High risk of asthma among early teens is associated with quantitative differences in mite and cat allergen specific IgE and IgG4: a modified Th2 related antibody response revisited

Abstract

Background: Although proteins derived from cats are an important contributor to indoor allergen exposure in relation to asthma, it has been known for at least twenty years that some children who live in a house with a cat can become clinically tolerant to these animals. In 2001, we reported that children exposed to high levels of cat allergens made high levels of IgG4 antibodies to the cat allergen Fel d 1, and we coined the term "a modified Th2 response". However, this phenomenon is still poorly understood.

Methods: We studied serum antibodies among 616 individuals in the Viva unselected birth cohort recruited at their early teen visit (mean age 13.1 SD 0.8). IgE and IgG4 antibodies were measured by ImmunoCAP to inhaled allergens as well as the best characterised component allergens of cat, Fel d 1, Fel d 2, Fel d 4, and Fel d 7, and the dust mite allergens Der p 1, Der p 2, Der p 10, and Der p 23.

Findings: The results confirm that young teens living in a home with a cat make high levels of IgG4 specific for cat allergens, and that those antibodies, and specifically those to Fel d 1 are negatively associated with asthma. By contrast, the IgG4 responses to Fel d 4 and Fel d 7 are significantly lower and have no significant association with asthma. Perhaps more surprisingly, a similar effect is seen in relation to dust-mite allergens. Although the allergen Der p 1 is a major part of the IgE response to mite allergens, this protein also induced high prevalence and levels of IgG4 antibodies and has a less strong relationship to asthma than IgE to Der p 2 or Der p 23. Indeed, values of specific IgE to Der p 1 >3.5 IU/mL were not significantly related to asthma (OR 1.5 CI 0.8-2.8, p = 0.3, Chi² test). The prevalence and levels of specific IgG4 to these less abundant allergens are significantly lower for Der p 2 and almost absent for Der p 23.

Interpretation: High exposure to specific allergens in household dust can enhance production of both sIgE and sIgG4 antibodies, while allergens where abundance is significantly lower in dust can induce sIgE with limited or no sIgG4. The result is that the less abundant allergens, i.e., Fel d 4, Fel d 7, Der p 2, and Der p 23, may have a significantly higher relevance to asthma than expected because they induce less sIgG4.

Funding: This work was funded by R01-AI20565 (TPM) and support for the IgE and IgG4 assays provided by Phadia/Thermo Fisher Kalamazoo, Michigan. Project Viva is also supported by NIH R01HD034568 and R24ES.

Keywords: Asthma; Component allergens from cat and mite; Early teens; IgE and IgG4 antibodies; Less abundant allergens in house dust.

Fig. 1

Flow diagram for assays for IgE and IgG4. The samples from 616 participants in the project viva birth cohort obtained during their early teen visit, came in the form of heparinised plasma. Work in our laboratory on ImmunoCAP antibody assays over the last few years has established that this form of plasma gives results for both IgG4 and IgE antibodies that are ≤5% different from results using serum. The samples are referred to in the text as sera because the study of these assays is called serology.

Fig. 2

Levels of sIgE to 8 inhalant allergens. Numbers below the dotted line indicate values below LOD (<0.35 IU/mL). Values expressed as geometric mean (95% CI) and compared by the Mann–Whitney U test.

Fig. 3

Antibodies to cat dander related to asthma and cat ownership. (a) Levels of slgE and sIgG4 expressed in ng/mL showing significantly higher levels of IgE in participants with asthma and a cat at home (p < 0.002, Mann–Whitney test). (b) Ratios of sIgG4:sIgE among those with positive values for both isotypes. The ratios were significantly lower among those with both asthma and a cat. (c) Plot of sIgG4 and slgE to cat dander, among 144 participants living in a house with a cat, showing participants with asthma (red dots); the subgroup with MSA (red dots with a black circle) and those without current asthma (green squares). The prevalence of asthma among those with a ratio <50:1, 13 of 27 (48%) was significantly higher than for those with a ratio >50:1, 2 of 20 (10%) (p < 0.01, Chi² test). For Fig. 3c, we have included the current generic level of quantitation for sIgG4 of 300 ng/mL (horizontal dashed grey line) as used in some previous studies, as well as the 70 ng/mL (horizontal dotted line) used for our analyses of the data in the present study.

Fig. 4

Specific IgE (a) and sIgG4 (b) levels to cat dander and three cat components stratified according to reported prevalence of a cat in the home and with or without asthma. Positive values are shown with GM values and 95% CI, and compared by Mann Whitney U test. For each set of measurements there are four groups; those with no cat and without current asthma (blue); those with no cat and asthma (green); those with a cat at home and no asthma (purple); and those with a cat in the home and asthma (grey). The reported presence of a cat in the home had a significant effect on the levels of sIgE to cat, Fel d 1 and Fel d 4. By contrast, the presence of a cat only had a significant effect on the level of sIgG4 to cat and Fel d 1. The prevalence of positive results for sIgG4 to Fel d 1, 52%, was significantly higher than that for Fel d 4 or Fel d 7 17% and 9% respectively (p < 0.01 and p < 0.001, Chi² test). In addition, the presence of a cat in the home had no effect on levels of sIgG4 to Fel d 4 either among those with asthma (p = 0.6) or those without asthma (p = 0.17). In Fig. 4b, we have included the current generic level of quantitation of 300 ng/mL (horizontal dashed grey line) as well as the 70 ng/mL (horizontal dotted line) used for our analyses of the data in the present study.

Fig. 5

Ratios of specific IgG4: sIgE (both in ng/mL) presented as values of IgG4: IgE specific for three allergens, cat dander extract; Fel d 1, and Fel d 4. Among cat owners, (a) the ratios for cat dander and Fel d 1 are significantly lower for those with asthma; (p = 0.009 and p = 0.006 respectively, Mann–Whitney U test). Among those without a cat in the home, (b) the ratios are not significantly lower among those with asthma. The values for Fel d 4 reflect the fact that cat owners make very little IgG4 specific for this allergen either in the presence or the absence of a cat in the home.

Fig. 6

Values for sIgE and sIgG4 antibodies (both in ng/mL) to dust mite and the mite allergen components Der p 1, Der p 2, Der p 10, and Der p 23 were available for 283 participants. (a) Levels of sIgE for 199 participants without current asthma and 84 with current asthma. (b) Levels of IgG4 in ng/mL are shown for the same 199 participants without asthma and 84 with current asthma. In Fig. 6b, we have included the current generic level of quantitation of 300 ng/mL (horizontal dashed grey line) as used in some previous studies, as well as the 70 ng/mL (horizontal dotted line) used for our analyses of the data in the present study.