In this study, we identified a mechanism that may underlie the important clinical observation that children with allergic sensitization, particularly those both sensitized and exposed, have more clinically significant lower respiratory tract illnesses and asthma exacerbations caused by human rhinoviruses (HRV).9,10,17
We have demonstrated that the frequency of pDCs expressing the high-affinity IgE receptor (FcεRI) is inversely associated with HRV-induced IFN-α and IFN-λ1 secretion. Moreover, cross-linking of this receptor prior to HRV stimulation using antibodies to either IgE or the receptor itself significantly inhibited IFN-α and IFN-λ1 production by half or more, and these effects were especially pronounced in children with allergic asthma. These findings are of particular clinical relevance because up to 90% of asthma exacerbations in children are related to HRV infection,8
they most often occur in children with concomitant aeroallergen sensitization10
and current therapies are only partially effective in preventing exacerbations.18
Notably, the inverse relationships between total IgE and diminished IFN secretion were only apparent after FcεRI cross-linking. An argument could be made that the observed lack of correlation with total IgE was due to culturing the PBMCs in IgE-free media; however, the half-life of the IgE-FcεRI complex has been found to be approximately 16 hours in suspension, 19
and our experiments were initiated within a few hours of blood sample collection. The significant correlations between total IgE levels and percentages of FcεRI-positive PBMCs identified in our patient population suggest that FcεRI crosslinking may represent a key event leading to impairment of virus-induced interferon production. More importantly, the significant inverse correlations between total IgE and HRV-induced interferon in the presence of FcεRI cross-linking provide direct evidence for the potential biologic relevance of this pathway in vivo
, where cross-linking of allergen-specific IgE in the scenario of sensitization and exposure could also result in significant impairment of interferon responses to HRV.
Plasmacytoid dendritic cells (pDCs) produce up to 95% of the IFN-α20
in peripheral blood upon stimulation with viruses, despite making up only 0.2–0.8% of the PBMC population.21
In our study, HRV-induced interferon secretion was most significantly inversely associated with pDC FcεRI expression, suggesting that these cells are principally involved in this effect. The mechanism by which increased FcεRI expression on pDCs, even in the absence of FcεRI cross-linking, leads to impaired IFN production is unclear. One possibility may be related to signaling through the FcεRIγ subunit, an immunoreceptor-based tyrosine activation motif (ITAM) that recruits and regulates tyrosine kinases such as the Src and Syc families.22
Interestingly, immunoglobulin-like transcript 7 (ILT7) and blood dendritic cell antigen 2 (BDCA2) are regulatory surface receptors specific to pDCs that both signal through FcεRIγ, and cross-linking either ILT7 or BDCA2 inhibits interferon synthesis in response to viruses.22,23
Thus, it is possible that cross-linking FcεRI directly inhibits HRV-induced IFN-α and IFN-λ1 production, but additional mechanisms may contribute to impaired interferon production in allergic asthmatic children as well.
Unchecked interferon production by pDCs has been associated with autoimmune diseases such as lupus24
and Sjogren syndrome;25
therefore, tight regulation of IFN responses is critical for immune homeostasis. Thus, it is possible that effects of FcεRI on interferon secretion comprise a counter-regulatory pathway in place to control interferon responses. Consequently, in allergic asthmatic individuals, overexpression of FcεRI may lead to excessive interferon inhibition. Gill and colleagues13
recently demonstrated diminished pDC IFN-α production in response to influenza virus in allergic asthmatics compared to non-allergic controls. Taken together with our findings, this counter-regulatory pathway may be important in the antiviral response to numerous respiratory viruses.
A novel aspect of our findings was the evaluation of IFN-λ1 production, especially given the recent data linking diminished IFN-λ1 responses to asthma.11
Specifically, Contoli and colleagues11
have demonstrated that insufficient levels of IFN-λ1 in the asthmatic airway are associated with more severe HRV induced illness and obstructive patterns on pulmonary function testing in allergic asthmatic adults.11
Interestingly, IFN-λ1 mediates its actions through a receptor distinct from the receptor for Type I IFNs. The results of our study suggest allergic asthmatics children have diminished Type III IFN production to rhinovirus, which may represent an exciting opportunity to develop distinct anti-viral therapies aimed at this pathway.
One strength of our study is the inclusion of allergic non-asthmatic children, which allows separate evaluation of effects on allergy vs. asthma. Additionally, we utilized PBMCs, rather than isolated pDCs, in order to evaluate the role of FcεRI expression and cross-linking on multiple innate immune cell types and to allow for cell-cell interactions. Furthermore, the subjects studied have been well characterized including comprehensive and repeated assessments of allergic and asthma phenotypes. A study limitation is that only 3 non-allergic asthmatics were evaluated and thus we lacked power to compare these children to the other phenotypes; however, the vast majority of school-age children with asthma have concomitant allergic sensitization.18,26
Our results may have particular clinical relevance to a recent study in inner city children with allergic asthma by Busse and colleagues,27
which demonstrated the efficacy of omalizumab in preventing exacerbations during peak HRV seasons. Studying HRV-induced IFN production pre-/post-omalizumab therapy could provide further evidence to support to our hypothesis. Further, it is well known that allergic sensitization is an important risk factor for asthma inception,28
and recent evidence supports a causal role for sensitization in the development of HRV wheezing in preschool children.1
It could be postulated from our study that preschool children with aeroallergen sensitization and exposure have reduced innate immune responses that could lead to greater severity of HRV illnesses in early life and, consequently, lead to the development of persistent airway inflammation and asthma.
In summary, we have identified a mechanism that may link allergic asthma in childhood to deficient antiviral responses. Specifically, increased expression and cross-linking of the high-affinity IgE receptor, FcεRI, prior to HRV infection inhibits IFN-α and IFN-λ1 secretion from PBMCs. These findings, which were most pronounced in the context of allergic asthma, suggest that therapeutic strategies aimed at reducing FcεRI expression and cross-linking represent viable approaches to prevent HRV-induced wheezing illnesses and asthma exacerbations.