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Evolution of the antibody repertoires to rhinoviruses and house dust mites in relation to asthma inception and persistence: A high-resolution analysis in humans and mice

Subject Area Clinical Immunology and Allergology
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 428518790
 
Final Report Year 2024

Final Report Abstract

Asthma is the most prevalent chronic respiratory disease in childhood, characterized by inflammation and narrowing of the airways, acute breathing difficulties, and long-term sequelae. Rhinoviruses (RV) and house dust mite allergens (HDM) contribute to asthma inception in early childhood. In two independent experimental approaches, mice were a) initially infected with RV1B intranasally, and 10 days post-infection, animals underwent an HDM sensitization protocol for a total of 8 weeks (Model 1) or b) infected with RV1B after 4 weeks of initial HDM treatment and 10 days post-infection the sensitization with HDM was continued (Model 2). Lung histology sections revealed that the additional RV infection had no impact on the HDM-induced airway inflammation and abundance of mucus-producing goblet cells in neither model. Flow cytometry-based analysis of airway cellularity showed that the presence of immune cell subsets in the bronchoalveolar lavage (BAL) of HDM animals of Model 2 was induced, while this was not the case for HDM/RV mice. Similarly, BAL IL-17 and TNF-a were induced in HDM animals of both models and not among HDM/RV mice. HDM/RV animals (Model 2) also showed fewer extracellular vesicles (EVs) in the BAL when compared to HDM alone mice, particularly CD115b- and AN2 positive markers associated with macrophages and pericytes and fibroblasts, respectively. We also investigated these determinants in population subsets of PAPS (n 220, born 2002-2007) and MAS (n 106, born 1990), two German birth cohort studies monitoring children until school age. In the PAPS cohort, we found high levels of maternal IgG antibodies to RV VP1 (RVsIgG) species (A,B,C) and their serotypes at age 1m, that decline or disappear at 7m. New RVsIgG, induced by RV infection, appear at 1, 2, and 3 years of age in 87%, 94%, and 95% of children. The longitudinal analysis shows increasing concentration and progressive stabilization of the “dominant” species and serotype specificity, suggesting an “imprinting” of the RVsIgG response. A deep analysis of the signals obtained with the 37 serotypes of the microarray strongly suggests a very high level of cross-reactivity among most of the VP1 N-terminal peptides examined, especially within and between the RV-A and RV-C species. At age 3y, RV-C (c025p1), followed by RV-A (01p1/12p1), and RV-B (69p1) are the dominant species (serotypes). An “early” RV-IgG response was associated with a “high” phenotype both at age 1y to 3y (p<0.001) and at school age (p 0.024). In both cohorts, no characteristic of the RVsIgG antibodies to VP1 (species or serotype specificity, “high”/”low” levels, “early/late” response) was associated with any of the putative determinants examined (gender, atopic heredity, occurrence and frequency of URI and LRI before age 3y, early exposure to HDM, etc.) or, most importantly, with the occurrence of asthma at school age. In the MAS birth cohort, IgE sensitization to HDM early in life was associated with higher serum RVsIgG levels to RV-A, RV-B, and RV-C at 10 years of age but not with asthma at school age. Our findings in mice suggest an RV-induced immunomodulation on HDM-related outcomes, which wanes over time and does not influence the expression of asthma. This outcome does not confirm our working hypotheses. However, our longitudinal analysis in two birth cohorts shows for the first time, to our knowledge, the imprinting in early childhood of the IgG response to RV VP1, operated by immunodominant RV species and serotypes, that also define the hierarchy of serotype recognition mostly based on the VP1 sequence homology and likely cross-reactivity.

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