Paradoxical Effect of Domestic Animals on Asthma and Allergic Sensitization

Over the last 20 years, the relationship between exposure to allergens and asthma has been intensively investigated because the prevalence and severity of the disease have increased, and because sensitization to common indoor allergens is strongly associated with asthma.^{1 - 2} Studies on exposure to dust mite allergens have consistently shown a direct relationship to sensitization, as judged by positive skin prick test responses, as well as a strong relationship between sensitization and asthma.^{3 - 6} By contrast, several studies of farming communities in Europe have indicated that early exposure to farm animals has a protective effect against both sensitization and asthma.⁷ Recent evidence has suggested that this effect might be mediated by high exposure to bacterial endotoxins.^{7 - 8} Farm animals have not been common in the big cities of America or Europe since before 1900; on the other hand, domestic pets are extremely common, a prolific source of allergens, and sensitization to these allergens is strongly associated with asthma.^{9 - 10} It was therefore of considerable interest when reports from Europe suggested that the presence of a cat in the home could decrease the risk of sensitization to cat allergens.^{11 - 12} Initial speculation that this effect could be secondary to decisions by families with allergic disease not to have pets has been made unlikely by reports that the same effect occurs in countries where domestic animals are equally common in the homes of families with a history of asthma as in the homes of families without a history of asthma.¹³ Furthermore, recent evidence from Sweden has shown that the presence of a cat in the home is associated with decreased incidence and prevalence of asthma among preteens.¹⁴

The study by Ownby and colleagues¹⁵ in this issue of THE JOURNAL provides an important new dimension to the debate. The authors report that children in a birth cohort raised in a house with 2 or more dogs or cats in the first year of life have not only less allergic sensitization to dog and cat as determined by skin prick tests and allergen-specific IgE levels, but also less sensitization to allergens in general at age 6 to 7 years. Among this cohort living in suburban Detroit, the percentage of families who kept dogs and cats was not significantly influenced by a family history of asthma or allergy. Because domestic animals can be a source of endotoxin, this finding opens up the possibility that the effect of pets in the United States could be comparable to the effect of cows in European farming communities.^{7 - 8 ,11 ,16}

Perhaps the most striking feature of the study by Ownby et al is that children who lived in a house with 2 or more dogs or cats in the first year of life had a decreased prevalence of positive skin prick test responses and serum IgE antibodies to other allergens, eg, pollens and molds.¹⁵ This result differs from some previous studies but is consistent with others, and raises important questions about possible immunologic mechanisms.^{4 ,14 ,17} It has been suggested that an antigen-specific immune response can influence the response to other antigens by altering the "cytokine milieu," shifting the balance between T helper cell type 2 (T_H2)-mediated immune response, which is associated with allergic inflammation, and T_H1-mediated response, which is associated with cellular immunity. Interleukin 4 exerts a positive feedback effect on T_H2 responses, whereas IL-12, which is involved in T_H1-mediated immune responses, can downregulate the development of T_H2 responses.^{18 - 19}

Given the possible role of endotoxin as a stimulant of IL-12, early exposure to endotoxin from animals could bias the overall immune response away from an allergic response so that children who did not become allergic despite high exposure to cat allergen might have some form of T_H1 response.^{19 - 20} The interpretation of differences in published results depends on specifically defining the type of immune response to both animal allergens and to other allergens among children raised with animals. In particular, it is important to know whether early T-cell priming, with shifts in the balance between T_H1 and T_H2 responses, is essential for controlling the nonallergic or tolerant response—an immune response that does not give rise to inflammation or tissue damage, and also, whether the effect is "permanent" or depends on continuing allergen exposure. The question of whether the effect of high allergen exposure is permanent is of great practical importance. Many physicians are asked to advise parents about the presence of an animal in the house. However, large numbers of children experience a dramatic reduction in allergen exposure when they leave home.

