and plasma cell
infiltrates. In many cases collections of foamy macrophages are noted within the
alveoli. In more chronic stages, noncaseating granulomas with epitheloid cells,
Langerhans' giant cells, and various degrees of fibrosis are observed. Pulmonary
vasculitis as noted in Arthus-type reactions (type III hypersensitivity) is almost always absent, although there have been occasional reports of vasculitis in acute cases
(2, 3). 453
454
LOPEZ & SALVAGGIO
Although pulmonary disease associated with organic dust inhalation has been
known since
1713 (4), the first modern report appeared in 1932 when farmer's lung
was described as an acute pneumonitis occurring in workers exposed to moldy hay
(5). In subsequent years an expanding list of similar diseases associated with a variety of occupations and avocations has been described. The entire subject has
been thoroughly reviewed by Pepys (1) and others (6-8). It is the intent of this paper
to review some of the recent advances in etiology and pathogenesis of hypersen
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sitivity pneumonitis obtained by using animal models.
ETIOLOGY There are numerous causes of hypersensitivity pneumonitis and the list continues
to expand as awareness of this possibility increases and newer forms of industrial and agricultural exposure develop. A list of causes is summarized in Table I. Among
the most important etiological agents are thermophilic and mesophilic ac tinomycetes including
Micropolyspora faeni, Thermoactinomyces vulgaris, Ther moactinomyces sacchari, and Thermoactinomyces candidus (9-13). Actinomycetes
are members of the true bacteria (Eubactereriales), although they have the mor
phology of fungi. These organisms grow best in decaying organic matter such as hay
and bagasse, under optimal conditions of humidity and high temperature ranging up to 60°C. The influence of these conditions is shown clearly in hay; moldy hay
with approximately 40% moisture content and temperature between 40 and 60°C will support abundant growth of actinomycetes in contrast to poor growth in fresh
hay. In addition to composts, actinomycetes are abundant in soils, foods, fresh waters, and other natural sources. They have also been isolated from the atmo sphere.
A wide range of antigens has been identified in several actinomycetes by immuno
electrophoresis (IEP) and chemical analysis. At least scribed in
29 antigens have been de M. faeni by IEP (14) and the properties and composition of actinomycete
antigens are currently under active investigation in several laboratories. The anti
gens include "metabolic" and "cellular" polysaccharides and glycoproteins with
various enzymatic activities (15-18). At present the relative clinical importance of these antigens has not been established. Edwards (19) has demonstrated the pres ence in M faeni of extremely thermolabile antigens not present in moldy hay.
Patients with farmer's lung have antibodies to these antigens, suggesting that at least
part of the antigenic stimulus is produced by minimal growth and development of
spores in the lungs of these patients. Fungal spores and hyphal fragments may also serve as important sources of antigen in other forms of hypersensitivity pneumonitis.
For example, Aspergillus clavatus has been shown to produce disease in malt work ers and
Alternaria sp. are associated with wood dust pneumonitis. In pigeon bree
der's lung, on the other hand, pigeon droppings are a rich source of antigen.
Extensive studies have shown that undegradable pigeon serum proteins with the mobility of gamma globulins are important antigens in this disorder
(20--22). Many
other antigens in organic dusts associated with these diseases have not been ade quately characterized and better understanding of the mechanisms by which these
HYPERSENSITIVITY PNEUMONITIS
455
materials cause clinical disease is necessary. The antigens studied have been ana lyzed within the framework of their capacity to produce precipitating antibodies in humans or in experimental animals. This approach narrows the studies to a limited area of the immune response. It is also likely that some of these inhaled organic dusts Table I Causes of hypersensitivity pneumonitis Di sease
Prob a ble antig ens
Source of antigen
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Vegetable products Farmer's lung
thermophilic actinomycetcs
moldy hay
Micropolyspora faeni ThermoactirlOmyces vulgaris Bagassosi s
moldy pressed sugarcane
Mushroom worker's disease
moldy compost
thermophilic actinomycctcs Thermoactillomyces sacchari
(bagasse)
thermophilic actinomycetes Micropolyspora jaelli Tltermoactirlomyces I'ldgaris
Subcrosis
moldy cork
unknown
Malt worker's lu ng
cuntaminated barley
fungi
Maple bark disease
contaminated maple logs
fungi
Seq u oiosis
contaminated wood dust
fungi
Asperl(il/lis clal'atus Cryptustruma corticale Graplzium "I', Plil/Illaria sp. other fungi Wood pulp worker ' s disc�sc
contaminated wood pulp
fungi
Humidifier lung
co ntaminated home humidifier
thermophilic actinomycctcs
Alternaria sp. and air conditioning ducts
TltermuactiNom.vces vulgaris ThermoactblOmyces calldidus
Paprika slicer's lu ng
moldy paprika pods
fungi
Grain measurer's lung
cereal grains
unknown
Mllcor stololli]er Thatched roof disease
dried grass and leaves
unknown
Tobacco grower's disea se
toba cco p lant s
unknown
Tea grower ' s disease
tca p lants
unknown
Coffee worker ' s lung
green coffee bean
unknown
Hypersensitivity pneumonitis
sawdust
unknown
Coptic disea se
doth wrappings of mummics
unknown
pigeon droppings
pigeon serum protein
Animal products Pigeon breeder's disease
(albumin. gamma globulin. and others) Duck fever
bird feathers
chicken proteins
Turkey handler's disease
turkey products
turkey proteins
wheat weavils
Sitopltilus granarilts
Insect products Miller 's lu ng
Bacterial Or viral products Hypersensitivity pneumonitIS
H. subtilis cnzymcs
Smallpox handler's lung
smallpox scabs
a
Bacil/IIS subtilis unknown
aprobably induces IgE mediated obstructive airways disease in the great majority or cases.
