© 2006 American Thoracic Society doi: 10.1164/rccm.2604005
Of Rats and Men (and Women)National Jewish Medical and Research Center Denver, Colorado The study of allergic disease in the workplace provides a window into pathogenesis, and allows us to address a question fundamental to prevention: with similar exposures, why do some workers become sensitized and symptomatic to an occupational allergen, while others do not? Atopy and cigarette smoking explain only part of the risk for occupational allergic rhinitis and asthma. Traditional exposure dose–allergic response relationships are difficult to demonstrate, as moderately exposed workers are more frequently sensitized than are the most highly exposed workers. This finding is often explained by the healthy worker effect: sensitized and symptomatic workers will move themselves out of jobs with high allergen exposure. However, the elegant study by Jeal and colleagues (1) in this issue of the Journal (pp. 21–25) provides an important insight into this finding: some workers do not develop disease in high exposure jobs because of the specific immune responses they develop to an occupational allergen. In this study by Jeal and colleagues, the authors report results from a remarkably complete cohort (689 of 718 ever–rat-exposed workers in six pharmaceutical plants) characterized by their rat exposures over time, workplace respiratory symptoms, and rat-specific IgE, IgG, and IgG4. Workers were skin tested to three common allergens, and rat urinary protein with good concordance with the rat-specific IgE radioallergosorbent test (RAST). The authors then created a multivariate model of immune and exposure factors predicting work-related chest symptoms. Important to this article is the understanding that it is possible to have allergic (IgE) sensitization without evidence of disease: the diagnosis of laboratory animal allergic disease requires both specific sensitization to the lab animal, and symptoms when one works with that animal. In Jeal and colleagues' cohort, having only rat-specific IgE was the strongest predictor of work-related chest symptoms, as has been demonstrated in other studies of laboratory animal workers (2). Workers with both rat-specific IgE and IgG4 had a lower, but not insignificant, risk of chest symptoms. However, the interaction of IgE and IgG4 was protective against work-related chest symptoms, especially in workers exposed for more than 3 years. Similar immune responses have been reported in cat-exposed children with frequent contact (3), and are replicated in immunotherapy (4, 5), which may require several years to demonstrate improvement in symptoms and immune markers. Jeal and colleagues speculate that the protective effect against symptomatic disease offered by a high IgG4: IgE ratio reflects a form of natural immunotherapy. Whether T-regulatory cells specific for rat allergen were induced in such workers was not addressed in this analysis but will be an important consideration in future studies. Similar results were noted in a study of highly exposed and sensitized mouse handlers in the Jackson Laboratories (6). The converse was reported in a longitudinal survey of laboratory animal workers exposed to rats (7). In the latter study, higher levels of rat-specific IgG4 predicted newly positive skin tests and allergic respiratory symptoms to rats. Levels of rat-specific IgG4, prevalence of rat positive skin tests, and allergic symptoms all increased with estimated exposure to rat urinary allergen over the past year, and was most pronounced in atopic workers exposed for fewer than 4 years. On closer inspection, however, the effect was reversed in atopic workers exposed for more than 4 years. With increasing estimated rat allergen exposures, this group had decreasing prevalence of rat sensitization and fewer allergic symptoms to rats, findings similar to the Jeal and colleagues' study. The authors did not evaluate the association among rat-specific IgG4, IgE, and symptoms, which might have been helpful in understanding these results. The discrepant findings may also reflect different exposure classifications. One of the strengths of the present manuscript is the categorization of exposure by the highest level, ever, of work with rats. This approach suggests that peak exposures are more important for the development of immune responses to laboratory animals than average exposures, and acknowledges that exposures responsible for sensitization may have occurred in the past. Of particular interest is the frequent presence of laboratory animal–specific antibodies in exposed workers. Jeal and colleagues detected rat-specific IgE in 6 to 16% of all workers, and rat-specific IgG and IgG4 in 15 to 30%. In mouse-exposed workers, up to 45% had mouse-specific IgG4, depending on their quintile of exposure (8), and 83% of rat-exposed workers had rat-specific IgG4 (7). These findings demonstrate that many workers recognize, and express, a specific immune response to these animal allergens. Far fewer, however, develop symptomatic disease, some of which may not be due to allergen (9). Classifying workers as allergic or nonallergic to workplace allergens, based on symptoms and laboratory animal–specific IgE, does not adequately reflect the complexity of their responses, and suggests that both immune responses and symptoms must be considered to adequately classify work-related allergy. Results reported by Jeal and colleagues, as well as by others (4), imply that we should categorize workers as follows: (1) no immune recognition of rat allergens, no disease; (2) no immune recognition of rat allergens, symptoms but not to rat allergens; (3) immune recognition of rat allergens, response with T-regulatory suppression, altered levels of IgE, IgG, and IgG4, and few symptoms and/or disease; and (4) immune recognition of rat allergens, response with IgE, symptoms, and disease. Perhaps rat IgG and IgG4 production should be considered markers of the immune recognition of exposure, and necessary for tolerance. This implies that when immune recognition is inadequate or dysfunctional, symptoms and disease result. Genetics likely play a role in the development of disease, in that interactions with exposures are most evident at exposure extremes (10, 11). Those workers who respond to high exposures with tolerance may well be characterized by protective genotypes worth further study. Jeal and colleagues are to be commended for beginning to elucidate protective immune responses in exposed but asymptomatic workers. Traditional interest in mechanisms of disease dictates that we should study exposed and symptomatic workers. If we are interested in prevention, however, then also studying the exposed and healthy worker will bring important new insights to preventing allergic disease in the workplace. FOOTNOTES Conflict of Interest Statement: K.A.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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