Old Friends in the Outdoors?: Interrogating a Prevailing Hypothesis of Allergic Disease Development in Rewilded Mice​

Abstract

Allergic conditions characterized by immunoglobulin E (IgE)-mediated hypersensitivity constitute a major public health issue in the United States and other industrialized nations. One explanation often invoked to address this geographic pattern is the old friends hypothesis, which posits that the loss of host-parasite co-evolutionary relationships in “hygienic” environments is responsible for improper immune system development. In particular, it is thought that allergy arises in the absence of sufficient encounters with organisms like helminths that temper the type-II response. Recent studies utilizing wildling and wild mice, however, conclude that microbial exposure may indeed “activate” this response by stimulating robust immune development, leading to more severe reactions upon allergic sensitization. To probe the validity of this hypothesis further, I collected data over the course of a summer on C57BL/6J female mice that were “rewilded” to an outdoor enclosure at Stony Ford Research Station in Princeton, NJ, USA. I aimed to understand how the hypersensitivity phenotypes of these rewilded mice, who were allowed to acquire a range of environmental microbes while outside, compared to those of laboratory controls over time. I collected blood samples and extracted plasma at several timepoints during the study for complete blood count (CBC) and IgE enzyme-linked immunosorbent assays (ELISAs). I also harvested jejunal tissue after euthanization, but no mast cells were identified upon staining with toluidine blue. I ultimately found that the cellular phenotypes of lab and rewilded mice diverged significantly, with lower WBC and eosinophil concentrations in the rewilded compared to the lab cohort except at the experimental endpoint. WBC and eosinophil concentrations also decreased over time in both groups, suggesting migration into tissue combined with aging/stress effects. Finally, rewilded mice had a significantly higher concentration of plasma IgE than the laboratory controls, challenging the old friends hypothesis. These results highlight that embracing complexity with naturalized animal models may be crucial in the study of allergic disease to improve the potential of translation to clinical settings.