456
LOPEZ & SALVAGGIO
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and microorganisms serve as immunologic adjuvants or act as irritants (23). Evi dence indicates that there are varying amounts of antigenically inert (as measured by antibody response) macromolecules present in M faeni extracts (24). Such materials could conceivably be very important in activation of macrophages or of the alternate complement pathway. It seems clear that definition and characteriza tion of antigens is essential for the development of more precise diagnostic tests. More data are also needed on identification of antigens for purposes of skin testing, serum antibody detection, and use in in vitro studies of delayed hypersensitivity in these diseases. PATHOGENESIS The manner by which inhaled organic dusts induce lesions of hypersensitivity pneumonitis is likely dependent on a complex interrelationship between environ mental, genetic, and other host-related factors. With regard to organic dusts, several factors may play an important role in their ability to induce pulmonary disease. Very heavy exposure to the offending dust is usually necessary to produce symptoms and it has been calculated that a farmer working with moldy hay can inhale and retain in his lungs 750,000 spores per minute, 98% of which are actinomycete in origin «l.0!-t in diameter) (25). Although the majority of hypersensitivity pneumonitis cases have been associated with inhalation of dusts containing bacteria and fungi capable of growth and reproduction in the host, the bulk of evidence points toward a hypersensitivity reaction rather than an infectious process. These organic dusts may enhance the immune response in many ways, including a possible adjuvant effect and an effect on macrophage activation. Toxic factors might also contribute to the induction of pulmonary lesions since potent enzymes have been detected in extracts of pigeon droppings (26) and thermophilic actinomycetes (16). With regard to the host response, one of the more important determining factors might be the association of HL-A haplotypes with disease. In one recent study of pigeon breeder's disease, HL-A 1, 8 was frequently found in association with active disease, suggesting the presence of an HL-associated immune response (Ir) gene in hypersensitivity pneumonitis (27). There is little evidence for participation of IgE mediated reactions (Type I) in these diseases; patients with hypersensitivity pneumonitis have normal IgE levels (28), eosinophilia is usually not present, and the disease incidence is not increased in atopic patients. Immune complex induced allergic tissue injury (Type III) has been thought to play an important role in the pathogenesis of hypersensitivity pneumonitis. The time interval between exposure and symptoms; the presence of precipitating antibodies in most patients against the offending organic dust; and the detection of antigen, immunoglobulins, and complement components in lung lesions are among the arguments favoring this hypothesis. However, precipitating antibod ies to organic dusts can be detected in a large percentage of unaffected exposed subjects (29) and lesions characterized by pulmonary vasculitis, as might be ex pected in immune complex reactions, usually are not seen in the disease, providing evidence against this hypothesis. Although complement fixing antibodies have been
HYPERSENSITIVITY PNEUMONITIS
457
detected in affected patients, the role of complement in disease production is un
known. During provocative challenge of asymptomatic and symptomatic pigeon breeders, complement levels were seen to decline in the asymptomatic rather
than the symptomatic patients (30).
In patients with pigeon breeder's disease, data
have been obtained (31) that suggest the presence of an unusually labile variant of
C3 proactivator, which when activated by components of pigeon droppings, initiates activation of C3• Other investigators (32) have suggested that the presence of com
plement components on the surface of alveolar macrophages of patients without
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evidence of necrotizing vasculitis is more consistent with the hypothesis that cyto toxic (Type
II) allergic tissue injury plays an important role in disease pathogenesis.
Recent evidence also indicates that organic dust antigens can directly activate the
alternate complement pathway, implying an ability to produce disease on a nonim
munologic basis (33).
There is increasing evidence for a role of delayed (Type
IV) hypersensitivity in
disease pathogenesis and the pathologic changes in these diseases are consistent with
those of delayed hypersensitivity. Antigen induced migration inhibition factor (MIF) production plus lymphocyte transformation, both of which are thought by many to be in vitro correlates of delayed hypersensitivity unde� certain circum
stances, have been detected in these patients and these tests seem to correlate with
disease activity (30, 34, 35). Skin testing with protein antigens such as pigeon serum
has, however, generally resulted in dual (Type I and III) rather than delayed (Type IV) responses in man, but it is possible that the presence of immediate reactions might obscure the expression of subsequent delayed hypersensitivity reactions. Fur
thermore, in animal models of these diseases where thermophilic actinomycete
antigens have been employed for respiratory tract immunization, classic delayed hypersensitivity reactions at 24 and 48 hr have been produced (36). Based on the currently available evidence it is perhaps naive to assume that only one immunopa
thogenic mechanism is involved in disease production. It is likely that in the final
analysis several types of allergic induced tissue injury as well as nonimmunologic
factors may be operative in the pathogenesis of hypersensitivity pneumonitis.
ANIMAL MODELS In an attempt to gain insight into the pathogenesis of hypersensitivity pneumonitis.
animal models have recently been developed. The different animal species, antigens.
routes of immunization, and methodology employed make analysis of these models
and their specific applicability to the human disease difficult to assess. A complete review of these models is beyond the scope of this manuscript; rather, we discuss
primarily our own experiences plus those of selected investigators as illustrative
examples.
With regard to acute pulmonary immunologic injury several models have been developed in the rat and the rabbit. In one such model. intrabronchial inoculation of anti-bovine serum albumin (BSA). followed by administration of labeled antigen
intravenously, resulted in acute hemorrhagic neutrophil-rich exudates appearing within the pulmonary parenchyma within 4 hr. By immunofluorescence, interstitial
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458
LOPEZ & SALVAGGIO
deposits of antigen and antibody, and accumulation of radiolabeled C) in developing lesions were noted in this model (37). In a similar rabbit model (38) animals were immunized so as to produce a hyperactive response to intravenously administered BSA. When maintained in a state of relative antigen-antibody equivalence by admin istration of multiple daily doses of BSA, these animals developed proliferative and/or membranous pulmonary lesions associated with deposits of host immuno globulins, antigen, complement, and fibrinogen. These two models of immune com plex induced allergic tissue injury may bear a resemblance to lesions seen in certain early and late forms of human interstitial pneumonitis. Although elegant in design, they do not seem to correspond to human hypersensitivity pneumonitis lesions, which are characterized by mononuclear infiltrates with epitheloid and Langerhans' giant cell formation in the later stages. Other recent animal models have focused specifically on the production of pulmo nary lesions that closely resemble those seen in human hypersensitivity pneumonitis by employing organic dust and actinomycete antigens. Some of these models, which involve active immunization of rabbits, guinea pigs, mice, and rats, follow. In an early model of pigeon breeder's disease, Fink and co-workers exposed rats to daily long-term inhalation of pigeon dropping extract