© 2002 American Thoracic Society
Cell-mediated immunity in asthma?To the Editor:In their thoughtful analysis, Salvi and colleagues (1) indicate that in asthma a heightened Th2 response coexists with the activation of Th1 lymphocytes. In principle, Th1 lymphocytes may be activated through an allergen–nonspecific pathway, via cytokines involved in Th2 response, or by a sensitizing allergen, a true cell-mediated immune reaction. Years ago, delayed hypersensitivity (DH) was the mechanism invoked for asthma attacks occurring 6–12 hours after occupational exposure to formaldehyde, potassium dichromate, or paraphenylene diamine (2). First, the patch tests to these agents produced an eczematous reaction, histologically characteristic of DH. Second, the inhalation tests with nonirritant concentrations of these simple chemicals induced reproducibly, isolated, delayed bronchoconstriction. Third, occasional intradermal testing with potassium dichromate and paraphenylene diamine led concomitantly to delayed skin reaction, asthma, and flare-up of contact dermatitis. Fourth, paraphenylene diamine frequently cross-reacted by patch test with its ortho or meta isomers and toluylene diamine; only the inhalation of the derivative cross-reacting by patch test could elicit delayed bronchoconstriction. Fifth, in contrast with these findings, other subjects with asthma attacks upon exposure to the same simple, irritant chemicals, had negative inhalation tests when the patch tests were negative ("irritant asthma"). Sixth, in that pre–radioallergosorbent testing era, skin sensitivity to these simple chemicals could not be passively transferred by serum. Occasionally, however, there was blood eosinophilia and bronchodilatation after an H1 blocker (Sandosten) administered intravenously (3). Seventh, as argued by negative history and inhalation tests with common allergens, the subjects were monosensitized. Subsequently, in animals, old tuberculin (4) or picryl chloride (5, 6) produced DH in the skin, and also, 48 hours after inhalation, tachypnea and a lung infiltrate with histopathologic features of DH. Although the mouse airway was hyperresponsive to carbachol, the bronchiolo-interstitial-alveolar location, the histological aspect, including the occasional presence of granuloma-like lesions was less evocative of asthma than of lung diseases with cell-mediated immunity (hypersensitivity pneumonitis, etc.). Appropriate transfer experiments argued that the delayed skin changes were lymphocyte-dependent (5, 6). The humoral response followed the DH response by a week (5), while serotonin, liberated perhaps from chemically irritated mast cells, was essential in initiating DH (6). As a schematic but neither absolute nor definitive paradigm, in the lung, cell-mediated immune reactions preferentially involve the bronchioles, alveoli and interstitium, and very seldom, the bronchi. Cells from Th2 pathway may participate as effector cells. An opposite location, and occasionally, effector cells from Th1 pathway characterize the IgE-mediated reaction.
University of California at Davis Davis, California REFERENCES
From the Authors:We entirely agree with Dr. Popa's analysis in offering one way in which non-Th2 directed mechanisms contribute to disordered airway function in asthma (1). Cell-mediated immune responses in the airways may well be important in certain types of asthma, especially those in which neutrophils increase or predominate in the airways or their secretions (2, 3). Asthma is a heterogeneous disorder in which different components of the innate and adaptive immune response play a role. Thus, although eosinophils and neutrophils may contribute differently to acute exacerbations of asthma according to disease severity, there may be other factors underlying disease chronicity that have their origin in the formed elements of the airways themselves, such as the epithelium and smooth muscle. Our recent reports of the marked increased mast cells within the smooth muscle compartment of asthma (in contrast to eosinophilic bronchitis) (4), and the identification of a major susceptibility gene, a disintegrin and metalloprotease 33 (ADAM 33) (5), as being closely associated with bronchial hyperresponsivness and variable airflow obstruction further reinforce this view. New insights into the relationship between airway inflammation and the clinical manifestations of asthma are providing new opportunities to identify targets. These will include factors involved in delayed hypersensitivity response, including interleukin-1ß, tumor necrosis factor- , interferon- , and interleukin-12.
Southampton General Hospital Southampton, United Kingdom REFERENCES
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