Local Metabolic-Hypoxic Conditioning as a Spatial Modulator of Immune-Mediated Tissue Injury: A Systems Framework with Application to Multiple Sclerosis

Immune-mediated tissue injury is typically conceptualized as a consequence of aberrant immune activation; however, spatial patterns of lesion formation and selective tissue vulnerability across diseases suggest that immune activity alone may not determine where damage becomes established. We propose a generalizable systems framework in which regional metabolic preconditioning, defined by local perfusion dynamics, oxygen availability, and bioenergetic resilience, modulates the threshold for immune-mediated injury. In this model, tissue susceptibility emerges from the interaction between (1) immune activation intensity and (2) region-specific metabolic state. Reduced perfusion and relative hypoxia stabilize hypoxia-inducible signaling pathways, alter endothelial integrity, reprogram cellular metabolism, and amplify inflammatory responsiveness. These processes do not initiate autoimmunity but reshape the energetic and vascular landscape in which immune mechanisms operate, thereby governing spatial lesion topology and progression. We formalize this interaction as a threshold-modulation framework in which tissue injury probability is a function of both immune effector load and metabolic resilience. Applied to multiple sclerosis as a model system, this perspective integrates cerebral hypoperfusion, mitochondrial dysfunction, blood-brain barrier instability, and compartmentalized inflammation into a unified explanatory structure. The framework generates falsifiable predictions regarding perfusion-lesion coupling, metabolic biomarkers of susceptibility, and cross-disease parallels in immune-driven pathology. By positioning metabolic state as a dynamic modifier of immune injury thresholds, this model shifts emphasis from single-axis causation toward systems-level interaction, offering a conceptual template for understanding spatial selectivity and progression in immune-mediated diseases.