Integrative multi-omics analysis identifies molecular signatures associated with high-risk of systemic reactions to honeybee venom and olive pollen

Background Disease manifestation in IgE-mediated allergies is highly heterogeneous, partly due to the distinct exposure patterns of different allergens. High-risk of systemic reactions to immunotherapy is characterized by molecular patterns that are still not well defined. Methods Two patient cohorts, one of bee venom and one of olive pollen allergic patients, were recruited and stratified into two groups, according to the risk of developing systemic reactions (low-risk or high-risk). Immunoglobulin profiling, basophil activation test and targeted metabolomics and proteomics of serum were performed, and data integration was carried out. Results High-risk phenotypes for both bee venom and olive pollen allergic patients differed in allergen sensitization, basophil reactivity, and metabolite and protein abundance patterns, which was further supported by strong clustering in multi-omics DIABLO model. Specifically, high-risk phenotypes for bee venom allergy was characterized by increased basophil activation after Api m 1, Api m 4, and Api m 10, and increased levels of urea, CXCL12, TNF, TNFSF12, TNFSF10, and CCL11, with no differences in immunoglobulin profiles; while high-risk phenotype olive pollen allergy showed increased levels of sIgE against Ole e 7, increased basophil activation after Ole e 1 and Ole e 3, but no Ole e 7, stimulation, decreased levels of LPC 17:1, carnitine, and IL-7, and increased levels of hypoxanthine, CXCL12, OLR1, CCL3, and EGF. Conclusions Integrative multi-omics profiling combined with functional immune assays consistently discriminated low-risk and high-risk of systemic reactions in two distinct allergy models and suggested allergen-specific cellular and molecular signatures. These findings highlight the potential added value of combining systems-level and functional approaches to better characterize severity in allergic phenotypes.