and were able to produce a serum precipitating antibody response plus pul monary lesions characterized by mononu clear cell infiltrates (39). In our laboratory similar models employing rabbits immu nized intratracheally (i. 1.) with Micropoiyspora jaeni, a rich source of farmer's lung hay antigen, were developed (36, 40). This type of i.t. immunization resulted in serum precipitating antibodies, delayed skin reactivity, antigen induced peripheral blood lymphocyte transformation, and alveolar macrophage migration inhibition. The immunologic events were associated with intense alveolar and interstitial mononuclear cell pulmonary infiltrates. These early findings indicated that in the rabbit and rat, intense local respiratory tract immunization could initiate a systemic immune response and could produce interstitial pneumonitis with pathologic char acteristics similar to those noted in the human disease. Several excellent animal models, which greatly enhanced our understanding of the immunopathogenesis of hypersensitivity pneumonitis, were also developed in the rabbit and guinea pig at this time by Richerson and co-workers (41). In the guinea pig these investigators employed both antigens, which favored the development of delayed hypersensitivity such as tuberculin and azobenzene arsenate N-acetyltyrosine, plus antigens such as ovalbumin, which favored antibody formation. They noted that animals immunized with the former antigens in Freund's complete adjuvant, when challenged by aerosol, developed mononuclear cell infiltrates consistent with the time course of delayed hypersensitivity. On the other hand, when ovalbumin was employed as antigen, acute hemorrhagic pneumonitis lesions rich in neutrophils occurred follow ing aerosol challenge. These animals also developed positive gamma- l globulin, passive cutaneous anaphylaxis (PCA) responses. In other experiments these investi gators administered ovalbumin in Freund's complete adjuvant followed by aerosol challenge and noted development of a mononuclear cell type alveolitis at 24 and 48 hr. Miyamoto & Kabe (42) developed a similar model employing guinea pigs immu nized with Freund's adjuvant and tuberculin followed by tuberculin aerosol chal-
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HYPERSENSITIVITY PNEUMONITIS
459
lenge. In this model striking mononuclear cell infiltrates were also produced 24-48 hr after aerosol challenge and these lesions could be passively transferred with sensitized lymphoid cells. In an attempt to demonstrate a role for either circulating antibody or delayed hypersensitivity in the production of experimental pneumonitis, hyperimmune serum and specifically sensitized lymphoid cells from animals previously immunized with ovalbumin were transferred to normal rabbits followed by ovalbumin aerosol or intratracheal challenge in our laboratory (43). Rabbits passively sensitized with hyperimmune serum demonstrated only mild and inconsistent peribronchial mononuclear cell infiltrates following aerosol challenge. Animals given between 2.5 X 108 and 10.9 X 108 sensitized lymphoid cells intraperitoneally followed by aerosol challenge developed markedly hyperplastic peribronchial lymphoid tissue with germinal center formation and peribronchial mononuclear cell infiltrates fol lowing challenge via the respiratory route. The cellular composition of these peri bronchial and alveolar lesions in sensitized challenged recipients was consistent with that noted in delayed hypersensitivity reactions. Large numbers of mature plasma cells were also noted in the lesions, suggesting either an additional process of active antibody synthesis by antigen-specific B cells passively transferred along with T cells and macrophages, or recruitment of host B lymphocytes by Iymphokines. Attempts at passive cell transfer in this species by the i.v. route have been unsuccessful due to the development of pulmonary vasculitis (41). In other studies of this type, passive transfer of hyperimmune serum or sensitized cells separately in the monkey followed by challenge with pigeon dropping extract (PDE) has been associated with either mild exudative pneumonitis, alveolar hemorrhage, or peribronchial edema (44). These studies suggested that both antibody and sensitized lymphoid cells may play a role in production of pulmonary lesions. Similar results have also been obtained in the guinea pig by passive transfer of serum and cells (45). In view of the fact that human hypersensitivity pneumonitis is associated with granuloma formation, several models have recently been developed in an attempt · to provide information on mechanisms involved in pulmonary granuloma produc tion. Among these are studies by Leake & Myrvik (46) and Moore, Myrvik & Leake (47) in which intravenous inoculation of Freund's adjuvant or BeG has led to the induction of "chronic" and "accelerated" pulmonary parenchymal granulomas associated with MIF production by alveolar wash cells but no dermal delayed hypersensitivity. These pulmonary granulomas have been shown to be antigen · specific. They are also inhibited in vivo by cortisone acetate and antimacrophage serum (48). Other workers have employed intravenously inoculated bentonite parti cles or polyacrylamide beads coated with soluble proteins (hemocyanin, mycobac teria, histoplasma, and schistosomal antigens) (49, 50). In these models, localized multifocal pulmonary granulomas have been produced following i.v. inoculation of antigen coated particles. The granulomas are noted to increase markedly in size and become "accelerated" or augmented when antigen coated particles are administered to previously sensitized animals. Some of these lesions have the histologic appear ance of delayed hypersensitivity reactions and can be transferred with specifically sensitized lymphoid cells (51).
460
LOPEZ & SALVAOOIO
In more recent studies in the mouse and chicken by Boros & Warren employing schistosome eggs
(51), it has been clearly demonstrated that hypersensitivity pulmo
nary granulomas are an expression of delayed (cell mediated) hypersensitivity and can be correlated with other in vivo and in vitro parameters of delayed hypersen sitivity. In these studies concerned with modulation of schistosoma I granulomatous hypersensitivity in the lung, the pulmonary granulomas were shown to be antigen specific and to possess the cellular composition of delayed hypersensitivity reactions. They were inhibited by neonatal thymectomy and could be induced in recipients
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following passive transfer with sensitized lymphoid cells. Furthermore, their pres ence did not correlate with antibody levels. Willoughby and co-workers
(52)
have
added to these observations by recently developing an animal model employing nonspecific T-cell mitogens such as concanavalin
A, with or without soluble protein
antigen administered via the respiratory route. T-cell mitogens alone produced focal interstitial inflammatio� of the lung, with cells predominantly mononuclear in nature, many blast forms, and some giant cells. In animals sensitized to a soluble protein antigen (BSA) followed by aerosol challenge with antigen and mitogen, vasculitis with interstitial inflammation and necrosis plus severe granulomatous injury bearing a resemblance to Wegener's granulomatosis were noted. Results of this study suggested that repetitive exposure to T-cell mitogens induced interstitial pulmonary lesions and that specific antigen challenge at a time when T-cell mediated injury was also in progress provoked an enhanced type of pulmonary injury. The authors concluded that T-cell stimulation might be quite important as an initiating event in immunologically mediated pulmonary tissue injury resulting from inhala tion exposure. In our laboratory we have recently begun further investigation on the role of delayed hypersensitivity and the alveolar macrophage in experimental granuloma tous pneumonitis. In these studies, repeated respiratory tract exposure of rabbits to
Micropolysporajaeni antigen has led to an early necrotizing inflammatory response of the respiratory bronchioles followed by gradual organization and interstitializa tion of peribronchial granulomas
(43, 53).
