Immune Recognition of Heat Shock Proteins Provides a Molecular Basis for the “Hygiene Hypothesis” Linking High Prevalence of Immune Disorders to Lack of Cell Stress Eliciting Events

A modern interpretation of the hygiene hypothesis proposes the so-called “old friends” to trigger tolerogenic responses through innate receptors of dendritic cells (DC). Tolerogenic DCs would drive regulatory T-cell polarization through induction of old-friend-specific Treg. In the tissues of the gut that are besieged by our old friends, these cells are held to produce a continuous bystander regulation. However, such local bystander regulation in the gut may be difficult to reconcile with suppression of responses to airway allergens or autoimmune antigens present in distant body tissues. Alternatively, the regulatory Tregs may be triggered through recognition of stress proteins or heat shock proteins (HSP). Microbial HSP are immunodominant and evolutionary conserved with homologs present in mammalian cells. Microbial HSP are now known to induce Tregs that cross-recognize mammalian HSP. In addition, microbial exposures, both friendly and nonfriendly, cause cell stress and, consequently, HSP upregulation in host cells. Also such upregulated HSP can activate HSP-specific Tregs that target the upregulated HSP at sites of inflammatory stress wherever in our body. Under inflammatory conditions, cell stress-associated HSP are abundant and therefore easy targets for cognate T-cell interactions. Herewith, they provide a molecular basis for the hygiene hypothesis.