The hygiene hypothesis: immunological mechanisms of airway tolerance

Abstract

The hygiene hypothesis was initially proposed as an explanation for the alarming rise in allergy prevalence in the last century. The immunological idea behind this hypothesis was a lack of infections associated with a Western lifestyle and a consequential reduction in type 1 immune responses. It is now understood that the development of tolerance to allergens depends on microbial colonization and immunostimulatory environmental signals during early-life or passed on by the mother. These environmental cues are sensed and integrated by barrier epithelial cells of the lungs and possibly skin, which in turn instruct dendritic cells to regulate or impede adaptive T cell responses. Recent reports also implicate immunoregulatory macrophages as powerful suppressors of allergy by the microbiome. We propose that loss of adequate microbial stimulation due to a Western lifestyle may result in hypersensitive barrier tissues and the observed rise in type 2 allergic disease.

Figure 1

Proposed model of airway tolerance. In the absence of immunoregulatory pathways, epithelial barrier cells readily respond to allergen binding on their pattern recognition receptors, among which TLR4, by the secretion of inflammatory mediators (IL-1α, IL-25, IL-33, GM-CSF, CCL20, and others). These mediators license antigen-bearing IRF4+ CD11b+ conventional dendritic cells (cDC2s) to polarize naïve T cells to T helper 2 (Th2) cells in the lung-draining lymph nodes. Neonatal and germ-free mice are especially prone to develop such Th2 responses. Respiratory syncytial virus (RSV) infection and second hand cigarette smoke, two known asthma risk factors, increase IL-33 secretion and may thereby stimulate this pathway. Exposure to endotoxin, farm dust or microbial colonization blunts the epithelial response by increasing the expression of negative regulators. Epithelial IL-33 release is also inhibited by helminth-derived excreted and secreted products (HES). DCs devoid of epithelial activation signals do not induce T cell activation (Th0). Other protective factors impede T cell activity by influencing the maturation, antigen presentation, or phagocytic capacity of DCs. Some protective factors induce DCs that provoke regulatory T cell (Treg) activity or T helper 1 (Th1) activity. Regulatory macrophages (rM) can also induce Tregs, or block DC-mediated Th2-polarization. Abbreviations: HDM, house dust mite; TLR4, Toll like receptor 4; IL-1R, IL-1 receptor; H. pylori, Helicobacter pylori; L. lactis, Lactococcus lactis; SCFA, short chain fatty acids; AIP-2, anti-inflammatory protein 2.