Concurrent cross-reactivity of microbiota-derived epitopes to both self and pathogens may underlie the "Hygiene...

The current iteration of the "Hygiene hypothesis" proposes precipitous decline in exposure to conserved microbial products and metabolites in individuals in developed countries undermines innate self-nonself "training" of immune system leading to allergy and autoimmunity. However, lack of innate "training" alone fails to account for the antigen-driven nature of these immunopathologies. Here, we advance an alternative, antigen-specific interpretive framework, SPIRAL (Specific ImmunoRegulatory Algorithm) that predicts "loss" of commensal microbiota-derived epitopes cross-reactive to both self and pathogens, rather than conserved microbial moieties or metabolites, underlies the "Hygiene hypothesis." By mechanistically delineating how loss of selective microbiota in predisposed individuals could lead to corresponding "holes" in the epitope-specific Foxp3⁺ regulatory T cell repertoire and subsequent selective immunopathologies, SPIRAL represents a novel interpretation of cross-reactivity that could enable targeted discovery of microbiota species and their associated Treg epitopes "missing" in the diseases "Hygiene hypothesis" implicates, and provides a roadmap for a novel unified interpretation of self-nonself discrimination and T helper phenotype selection.