By Klaus Bønnelykke, MD, PhD
Chairman: Torkil Menne
Opponent: Peter Oluf Schiøtz
Opponent: Johan de Jongste
The allergy-associated (atopic) diseases; asthma, eczema and rhinoconjunctivitis, are the most common chronic diseases in childhood. A large number of environmental and genetic risk factors have been suggested, but still our understanding of the underlying disease mechanisms and etiologies is limited. One limiting step for research is the large heterogeneity of atopic diseases, especially in early childhood. The diseases are likely to represent several underlying subtypes, and identifying these is essential for improved treatment and prevention.
A hallmark of atopic disease is sensitization with production of specific IgE-antibodies against allergens. Sensitization may cause allergic symptoms, and sensitization early in life is a strong risk factor for later disease. Fetal and early postnatal life seems to be a critical period for development of atopic disease and may be an important “window of opportunity” for prevention. The aim of this thesis was to increase the understanding of sensitization in early life. We studied indicators of sensitization in the newborn, and early development of sensitization and disease associated with a newly discovered genetic risk factor. Such insight may increase our understanding of disease pathogenesis in general, direct future research and help developing relevant and correctly timed preventive measures.
It has been suggested that sensitization may occur already in utero and this has led to guidelines recommending allergen avoidance during pregnancy. We studied intrauterine sensitization measured by allergen-specific IgE in cord blood. Allergen-specific IgE, primarily against inhalant allergens, was detected in 14 % of cord blood samples. However, corresponding specific IgE was not detectable in infant blood at 6 months of age. Furthermore, specific IgE in cord blood completely matched specific IgE in maternal blood both with respect to allergen specificity, level of specific IgE and ratio of total IgE/specific IgE. This suggests that allergen-specific IgE in cord blood does not reflect intrauterine sensitization but seems to be the result of transfer of maternal IgE to the fetus. Our results do not support the concept of intrauterine sensitization and thereby the rationale behind allergen avoidance during pregnancy. Furthermore, such recommendations are not supported by randomized clinical trials and should be withdrawn.
Elevated levels of non-specific (total) IgE is thought to be the result of fetal production and has been used as a marker of atopy through decades. It has been used both as an outcome in studies of prenatal risk factors and as a predictor of disease to decide on preventive measures in the infant. It is well known that falsely elevated IgE levels may occur due to “contamination” of cord blood with maternal blood, but this is usually controlled for by measuring cord blood IgA and is found to be an infrequent event. Our previous study suggesting that allergen-specific IgE is the result of materno-fetal transfer of IgE suggests that also total IgE may be significantly affected by such transfer. On the other hand, production of non-specific IgE by the fetus is well documented, and materno-fetal transfer may be less of a problem in studies of total IgE. We found indication of materno-fetal transfer in 46% of cord blood samples with elevated IgE. Furthermore, detection of such transfer seemed not to be appropriately done by the standard method of IgA-measurement. This suggests that previous studies using total IgE as outcome probably included a number of samples with falsely elevated levels and should be interpreted with caution. This may also explain the low predictive value of elevated cord blood IgE found in recent studies. Future studies should control for materno-fetal transfer of IgE or preferably use other markers of atopy.
Variation in the gene coding for the skin barrier protein filaggrin (FLG) is the strongest known genetic risk factor for eczema. FLG seems only to be expressed in the skin but interestingly, FLG variants are also associated with increased risk of sensitization and asthma. Longitudinal studies in early life describing the FLG-associated development of sensitization and atopic diseases may help understanding disease mechanisms and identifying the environmental risk factors interacting with this genetic susceptibility and the age at which intervention should be initiated. We found a FLG-associated pattern of atopic disease in early childhood characterized by early onset of eczema, early onset of asthma with severe exacerbations and later development of sensitization. This suggests a specific subtype of preschool asthma initiated by skin barrier dysfunction. Early asthma seemed not to be driven by sensitization, which was a later phenomenon. Future research of FLG gene variants should focus on infancy and relevant outcomes other than eczema will be early asthma symptoms and later sensitization.
In conclusion, studies of sensitization and atopic disease in early life may be essential in order to improve understanding of disease pathogenesis in general and help developing relevant and correctly timed preventive measures. For this purpose, early markers of disease are important but the validity of such measures is essential. Our studies suggest that allergen-specific IgE in cord blood is entirely a maternal product while elevated total IgE is often caused by materno-fetal transfer of IgE . FLG gene variants seem to identify a subtype of disease where skin barrier dysfunction leads to early eczema, early asthma symptoms and later sensitization. Future FLG-targeted research has the potential of improving understanding prevention and treatment of atopic diseases in childhood.