The adaptive immune system tailors its effector responses to pathogen type: type 1 responses fight viruses and bacteria, and type 2 responses protect against parasites, toxins, and environmental irritants. Allergic diseases, such as food allergy, asthma, and atopic dermatitis, are characterized by exaggerated type 2 responses to otherwise harmless stimuli. Although genetic predisposition contributes to allergy risk, strong epidemiological evidence indicates that environmental changes increase the incidence of allergic disease, as reflected in regional variation and rapid increases over the past century. Allergic immune states are often initiated early in life and remain long-lasting; therefore, this study investigated environmental factors that might prevent allergic sensitization using a mouse model.
Pet shop mice (8-12 weeks) were used in this study. Pathogen screening, cytokine assays, microbiome 16S rRNA sequencing, and co-housing/fostering models were performed. Allergic sensitization was induced through intestinal, skin, perinatal, or lung routes, followed by anaphylaxis and monitoring of the temperature. Additional models included oral tolerance, chicken ovalbumen (cOVA) sensitization, passive anaphylaxis, complete Freund’s adjuvant (CFA) immunization, mediator-induced shock, and Listeria infection. Immune responses were assessed using enzyme-linked immunoSpot (ELISpot), bacterial peptide display, next-generation sequencing (NGS), flow cytometry, and enzyme-linked immunosorbent assay (ELISA). All statistical analyses were performed using GraphPad Prism.
Mice raised under specific pathogen-free (SPF) conditions resemble immunologically mature adult humans and are resistant to allergic sensitization. In contrast, outbred non-SPF “pet shop” mice harbor diverse pathogens and microbiota and exhibit broad serological memory. Following sensitization with cOVA through skin/lung/intestinal routes from days 0 to day 7, and systemic challenge (day 14), pet shop mice showed only mild hypothermia, whereas SPF mice showed severe anaphylaxis. Despite comparable or higher anti-cOVA IgE after skin sensitization, pet shop mice exhibited markedly elevated allergen-reactive IgG and higher IgG: IgE ratios. Passive and mediator-induced responses were similar between groups, indicating intact effector pathways. Transfer of IgG-rich serum reduced anaphylaxis in SPF mice. Pet shop mice also possessed baseline cOVA-reactive IgG and IFNγ-producing CD4+T cell memory, supporting IgG-dominant, cross-reactive immunity as a mechanism of protection.
Adult humans and pet-shop mice mount mixed type 1/type 2 responses to alum, unlike infants or SPF mice, which exhibit a pronounced type 2 bias. To define the relevant environmental window, pet-shop neonates were fostered with SPF dams at birth (P0). Fostered mice lacked baseline cOVA-reactive IgG, showed reduced serum immunoglobulins, and were highly susceptible to allergy as adults (SPF dam: n = 18, pet shop dam: n = 19), with reduced post-sensitization IgG2.
Conversely, co-housing or fostering SPF mice with pet shop mice conferred protection and baseline cOVA-reactive IgG and CD4+Â TÂ cell memory. Direct testing showed that perinatal sensitization (P7) of pet shop mice induced severe anaphylaxis with approximately 33% mortality (n = 9), whereas adult sensitization (P56; n = 8) was protective and IgG-dominant. Thus, allergy susceptibility is confined to an early-life window shaped by environment.
Overall, this study shows that prior type 1 inflammatory or tolerogenic exposure to an antigen can protect against allergic sensitization to related proteins, through IgG-dominant or tolerance-based mechanisms. These findings provide a mechanistic link between allergies and environmental factors, with broad implications for adaptive immune function in natural environments.
References: Erickson S, Lauring B, Cullen J, et al. Environmentally driven immune imprinting protects against allergy. Nature. 2026. doi:10.1038/s41586-025-10001-5
