Role of polyclonal cell activation in the initiation of immune complex-mediated pulmonary injury following antigen inhalation.

Abstract

The lung, by virtue of its anatomic situation, provides environmental antigens with unique access to host lymphoid tissues. In order to better understand the biologic consequences of antigen inhalation, we developed in animal model in which soluble proteins are administered in aerosol form to rabbits. By labeling these proteins with fluorochrome dyes or radioactive isotopes, the uptake, distribution, and fate of such proteins can be demonstrated both morphologically and quantitatively. Prompt host-antibody responses can be demonstrated to inhaled antigen, but not to comparable amounts of ingested antigen. Repeated administrations of antigen aerosol to immune animals produced little injury; in contrast, administration of aerosols containing phytohemagglutinin or cancanavalin A (Con A), plant lectins which activate leucocytes in a polyclonal fashion, induced a diffuse interstitial pneumonitis. When immune animals inhaled antigen plus Con A, devastating pulmonary necrosis was induced, in association with localized deposits of immune complexes containing antigen, antibody and complement. Such necrotic injury healed by scarring within 4 weeks. The necrotizing injury could be prevented by either decomplementation with cobra venom factor, or through inhibition of leucocyte responsiveness to Con A by administration of cholera toxin, a cAMP agonist. These studies indicate that antigen inhalation may serve as an important means of establishing "natural" immunity to environmental agents, but also may lead to severe pulmonary injury and fibrosis where the agents inhaled act not only as antigens but as polyclonal leucocyte activators as well.ImagesFIGURE 2. (a)FIGURE 2. (b)FIGURE 3. (a)FIGURE 3. (b)FIGURE 4. (a)FIGURE 4. (b)

Immunologic Mechanisms of Parenchymal Lung Injury

“…Since Con A is known to activate T-lymphoetes (and, in some instances, basophils as well) in a polyclonal fashion in vitro, we have proposed that its unusual toxicity for the lung results from its ability to activate these cells in vivo, again in an amplified, polyclonal fashion (90). The hypothesis was supported by the experimental data; both forms of pulmonary inflammation were prevented by cholera toxin administration (104,105). 11a), mediators released by mitogenstimulated lung lymphocytes and macrophages may alter or disrupt this barrier (Fig.…”

“…Second, they trigger formation of pathogenic immune complexes between inhaled antigen, humoral antibody and complement. It also inhibited the tuberculinlike response to intradermal injections of Con A, but did not affect the immune complex-mediated cutaneous Arthus vasculitis (104,105), thereby demonstrating a selective inhibition of cell-mediated reactions. We further suggest that, whereas under usual circumstances inhaled antigen normally does not come into direct contact with humoral antibody, probably because the type I pneumocytes serve as an effective anatomic barrier (Fig.…”

“…First, they induce interstitial pulmonary inflammation when inhaled, even in an unimmunized -host. Tb test the hypothesis that inhaled mitogens initiate or "trigger" immune complex formation between inhaled antigen and circulating antibody, Shenker et al (104,105) blocked the responsiveness of lymphocytes to T-cell mitogens in vivo by parenteral administration of cholera toxin. Since Con A is known to activate T-lymphoetes (and, in some instances, basophils as well) in a polyclonal fashion in vitro, we have proposed that its unusual toxicity for the lung results from its ability to activate these cells in vivo, again in an amplified, polyclonal fashion (90).…”

Immunologic mechanisms of parenchymal lung injury.

“…Such treatment elevated the cAMP levels of peripheral blood lymphocytes and blocked their proliferative responses to subsequent stimulation by Con A in vitro. It also inhibited the tuberculinlike response to intradermal injections of Con A, but did not affect the immune complex-mediated cutaneous Arthus vasculitis (104,105), thereby demonstrating a selective inhibition of cell-mediated reactions. If immune complex formation in the lung is dependent upon initiation by mitogen-activated leukocytes, it may be predicted that cholera toxin should inhibit both the mitogeninduced interstitial inflammation and immune complexmediated parenchymal necrosis.…”

“…To test the hypothesis that inhaled mitogens initiate or "trigger" immune complex formation between inhaled antigen and circulating antibody, Shenker et al (104,105) blocked the responsiveness of lymphocytes to T-cell mitogens in vivo by parenteral administration of cholera toxin. Such treatment elevated the cAMP levels of peripheral blood lymphocytes and blocked their proliferative responses to subsequent stimulation by Con A in vitro.…”