Getting Down to Detail: Exploring the Sometimes Pathogenic Versatility of Discrete Immune Logic

Objective: Feedback mechanisms in the immune and endocrine systems play a significant role in maintaining stable homeostatic states. Specifically, the hypo-thalamic-pituitary-adrenal (HPA), and hypo-thalamic-pituitary-gonadal (HPG) axes contribute important regulation of immune activity. We propose that these components form an over-arching regulatory system capable of supporting multiple stable regimes. Here we explore the role of these interactions in perpetuating chronic endocrine-immune dysfunction in chronic fatigue syndrome (CFS) and Gulf War Illness (GWI). Methods: We represent documented interactions within and between components of the HPA-HPG-immune system as a set of logic circuits. Logical analysis of these regulatory circuits reveals the allowed stable homeostatic states of the overall system. Using standard t-tests clinical endocrine/immune profiles of male GWI and CFS subjects, obtained from an ongoing study, are compared against controls. A metaanalysis technique is then used to combine the resulting significance measures into the probability of alignment with model predicted states. Results: In the absence of external perturbations the HPAHPG-immune model supports three stable homeostatic states. Endocrine-immune profiles observed experimentally in GWI and CFS males were both distinct from the normal resting state. Male GWI aligned closely with a state corresponding to persistent hypercortisolism, decreased testosterone, and inflammation. While male CFS was also closest to this state, it was relatively distant from all three predicted states. Conclusion: Our results suggest that endocrine-immune regulatory circuitry is largely intact in male GWI and that the persistent immune dysfunction in this illness may at least in part be facilitated by the body’s own homeostatic drive. For male CFS, results suggest a continued influence of an exogenous agent or lasting changes to the regulatory circuitry