In some cases progressive bronchiolar
fibrosis with destructive lesions similar to those noted in human centriacinar em physema developed by one month after initial inoculation. Granulomas often as sumed the appearance of hard tubercles, including Langerhans' giant cells, which at times contained asteroid and Schaumann bodies similar to those noted in sar coidosis and human hypersensitivity pneumonitis. We have been unable to detect necrotizing vasculitis or vascular deposits of complement components and immuno globulins in these lesions by fluorescent microscopy, although C3 was demonstrable in alveolar macrophages and some plasma cells staining for IgG, A, and M were scattered in and about the developing lesions. Alveolar wash cell counts were significantly elevated following i.t. immunization with actinomycete antigen when
compared to saline inoculated controls. Glucose oxidation by alveolar wash cells of
these animals was also significantly increased over that of saline inoculated controls and morphologic evidence of macrophage activation was noted on electron micros copy. However, phagocytosis of Staphylococcus aureus by alveolar macrophages of
M jaeni
inoculated animals was not significantly increased above that of controls,
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HYPERSENSITIVITY PNEUMONITIS
461
nor were acid protease or lysozyme levels elevated, suggesting that perhaps the total number of activated macrophages was relatively small. Concurrent with granuloma formation in this model, antigen induced alveolar macrophage migration became progressively inhibited by both direct and indirect assay, and animals developed specific precipitating antibody and delayed skin reac tivity. Anti-M faeni precipitating antibody was also exhibited in concentrated bronchial wash fluids of sensitized animals. The time course and histologic features of pulmonary granulomatous lesions suggested that a combination of direct irrita tion and subsequent hypersensitivity were operative in disease pathogenesis. Overall, these results suggest that multiple immunologic and nonimmunologic processes develop simultaneously at the bronchopulmonary level following respiratory tract exposure to thermophilic actinomycete antigen and it is reasonable to postulate that such a heterogeneous response also occurs in the human disease. In conclusion, it would appear that a variety of soluble and particulate antigens may induce acute or chronic pulmonary infiltrates in several animal species. These lesions may be associated with Type IV (cellular), Type III (immune complex), and possibly Type II (cytotoxic) allergic tissue injury, depending on the experimental conditions employed. It is also likely that particulate organic dust antigens may possess adjuvant, irritant, alternate complement pathway activating, or toxic prop erties, all of which could be important in the production of pulmonary lesions. Literature Cited
I. Pepys, J. 1969. Hypersensitivity dis 2. 3.
4. 5.
eases of the lungs due to fungi and or ganic dusts. Monogr. Allergy, Vol. 4. Barrowc1iff, D. F., Arblaster, R. 1968. Farmer's lung: a study of an early acute fatal case. Thorax 23:490 Ghose, T., Landrigan, P., Killeen, R., Dill, I. 1974. Immunopathological studies in patients with farmer's lung. Clin. Allergy 4:119 Ramazzini, B. 1713. De Morbus Art ificum Diatriba. Reprinted 1940. Chicago: Univ. Chicago Press Campbell, J. M. 1932. Acute symptoms following work with hay. Br. Med. J.
2:1143
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16. Walbaum, S., Biguet, J., Tran Van Ky, P. 1969. Structure antigenique de Ther mopolyspora polyspora repercussion pratique sur Ie diagnostic du "Poumon du Fermier." Ann. Inst. Pasteur, Lille 117:673 17. LaBerge, D. E., Strohmann, M. A. 1966. Antigens from moldy hay in volved in farmer's lung. Proc. Soc. Exp. Bioi. NY 121:463 18. Fletcher, S., Rondle, C. 1973. Mi cropolyspora Faeni and farmer's lung disease. J. Hyg. 71:185 19. Edwards, J. H. 1972. The antigenic background to farmer's lung. Clin. Exp. Immunol. 11:341 20. Edwards, J. M., Barboriak, J. J., Fink, J. N. 1970. Antigens in pigeon breeders disease. Immunology London 19:729 21. Fink, J. N., Barboriak, J. I., Sosman, A. J. 1967. Immunologic studies in pi geon breeder's disease. 1. Allergy 39:214 22. Fink, J. N., Tebo, T., Barboriak, J. J. 1969. Differences in the immune re sponse of pigeon breeders to pigeon serum proteins. 1. Lab. Clin. Med. 74:325 23. Salvaggio, J., Phanuphak, P., Stanford, R., Bice, D., Claman, H. 1975. Experi mental production of granulomatous pneumonitis. Comparison of immuno logical and morphological sequelae with particulate and soluble antigens administered via the respiratory route. 1. Allergy Clin. Immunol. 56:364 24. Roberts, R. C. 1974. Fractionation and chemical characterization studies on Micropolyspora /aeni antigens. Ann.NY Acad. Sci. 221:199 25. Lacey, J. Lacey, M. 1964. Spore con centration in the air of farm buildings. Trans. Br. Mycol. Soc. 47:547 26. Berrens, L., Guikers, C. L. H. 1973. An immunochemical study of pigeon bree der's disease. Int. Arch. Allergy Appl. Immunol. 43:347 27. Allen, D. H., Basten, A., Woodcock, A. H. 1975. Family studies hypersen sitivity pneumonitis, Proc. Aspen Lung Con! 18th. Chest. In press 28. Patterson, R., Fink, J. N., Pruzansky, J. J., Reed, C., Roberts, M., Slavin, R., Zeiss, C. R. 1973. Serum immunoglobu lin levels in pulmonary allergic aspergil lus and certain other lung diseases, with special reference to immunoglobulin E. Am. 1. Med. 54:16 29. Fink, J. N., Schlueter, D., Sosman, A. 1972. Clinical survey of pigeon breed ers. Chest 62:277
30. Moore, V. L., Fink, J. N., Barboriak, J. J., Ruff, L. L., Schlueter, D. P. 1974. Immunologic events in pigeon breeder's disease. 1. Allergy Clin. Immunol. 53:319 31. Berrens, L., Guikers, C. L. H., Van Dijk, A. 1974. Inhalant allergens in hu man atopic disease: Their chemistry and modes of action. Ann. NY Acad. Sci. 221:153 32. Wenzel, F. J., Emanuel. D. A., Gray, R. L. 1971. Immunofluorescent studies in patients with farmer's lung. J. Allergy 48:224 33. Marx, 1. J., Flaherty, D. J. 1975. Alter nate pathway activation of complement by antigens associated with hypersen sitivity pneumonitis. J. Allergy Clin. Immunol. 55:70 34. Caldwell, J. R., Pearce, D. E., Spencer, C., Leder, R., Waldman, R. H. 1973. Immunologic mechanisms in hypersen sitivity pneumonitis. 1. Allergy Clin. Immunol. 52:225 35. Hansen, P. J., Penny, R. 1974. Pigeon breeder's disease: Study of cell mediated immune response to pigeon antigens by the lymphocyte culture technique. Int. Arch. Allergy Appl. Im munol. 47:498 36. Kawai, T., Salvaggio, J., Lake, W., Har ris, J. O. 1972. Experimental produc tion of hypersensitivity pneumonitis with bagasse and thermophilic ac tinomycete antigen. 1. Allergy Clin. 1m munoL 50: 276 37. Johnson, K. J., Ward, P. 1974. Acute immunologic pulmonary alveolitis. J. Clin. Invest. 54:349 38. Brentjens, 1. R., O'Connell, D. W., Pawlowski, I. B., Hsu, K. C., Andres, G. 1974. Experimental immune com plex disease of the lung: The pathogene sis of a laboratory model resembling certain human interstitial lung diseases. J. Exp. Med. 140:105 39. Fink, J., Hensley, G., Barboriak, J. 1970. An animal model of hypersen sitivity pneumonitis. 1. Allergy 46:156 40. Kawai, T., Salvaggio, J., Harris, J. 0., Arquembourg, P. 1973. Alveolar mac rophage migration inhibition in ani mals immunized with thermophilic ac tinomycete antigen. Clin. Exp. 1m munol. 15:123 41. Richerson, H. B. 1974. Varieties of acute immunologic damage to the rab bit lung. Ann. NY Acad. Sci. 221 :340 42. Miyamoto, T., Kabe, J. 1971. The lungs as the site of delayed-type hypersen-
