Schistosoma mansoni initiates infection through active skin penetration by cercariae, triggering early immune responses that are crucial to disease establishment. In naïve hosts, parasite antigens elicit an initial Th1-type response that is rapidly modulated to a Th2 profile by parasite-derived immunomodulatory molecules, including proteases and eicosanoids. Upon reinfection, prior sensitization enhances Th2 responses, IgE production, and eosinophil recruitment, while promoting regulatory mechanisms that limit pathology and favor chronic infection. Key molecules such as cercarial elastase (SmCE) interfere with antigen presentation and antibody function, facilitating immune evasion. This review explores the early immune responses elicited at the cutaneous interface during primary S. mansoni infection and reinfection, emphasizing the dynamic interplay between host defense mechanisms and parasite-driven immunoregulation. Understanding these early skin-stage events reveals how S. mansoni balances immune activation and suppression, offering valuable targets for vaccine development and immune-based interventions.

(1) Background: Modification of the structural elements of allergens is widely used in the field of allergies. The goal of the present research was to express, purify, and characterize the shortened recombinant group 5 allergen of Dermatophagoides pteronyssinus (rDer p 5). (2) Methods: rDer p 5 storage stability and aggregation capacity were explored through in silico analysis, dynamic light scattering (DLS), and SDS-PAGE. Serum IgE reactivity and cytokine amount were investigated in sera or cell culture supernatants through ELISA, MULTIPLEX^®, and Western blot analysis using sera from sensitized humans from Brazil, Colombia, and Ecuador. (3) Results: Dimeric rDer p 5 was detected through native PAGE, and this result was confirmed by data from DLS. The protein was thermically stable, as it did not degrade at 4 °C for 21 days. The shortened rDer p 5 was classified as a major IgE allergen in Brazil and Colombia, but minor in Ecuador. IL-13, IL-10, IL-1β, and IL-6 were significantly elevated in the sera of rDer p 5-reactive patients. The same cytokines plus IL-5 were more secreted by human cells upon rDer p 5 stimulation. (4) Conclusions: N-terminal peptide deletion led to a higher rDer p 5 folding stability, which, even though dimeric, was an IgE-reactive protein. Therefore, rDer p 5 could be used for molecular diagnostic applications or as backbone for hypoallergen design.