Psychoneuroimmunology in the Daily Clinic is Only Possible Within a Contextual Frame

Contextual factors affect both the brain and the immune system via direct and indirect mechanisms and biological sensitivity is a consequence of genetic, epigeneticEpigenetics, physiological, and psychological factors (Lionetti and Aron in Transl Psychiatry 8:24, 2018). Contextual risk factors vary from chronic social stress and defeat, via deficient nutrition and lack of exercise, up to air/soil pollution and the (chronic) use of medicines. The different risk factors activate the immune system through the production or presence of associated molecular patterns (AMPs) induced by or part of those risk factors. AMPs may be risk factor specific (PAMPs, DAMPs, LAMPs) but will also share a global pathophysiological mechanism, endotoxemia (microbe associated molecular pattern, MAMP) (Punder and Pruimboom in Front Immunol, 2015), caused by gut barrier hyperpermeability as a consequence of an energy demanding activation of multiple stress axes and their products, including cortisol, adrenalineAdrenaline, aldosterone, and pro-inflammatory cytokines (Punder and Pruimboom in Front Immunol, 2015). The interaction of humans with their environment has been based on the need for adaptation or self-management by humans to a (mostly slow) changing environment. With the start of the Anthropocene, 250 years ago, humans started to create an environment adapted to their needs and comfort (Valladares F, Magro S (2019). Anthropocene, The Challenge for Homo Sapiens to Set its Own Limits. 45:33–59. https://doi.org/10.18172/cig.3681 ). Culture changed as a result of nature and evolution, but humans have probably come to the limit of culture elicited changes in our context. Novel cultural factors activate biological robust stress-systems in the same way as ancient stress factors do. Those robust systems include the immune system, the brain and its connectomeConnectome and this robustness developed in a completely different context, opposite to the modern context that is characterized by sedentary lifestyleLifestyle, overeating, chemical toxins, nanoparticles and other (false) danger signals. Today the modern context affects many, but luckily not all, individuals. Susceptibility depends on the individuals genetic and epigeneticEpigenetics make-up (the text) and both text and context interact constantly. A new context, modern culture, demands adaptation, and/or self-management that leads to solutions and elimination of possible risk factors. Stress is no stress when adaptive strategies or decision making eliminates their impact at time. Stress becomes distress, and therefore chronic irritation, when the challenging factor is long lasting and immunogenic. In this way it is the text choosing the disease (genetic and epigeneticEpigenetics susceptibility) and the context producing the conflict.