HYPERSENSITIVITY PNEUMONITIS sitivity reactions in guinea pigs. J. Al lergy Clin. Immunol 47:181 43. Bice, D., Salvaggio, I., Hoffmann, E. 1975. Passive transfer of experimental hypersensitivity pneumonitis with lym phoid cells. J. Allergy Clin. Immunol
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55:71 44. Fink, I., Hensley, G., Barboriak, I. 1973. A primate model of hypersen sitivity pneumonitis. J. Allergy Clin. Immunol 51:125
45. Wilkie, W. F., Pauli, B., Gygax, M. 1973. Hypersensitivity pneumonitis: Experimental production in guinea pigs with antigens of Micropolyspora faeni. Pathol. Micro bial. 39:393 46. Leake, E. S., Myrvik, Q. N. 1968. Changes in morphology and in lyso zyme content of free alveolar cells after the intravenous injection of killed BCG in oil. J. Reticuloendothel. Soc. 5:33 47. Moore, V. L., Myrvik, Q. N., Leake, E. S. 1973. Specificity of BCG-induced pulmonary granulomatous response in rabbits. Infect. Immun. 7:743 48. Moore, V. L., Myrvik, Q. N. 1973. Re lationship of BCG-induced pulmonary
delayed hypersensitivity to accelerated
granuloma formation in rabbit lungs: effect of cortisone acetate. Infect. Im-
463
mun. 7:764 49. Boros, D. L., Warren, K. S. 1970. De layed hypersensitivity-type granuloma
formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosome mansoni eggs. J. Exp. Med. 132:488 50. Boros, D. L., Warren, K. S. 1973. The bentonite granuloma: characterization of a model system for infectious and foreign body granulomatous inflamma tion using soluble mycobacterial, histo plasma, and schistosoma antigens. I m munology 24:511
51. Boros, D. L., Warren, K. S. 1974. Mod els of granulomatous inflammation in:
pulmonary reactions to organic materi als. Ann. NY Acad. Sci. 221 :331 52. Willoughby, W. F., Barb aras, I. E., Wheelis, R. F. 1975. Immunologic mechanisms in experimental instersti tial pneumonitis. Proc. Aspen Lung Conf., 18th. Chest. In press 53. Harris, I. P., Bice, D., Salvaggio, I.
1975.
Experimental
granulomatous
pneumonitis: bronchopulmonary re sponse to Micropolyspora faeni in the
rabbit. Proc. Aspen LUng Conf., 18th. Chest. In press
Further
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HYPERSENSITIVITY
.7214
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PNEUMONITIS: CURRENT CONCEPTS OF ETIOLOGY AND PATHOGENESIS M
Lopez, MD. and J. Salvaggio, MD.
Department of Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112
INTRODUCTION Hypersensitivity pneumonitis or extrinsic allergic alveolitis can be defined as a group
of diffuse interstitial and/or alveolar-filling "granulomatous" pulmonary diseases,
associated with intense respiratory exposure to finely dispersed organic dusts of appropriate particle size. These diseases are characterized by symptoms and signs
attributable to a reaction in the peripheral part of the bronchial system giving rise
to defects in gas exchange
(1). Clinically, affected patients have episodes of fever,
cough, and dyspnea 4 to 6 hours following exposure to an organic dust (hay, bagasse,
pigeon droppings, etc). These acute symptoms are frequently mistaken for those of
bacterial or viral pneumonia. In more insidious cases associated with long-term
exposure to small quantities of antigen, an afebrile, chronic form of the disease may occur, often associated with dyspnea, malaise, weakness, and weight loss. Func
tional abnormalities in classic cases consist of defects in alveolar gas exchange, arterial oxygen unsaturation, and decreased pulmonary compliance. Mild but per
sistent airway obstruction has been reported, and changes similar to those found in
emphysema, including irreversible obstructive and restrictive defects with severe disturbances in diffusion capacity may be seen in some chronic cases.
The basic pathology in these diseases consists of inflammation of the alveoli and interstitial pulmonary tissue, plus some involvement of bronchioles. In acute stages,
there is thickening of alveolar septi with predominant lymphocyte and plasma cell
infiltrates. In many cases collections of foamy macrophages are noted within the
alveoli. In more chronic stages, noncaseating granulomas with epitheloid cells,
Langerhans' giant cells, and various degrees of fibrosis are observed. Pulmonary
vasculitis as noted in Arthus-type reactions (type III hypersensitivity) is almost always absent, although there have been occasional reports of vasculitis in acute cases
(2, 3). 453
454
LOPEZ & SALVAGGIO
Although pulmonary disease associated with organic dust inhalation has been
known since
1713 (4), the first modern report appeared in 1932 when farmer's lung
was described as an acute pneumonitis occurring in workers exposed to moldy hay
(5). In subsequent years an expanding list of similar diseases associated with a variety of occupations and avocations has been described. The entire subject has
been thoroughly reviewed by Pepys (1) and others (6-8). It is the intent of this paper
to review some of the recent advances in etiology and pathogenesis of hypersen
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sitivity pneumonitis obtained by using animal models.
ETIOLOGY There are numerous causes of hypersensitivity pneumonitis and the list continues
to expand as awareness of this possibility increases and newer forms of industrial and agricultural exposure develop. A list of causes is summarized in Table I. Among
the most important etiological agents are thermophilic and mesophilic ac tinomycetes including
Micropolyspora faeni, Thermoactinomyces vulgaris, Ther moactinomyces sacchari, and Thermoactinomyces candidus (9-13). Actinomycetes
are members of the true bacteria (Eubactereriales), although they have the mor
phology of fungi. These organisms grow best in decaying organic matter such as hay
and bagasse, under optimal conditions of humidity and high temperature ranging up to 60°C. The influence of these conditions is shown clearly in hay; moldy hay
with approximately 40% moisture content and temperature between 40 and 60°C will support abundant growth of actinomycetes in contrast to poor growth in fresh
hay. In addition to composts, actinomycetes are abundant in soils, foods, fresh waters, and other natural sources. They have also been isolated from the atmo sphere.
