Cross-sensitization between Cannabis sativa and Lipid transfer proteins: Evidence from a large molecular cohort

Backgroud: Nonspecific lipid transfer proteins (nsLTP) are major plant allergens associated with systemic allergic reactions. The major Cannabis allergen, Can s 3, has recently emerged as a potential contributor to nsLTP-mediated allergy and cross-reactivity. However, its role within the broader nsLTP sensitization network remains insufficiently characterized. Objective: This study aimed to evaluate the prevalence of sensitization to Can s 3 and to characterize its co-sensitization patterns with food- and pollen-derived nsLTPs in a large molecular cohort. Methods: A retrospective observational study, including 2409 patients referred for allergological evaluation, was conducted. Allergen-specific immunoglobulin E (IgE) was measured by using a multiplex allergen-specific IgE platform. Sensitization was defined as specific IgE level ≥ 0.35 kUA/L. Associations among allergens were assessed by using the Fisher exact test with odds ratios (OR) and 95% confidence intervals. Quantitative relationships between nsLTP components were evaluated by using the Spearman correlation. Principal component analysis and k-means clustering were applied to identify sensitization profiles. Results: Overall, 35.0% of the patients were sensitized to at least one nsLTP component. Strong associations were observed between Can s 3 and several food-derived nsLTPs, particularly Pru p 3 (peach) and Mal d 3 (apple) (ORs 222.9 and 227.6, respectively; p < 0.001). Can s 3 sensitization rarely occurred in isolation and was typically part of a broader nsLTP polysensitization pattern that involved both food and pollen allergens. Conclusion: Can s 3 sensitization seems integrated within the broader nsLTP sensitization landscape and is strongly associated with polysensitization to multiple nsLTP allergens. These findings support a shared nsLTP-mediated cross-reactivity network and highlight the relevance of including Can s 3 in molecular diagnostic panels for suspected nsLTP-mediated allergy.