Childhood microbial experience, immunoregulation, inflammation and adult susceptibility to psychosocial stressors and depression in rich and poor countries

As communities undergo the transition from traditional rural life to modern urban lifestyles, the prevalence of chronic inflammatory disorders such as allergies, autoimmunity and inflammatory bowel diseases increases dramatically. It now appears that this is at least in part attributable to diminished efficiency of immunoregulation resulting from inadequate exposure to macroand microorganisms (“Old Friends”). These Old Friends had to be tolerated, and they evolved methods of manipulating host immune systems, e.g. priming immunoregulatory pathways, sometimes by secreting molecules that directly expand Treg populations [reviewed and referenced in 1]. Thus they were entrusted by co-evolutionary processes with setting up immunoregulatory circuits. Recently these ideas have been expanded to include a subset of depressed patients who demonstrate persistently high levels of inflammatory mediators “at rest” and an exaggerated cytokine response to psychosocial stressors [2]. Such observations prompted the suggestion that some depression in rich urbanized societies is a chronic inflammatory disorder attributable to an immunoregulatory deficit. Several lines of evidence converge to support this possibility. First, prolonged administration of inflammatory mediators such as interferon (IFN)-alpha causes a depression-like state that is treatable with selective serotonin reuptake inhibitor (SSRI) antidepressants. Second, the cytokine antagonist infliximab demonstrates antidepressant properties, but only in depressed individuals with evidence of increased peripheral inflammation prior to treatment [3].