A wide range of antigens has been identified in several actinomycetes by immuno
electrophoresis (IEP) and chemical analysis. At least scribed in
29 antigens have been de M. faeni by IEP (14) and the properties and composition of actinomycete
antigens are currently under active investigation in several laboratories. The anti
gens include "metabolic" and "cellular" polysaccharides and glycoproteins with
various enzymatic activities (15-18). At present the relative clinical importance of these antigens has not been established. Edwards (19) has demonstrated the pres ence in M faeni of extremely thermolabile antigens not present in moldy hay.
Patients with farmer's lung have antibodies to these antigens, suggesting that at least
part of the antigenic stimulus is produced by minimal growth and development of
spores in the lungs of these patients. Fungal spores and hyphal fragments may also serve as important sources of antigen in other forms of hypersensitivity pneumonitis.
For example, Aspergillus clavatus has been shown to produce disease in malt work ers and
Alternaria sp. are associated with wood dust pneumonitis. In pigeon bree
der's lung, on the other hand, pigeon droppings are a rich source of antigen.
Extensive studies have shown that undegradable pigeon serum proteins with the mobility of gamma globulins are important antigens in this disorder
(20--22). Many
other antigens in organic dusts associated with these diseases have not been ade quately characterized and better understanding of the mechanisms by which these
HYPERSENSITIVITY PNEUMONITIS
455
materials cause clinical disease is necessary. The antigens studied have been ana lyzed within the framework of their capacity to produce precipitating antibodies in humans or in experimental animals. This approach narrows the studies to a limited area of the immune response. It is also likely that some of these inhaled organic dusts Table I Causes of hypersensitivity pneumonitis Di sease
Prob a ble antig ens
Source of antigen
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Vegetable products Farmer's lung
thermophilic actinomycetcs
moldy hay
Micropolyspora faeni ThermoactirlOmyces vulgaris Bagassosi s
moldy pressed sugarcane
Mushroom worker's disease
moldy compost
thermophilic actinomycctcs Thermoactillomyces sacchari
(bagasse)
thermophilic actinomycetes Micropolyspora jaelli Tltermoactirlomyces I'ldgaris
Subcrosis
moldy cork
unknown
Malt worker's lu ng
cuntaminated barley
fungi
Maple bark disease
contaminated maple logs
fungi
Seq u oiosis
contaminated wood dust
fungi
Asperl(il/lis clal'atus Cryptustruma corticale Graplzium "I', Plil/Illaria sp. other fungi Wood pulp worker ' s disc�sc
contaminated wood pulp
fungi
Humidifier lung
co ntaminated home humidifier
thermophilic actinomycctcs
Alternaria sp. and air conditioning ducts
TltermuactiNom.vces vulgaris ThermoactblOmyces calldidus
Paprika slicer's lu ng
moldy paprika pods
fungi
Grain measurer's lung
cereal grains
unknown
Mllcor stololli]er Thatched roof disease
dried grass and leaves
unknown
Tobacco grower's disea se
toba cco p lant s
unknown
Tea grower ' s disease
tca p lants
unknown
Coffee worker ' s lung
green coffee bean
unknown
Hypersensitivity pneumonitis
sawdust
unknown
Coptic disea se
doth wrappings of mummics
unknown
pigeon droppings
pigeon serum protein
Animal products Pigeon breeder's disease
(albumin. gamma globulin. and others) Duck fever
bird feathers
chicken proteins
Turkey handler's disease
turkey products
turkey proteins
wheat weavils
Sitopltilus granarilts
Insect products Miller 's lu ng
Bacterial Or viral products Hypersensitivity pneumonitIS
H. subtilis cnzymcs
Smallpox handler's lung
smallpox scabs
a
Bacil/IIS subtilis unknown
aprobably induces IgE mediated obstructive airways disease in the great majority or cases.
456
LOPEZ & SALVAGGIO
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and microorganisms serve as immunologic adjuvants or act as irritants (23). Evi dence indicates that there are varying amounts of antigenically inert (as measured by antibody response) macromolecules present in M faeni extracts (24). Such materials could conceivably be very important in activation of macrophages or of the alternate complement pathway. It seems clear that definition and characteriza tion of antigens is essential for the development of more precise diagnostic tests. More data are also needed on identification of antigens for purposes of skin testing, serum antibody detection, and use in in vitro studies of delayed hypersensitivity in these diseases. PATHOGENESIS The manner by which inhaled organic dusts induce lesions of hypersensitivity pneumonitis is likely dependent on a complex interrelationship between environ mental, genetic, and other host-related factors. With regard to organic dusts, several factors may play an important role in their ability to induce pulmonary disease. Very heavy exposure to the offending dust is usually necessary to produce symptoms and it has been calculated that a farmer working with moldy hay can inhale and retain in his lungs 750,000 spores per minute, 98% of which are actinomycete in origin «l.0!-t in diameter) (25). Although the majority of hypersensitivity pneumonitis cases have been associated with inhalation of dusts containing bacteria and fungi capable of growth and reproduction in the host, the bulk of evidence points toward a hypersensitivity reaction rather than an infectious process. These organic dusts may enhance the immune response in many ways, including a possible adjuvant effect and an effect on macrophage activation. Toxic factors might also contribute to the induction of pulmonary lesions since potent enzymes have been detected in extracts of pigeon droppings (26) and thermophilic actinomycetes (16). With regard to the host response, one of the more important determining factors might be the association of HL-A haplotypes with disease. In one recent study of pigeon breeder's disease, HL-A 1, 8 was frequently found in association with active disease, suggesting the presence of an HL-associated immune response (Ir) gene in hypersensitivity pneumonitis (27). There is little evidence for participation of IgE mediated reactions (Type I) in these diseases; patients with hypersensitivity pneumonitis have normal IgE levels (28), eosinophilia is usually not present, and the disease incidence is not increased in atopic patients. Immune complex induced allergic tissue injury (Type III) has been thought to play an important role in the pathogenesis of hypersensitivity pneumonitis. The time interval between exposure and symptoms; the presence of precipitating antibodies in most patients against the offending organic dust; and the detection of antigen, immunoglobulins, and complement components in lung lesions are among the arguments favoring this hypothesis. However, precipitating antibod ies to organic dusts can be detected in a large percentage of unaffected exposed subjects (29) and lesions characterized by pulmonary vasculitis, as might be ex pected in immune complex reactions, usually are not seen in the disease, providing evidence against this hypothesis. Although complement fixing antibodies have been
HYPERSENSITIVITY PNEUMONITIS
457
detected in affected patients, the role of complement in disease production is un
known. During provocative challenge of asymptomatic and symptomatic pigeon breeders, complement levels were seen to decline in the asymptomatic rather
than the symptomatic patients (30).
