Fig. 2.

Potential sources of the three categories of “Old Friends” and how they interact with the immune system to induce anti-inflammatory and immunoregulatory effects. The three categories of “Old Friends” are: (1) harmless environmental microorganisms found in mud, untreated water, and fermenting vegetable material that have been depleted during the transition from a rural to an urban lifestyle; (2) organisms that form part of the co-evolved human microbiota (including commensal microorganisms); and (3) “Old Infections,” i.e., infections present in early man that usually do not sterilize or kill the host and that have also been depleted since urbanization. (A) The soil in this diagram depicts a diverse set of microorganisms that live within it, an environment that is rare to find in an urban environment compared to a rural one, thus depicting the first category of “Old Friends.” Here, a person harvesting lettuce they have grown is agitating the soil enough to form soil particulates that they eventually breathe in, exposing themselves to “Old Friends.” (B) One broad subset of soil microbes, Actinobacteria, are commonly found in the upper airway, depicted by mycobacteria from the genus Mycobacterium being inhaled into the nasal cavity (Macovei et al. 2015; Kim et al. 2022). Dendritic cells “sample” the contents of the nasal lumen by extending pseudopods that allow the cell to phagocytize a bacterium. The dendritic cell will then digest it and CD103⁺, CCR7⁺ dendritic cells migrate to a nearby lymph node via a lymphatic vessel to present processed antigens of the bacterium to lymphocytes. (C) Dendritic cell sampling is a common theme of the innate immune system – in the lumen of the small intestine, home to part of the gut microbiome, dendritic cells undergo a similar process of phagocytizing microorganisms in the lumen, digesting them, and ultimately presenting the processed antigens to lymphocytes. Unlike in the upper airway, dendritic cells in the small intestine mostly sample microorganisms that form part of the co-evolved human microbiota – the second category of “Old Friends.” The commensal microbes in the small intestine are especially influenced by whether a person was raised in an urban/rural environment as well as diet. (D) Animals that humans are in close contact with, such as dogs, can also influence the composition of the human microbiota. Commensal microbes from a dog’s skin microbiome can be transferred to a person’s skin, where they can colonize to form part of the person’s skin microbiome (Song et al. 2013); further, dogs can expose their owners to “Old Friends” by bringing microbes found in mud and untreated water into the house. (E) The last category of “Old Friends” is depicted by Helicobacter pylori infecting the epithelial cells of the stomach. Unlike a regular infection that produces a robust inflammatory response, if H. pylori is tolerated by the dendritic cells and lymphocytes of the immune system, then an anti-inflammatory and immunoregulatory response (i.e., characterized by a balanced expression of regulatory and effector T cells) arises instead (Arnold et al. 2012; Lundgren et al. 2005). Abbreviations: DC, dendritic cell; IL, interleukin; TGF-β, transforming growth factor beta; Treg, regulatory T cell. Not to scale. Figure created with biorender.com