Although Ownby et al speculate about a T_H1 response to animal dander related to early dog and cat exposure, like other researchers, they provide no objective evidence for an allergen-specific T_H1 response.^{8 ,20 - 21} Three approaches have been used to investigate the immune response associated with domestic animal exposure: skin prick tests, serum antibody assays, and in vitro studies on peripheral blood mononuclear cells. The results of skin prick tests are consistent; individuals who have allergic symptoms around animals have positive immediate skin prick test responses, whereas nonallergic individuals with either high or low exposure to cats have negative immediate skin prick test responses and no delayed responses. In a study using antigen-binding radioimmunoprecipitation to measure IgG antibodies in children, many of the children with negative skin prick test responses had serum IgG antibodies to the cat allergen Fel d 1. Further investigation revealed that many of these children had a high proportion of IgG4 antibodies.¹⁷ Expression of the gene for IgG4 is dependent on the T_H2 cytokine IL-4. Thus, an IgG and IgG4 antibody response without IgE antibody might be regarded as a "modified T_H2 response."^{17 ,22} Consistent with this model, preliminary evidence from Reefer et al²³ has shown that T cells from individuals with high exposure to cat allergens produce high levels of IL-10, an anti-inflammatory cytokine, in response to Fel d 1 in vitro regardless of their skin prick test responses and allergen-specific serum antibody levels. Increased IL-10 levels are consistent with a CD4-positive T regulatory cell (T_R1) response, suggesting that the response to cat allergens may be suppressed or modified by regulatory cells in individuals with both positive and negative skin prick test responses.²³ Observation of an IgG4 antibody response to Fel d 1 raises doubts about the hypothesis that shifts in the balance between T_H1 and T_H2 immune responses can explain changes in the prevalence or severity of asthma. However, it is possible that the presence of animals early in life, as in the study by Ownby et al, results in a different immune response than does exposure later in childhood.

In many parts of the world, proteins derived from dust mites are the dominant allergen associated with asthma.^{3 - 6 ,24} This is not because exposure to mite allergens is quantitatively higher than exposure to other allergens, such as that from domestic cats.⁹ Indeed, there is abundant evidence that levels of airborne Fel d 1 in houses with a cat are much higher than levels of airborne dust mite allergens in homes that are infested with dust mites.⁹ Several studies suggest that the prevalence of sensitization to cat allergens is one half or one third of the value that would be expected.^{12 ,24} In many communities, the prevalence of positive skin prick test responses to dust mites or pollens is 30%, whereas sensitization to cats is only 10%.^{6 ,12 ,24} Exposure to animal dander in homes is greater than exposure to dust mite or pollen antigens, suggesting that as many as 15% to 20% of the population may develop some form of tolerance to animal allergens. In contrast to results with animal dander, currently available data provide no evidence that any form of tolerance occurs with high exposure to mite or cockroach allergens.^{16 ,25} In addition, in a cross-sectional study of middle-school children, high exposure to cat allergens did not decrease the risk of sensitization to dust mite.^{16 - 17} In prior studies, allergic sensitization, as defined by skin prick test positivity to dog or cat allergens, has been consistently associated with asthma, and in some studies, this sensitization to animal allergens was positively associated with exposure to the allergens.^{4 ,10} These results may reflect lower average levels of allergens in homes secondary to differences in furnishings, cleaning habits, or ventilation,⁴ or alternatively, response to high exposure may be genetically controlled. Another possible explanation is that there may be a "pecking order" of allergens such that a tolerant immune response to dog or cat can decrease the prevalence of responses to pollens, but has little effect on responses to dust mite. Other possible explanations for differences include the timing of responses during childhood, the role of concomitant endotoxin exposure, and the enzymatic activity of mite allergen.²⁶

In conclusion, growing up in a house with pets appears to decrease the risk of developing positive skin test responses and IgE antibodies to allergens derived from the pet. Although the underlying mechanisms remain to be resolved, this finding presents an opportunity to investigate the immunopathology of allergic disease including asthma. At a simple level, avoiding having a cat cannot be recommended as a method of preventing sensitization, since children living without an animal in the home are more likely to develop positive skin test responses to animal allergens. Furthermore, children who develop positive skin prick test responses or IgE antibodies are at increased risk of asthma whether they live in a house with an animal or not. These findings provide evidence that the risk of asthma relates to the IgE portion of the T_H2 response. The number of children living in a house with a pet, and the low overall prevalence of positive skin prick test responses to allergens from these animals, suggest that as much as 20% of the population has become immunologically tolerant to proteins or allergens derived from the animals. The new findings in relation to domestic animals provide an opportunity to understand the aspects of the allergic response that create risk for asthma; the mechanisms by which high exposure to a foreign protein (ie, the allergens in animal dander) can give rise to tolerance; and also, the factors that control the prevalence of allergic disease.