In patients with pigeon breeder's disease, data
have been obtained (31) that suggest the presence of an unusually labile variant of
C3 proactivator, which when activated by components of pigeon droppings, initiates activation of C3• Other investigators (32) have suggested that the presence of com
plement components on the surface of alveolar macrophages of patients without
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evidence of necrotizing vasculitis is more consistent with the hypothesis that cyto toxic (Type
II) allergic tissue injury plays an important role in disease pathogenesis.
Recent evidence also indicates that organic dust antigens can directly activate the
alternate complement pathway, implying an ability to produce disease on a nonim
munologic basis (33).
There is increasing evidence for a role of delayed (Type
IV) hypersensitivity in
disease pathogenesis and the pathologic changes in these diseases are consistent with
those of delayed hypersensitivity. Antigen induced migration inhibition factor (MIF) production plus lymphocyte transformation, both of which are thought by many to be in vitro correlates of delayed hypersensitivity unde� certain circum
stances, have been detected in these patients and these tests seem to correlate with
disease activity (30, 34, 35). Skin testing with protein antigens such as pigeon serum
has, however, generally resulted in dual (Type I and III) rather than delayed (Type IV) responses in man, but it is possible that the presence of immediate reactions might obscure the expression of subsequent delayed hypersensitivity reactions. Fur
thermore, in animal models of these diseases where thermophilic actinomycete
antigens have been employed for respiratory tract immunization, classic delayed hypersensitivity reactions at 24 and 48 hr have been produced (36). Based on the currently available evidence it is perhaps naive to assume that only one immunopa
thogenic mechanism is involved in disease production. It is likely that in the final
analysis several types of allergic induced tissue injury as well as nonimmunologic
factors may be operative in the pathogenesis of hypersensitivity pneumonitis.
ANIMAL MODELS In an attempt to gain insight into the pathogenesis of hypersensitivity pneumonitis.
animal models have recently been developed. The different animal species, antigens.
routes of immunization, and methodology employed make analysis of these models
and their specific applicability to the human disease difficult to assess. A complete review of these models is beyond the scope of this manuscript; rather, we discuss
primarily our own experiences plus those of selected investigators as illustrative
examples.
With regard to acute pulmonary immunologic injury several models have been developed in the rat and the rabbit. In one such model. intrabronchial inoculation of anti-bovine serum albumin (BSA). followed by administration of labeled antigen
intravenously, resulted in acute hemorrhagic neutrophil-rich exudates appearing within the pulmonary parenchyma within 4 hr. By immunofluorescence, interstitial
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458
LOPEZ & SALVAGGIO
deposits of antigen and antibody, and accumulation of radiolabeled C) in developing lesions were noted in this model (37). In a similar rabbit model (38) animals were immunized so as to produce a hyperactive response to intravenously administered BSA. When maintained in a state of relative antigen-antibody equivalence by admin istration of multiple daily doses of BSA, these animals developed proliferative and/or membranous pulmonary lesions associated with deposits of host immuno globulins, antigen, complement, and fibrinogen. These two models of immune com plex induced allergic tissue injury may bear a resemblance to lesions seen in certain early and late forms of human interstitial pneumonitis. Although elegant in design, they do not seem to correspond to human hypersensitivity pneumonitis lesions, which are characterized by mononuclear infiltrates with epitheloid and Langerhans' giant cell formation in the later stages. Other recent animal models have focused specifically on the production of pulmo nary lesions that closely resemble those seen in human hypersensitivity pneumonitis by employing organic dust and actinomycete antigens. Some of these models, which involve active immunization of rabbits, guinea pigs, mice, and rats, follow. In an early model of pigeon breeder's disease, Fink and co-workers exposed rats to daily long-term inhalation of pigeon dropping extract and were able to produce a serum precipitating antibody response plus pul monary lesions characterized by mononu clear cell infiltrates (39). In our laboratory similar models employing rabbits immu nized intratracheally (i. 1.) with Micropoiyspora jaeni, a rich source of farmer's lung hay antigen, were developed (36, 40). This type of i.t. immunization resulted in serum precipitating antibodies, delayed skin reactivity, antigen induced peripheral blood lymphocyte transformation, and alveolar macrophage migration inhibition. The immunologic events were associated with intense alveolar and interstitial mononuclear cell pulmonary infiltrates. These early findings indicated that in the rabbit and rat, intense local respiratory tract immunization could initiate a systemic immune response and could produce interstitial pneumonitis with pathologic char acteristics similar to those noted in the human disease. Several excellent animal models, which greatly enhanced our understanding of the immunopathogenesis of hypersensitivity pneumonitis, were also developed in the rabbit and guinea pig at this time by Richerson and co-workers (41). In the guinea pig these investigators employed both antigens, which favored the development of delayed hypersensitivity such as tuberculin and azobenzene arsenate N-acetyltyrosine, plus antigens such as ovalbumin, which favored antibody formation. They noted that animals immunized with the former antigens in Freund's complete adjuvant, when challenged by aerosol, developed mononuclear cell infiltrates consistent with the time course of delayed hypersensitivity. On the other hand, when ovalbumin was employed as antigen, acute hemorrhagic pneumonitis lesions rich in neutrophils occurred follow ing aerosol challenge. These animals also developed positive gamma- l globulin, passive cutaneous anaphylaxis (PCA) responses. In other experiments these investi gators administered ovalbumin in Freund's complete adjuvant followed by aerosol challenge and noted development of a mononuclear cell type alveolitis at 24 and 48 hr. Miyamoto & Kabe (42) developed a similar model employing guinea pigs immu nized with Freund's adjuvant and tuberculin followed by tuberculin aerosol chal-
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HYPERSENSITIVITY PNEUMONITIS
459
