Immediate and longterm effects of immune stimulation: hypothesis linking the immune response to subsequent physical...

We hypothesize that antigenic stimuli in susceptible persons during key developmental life stages alters neuroendocrine-immune organization and leads to the development of aberrant immune and neuroendocrine responses to subsequent environmental stressors, with longterm physical and psychological consequences. The release of interleukin-1beta (IL-1beta) and other proinflammatory cytokines associated with the immune response during times when individuals are most vulnerable to the effects of environmental influences activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to maladaptive responses to subsequent stressors. The primed HPA axis is reactivated by proinflammatory cytokines, resulting in the secretion of corticotropin-releasing hormone (CRH) and cortisol, followed by physical and psychological effects that feedback on the HPA axis to produce an array of outcomes affecting general wellbeing. Through the release of histamine and other mediators and their effects on the mast cell-leukocyte cytokine cascade, immune stimuli in susceptible persons increase allergic inflammation and magnify stressors' effects through the release of HPA-axis-activating cytokines, such as IL-1beta, that drive the axis and reinforce the physiological and behavioral effects. Thus, specific proinflammatory cytokines and allergic reactions initiate, promote, and maintain immune-stimulus-associated HPA axis activity, and with CRH and cortisol, participate in a positive feedback loop, resulting in aberrant, maladaptive responses to physical or psychological stressors, with outcomes such as depression, hyperalgesia, and pain-related behavior.