lenge. In this model striking mononuclear cell infiltrates were also produced 24-48 hr after aerosol challenge and these lesions could be passively transferred with sensitized lymphoid cells. In an attempt to demonstrate a role for either circulating antibody or delayed hypersensitivity in the production of experimental pneumonitis, hyperimmune serum and specifically sensitized lymphoid cells from animals previously immunized with ovalbumin were transferred to normal rabbits followed by ovalbumin aerosol or intratracheal challenge in our laboratory (43). Rabbits passively sensitized with hyperimmune serum demonstrated only mild and inconsistent peribronchial mononuclear cell infiltrates following aerosol challenge. Animals given between 2.5 X 108 and 10.9 X 108 sensitized lymphoid cells intraperitoneally followed by aerosol challenge developed markedly hyperplastic peribronchial lymphoid tissue with germinal center formation and peribronchial mononuclear cell infiltrates fol lowing challenge via the respiratory route. The cellular composition of these peri bronchial and alveolar lesions in sensitized challenged recipients was consistent with that noted in delayed hypersensitivity reactions. Large numbers of mature plasma cells were also noted in the lesions, suggesting either an additional process of active antibody synthesis by antigen-specific B cells passively transferred along with T cells and macrophages, or recruitment of host B lymphocytes by Iymphokines. Attempts at passive cell transfer in this species by the i.v. route have been unsuccessful due to the development of pulmonary vasculitis (41). In other studies of this type, passive transfer of hyperimmune serum or sensitized cells separately in the monkey followed by challenge with pigeon dropping extract (PDE) has been associated with either mild exudative pneumonitis, alveolar hemorrhage, or peribronchial edema (44). These studies suggested that both antibody and sensitized lymphoid cells may play a role in production of pulmonary lesions. Similar results have also been obtained in the guinea pig by passive transfer of serum and cells (45). In view of the fact that human hypersensitivity pneumonitis is associated with granuloma formation, several models have recently been developed in an attempt · to provide information on mechanisms involved in pulmonary granuloma produc tion. Among these are studies by Leake & Myrvik (46) and Moore, Myrvik & Leake (47) in which intravenous inoculation of Freund's adjuvant or BeG has led to the induction of "chronic" and "accelerated" pulmonary parenchymal granulomas associated with MIF production by alveolar wash cells but no dermal delayed hypersensitivity. These pulmonary granulomas have been shown to be antigen · specific. They are also inhibited in vivo by cortisone acetate and antimacrophage serum (48). Other workers have employed intravenously inoculated bentonite parti cles or polyacrylamide beads coated with soluble proteins (hemocyanin, mycobac teria, histoplasma, and schistosomal antigens) (49, 50). In these models, localized multifocal pulmonary granulomas have been produced following i.v. inoculation of antigen coated particles. The granulomas are noted to increase markedly in size and become "accelerated" or augmented when antigen coated particles are administered to previously sensitized animals. Some of these lesions have the histologic appear ance of delayed hypersensitivity reactions and can be transferred with specifically sensitized lymphoid cells (51).
460
LOPEZ & SALVAOOIO
In more recent studies in the mouse and chicken by Boros & Warren employing schistosome eggs
(51), it has been clearly demonstrated that hypersensitivity pulmo
nary granulomas are an expression of delayed (cell mediated) hypersensitivity and can be correlated with other in vivo and in vitro parameters of delayed hypersen sitivity. In these studies concerned with modulation of schistosoma I granulomatous hypersensitivity in the lung, the pulmonary granulomas were shown to be antigen specific and to possess the cellular composition of delayed hypersensitivity reactions. They were inhibited by neonatal thymectomy and could be induced in recipients
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following passive transfer with sensitized lymphoid cells. Furthermore, their pres ence did not correlate with antibody levels. Willoughby and co-workers
(52)
have
added to these observations by recently developing an animal model employing nonspecific T-cell mitogens such as concanavalin
A, with or without soluble protein
antigen administered via the respiratory route. T-cell mitogens alone produced focal interstitial inflammatio� of the lung, with cells predominantly mononuclear in nature, many blast forms, and some giant cells. In animals sensitized to a soluble protein antigen (BSA) followed by aerosol challenge with antigen and mitogen, vasculitis with interstitial inflammation and necrosis plus severe granulomatous injury bearing a resemblance to Wegener's granulomatosis were noted. Results of this study suggested that repetitive exposure to T-cell mitogens induced interstitial pulmonary lesions and that specific antigen challenge at a time when T-cell mediated injury was also in progress provoked an enhanced type of pulmonary injury. The authors concluded that T-cell stimulation might be quite important as an initiating event in immunologically mediated pulmonary tissue injury resulting from inhala tion exposure. In our laboratory we have recently begun further investigation on the role of delayed hypersensitivity and the alveolar macrophage in experimental granuloma tous pneumonitis. In these studies, repeated respiratory tract exposure of rabbits to
Micropolysporajaeni antigen has led to an early necrotizing inflammatory response of the respiratory bronchioles followed by gradual organization and interstitializa tion of peribronchial granulomas
(43, 53).
In some cases progressive bronchiolar
fibrosis with destructive lesions similar to those noted in human centriacinar em physema developed by one month after initial inoculation. Granulomas often as sumed the appearance of hard tubercles, including Langerhans' giant cells, which at times contained asteroid and Schaumann bodies similar to those noted in sar coidosis and human hypersensitivity pneumonitis. We have been unable to detect necrotizing vasculitis or vascular deposits of complement components and immuno globulins in these lesions by fluorescent microscopy, although C3 was demonstrable in alveolar macrophages and some plasma cells staining for IgG, A, and M were scattered in and about the developing lesions. Alveolar wash cell counts were significantly elevated following i.t. immunization with actinomycete antigen when
compared to saline inoculated controls. Glucose oxidation by alveolar wash cells of
these animals was also significantly increased over that of saline inoculated controls and morphologic evidence of macrophage activation was noted on electron micros copy. However, phagocytosis of Staphylococcus aureus by alveolar macrophages of
M jaeni
inoculated animals was not significantly increased above that of controls,
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HYPERSENSITIVITY PNEUMONITIS
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nor were acid protease or lysozyme levels elevated, suggesting that perhaps the total number of activated macrophages was relatively small. Concurrent with granuloma formation in this model, antigen induced alveolar macrophage migration became progressively inhibited by both direct and indirect assay, and animals developed specific precipitating antibody and delayed skin reac tivity. Anti-M faeni precipitating antibody was also exhibited in concentrated bronchial wash fluids of sensitized animals. The time course and histologic features of pulmonary granulomatous lesions suggested that a combination of direct irrita tion and subsequent hypersensitivity were operative in disease pathogenesis. Overall, these results suggest that multiple immunologic and nonimmunologic processes develop simultaneously at the bronchopulmonary level following respiratory tract exposure to thermophilic actinomycete antigen and it is reasonable to postulate that such a heterogeneous response also occurs in the human disease. In conclusion, it would appear that a variety of soluble and particulate antigens may induce acute or chronic pulmonary infiltrates in several animal species. These lesions may be associated with Type IV (cellular), Type III (immune complex), and possibly Type II (cytotoxic) allergic tissue injury, depending on the experimental conditions employed. It is also likely that particulate organic dust antigens may possess adjuvant, irritant, alternate complement pathway activating, or toxic prop erties, all of which could be important in the production of pulmonary lesions. Literature Cited
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