From Molecular Dysregulation to Systemic Disease: Mechanistic Insights into Pathogenesis

Abstract

The classical perspective of disease as a localized organ failure has been greatly replaced with the paradigm that views illness as a family-wide derailment that can be traced to molecular-scale errors. In this article, the pathogenic continuum of molecular lesion to dysfunction of the organ is traced, leading to the argument of various etiologies focusing on three overlapping primary themes of immune dysregulation, protein homeostasis (proteostasis) loss, and cellular stress. These themes are not independent, but they interact in pathogenic cross-talk, developing selfenhancing loops that spread destruction. We consider underlying pathophysiology, such as Treg / Th17 imbalance, propagation of prion like proteins and immunometabolic reprogramming, which enhance the original insults. This dysregulation intensifies into microenvironmental axes (food gut-brain-immune axis and stromal-immune feedback loops) that propagate and institutionalize tissues pathology. We employ this integrative framework to show paradigmatic systemic diseases, such as rheumatoid arthritis, system sclerosis, multiple system atrophy, and inflammatory bowel disease, in which common mechanisms are observed to have different clinical phenotypes. Lastly, we argue that such a mechanistic knowledge requires a shift onto network-based therapeutics and systems-level diagnostics that will address the higher points of dysregulation and not the terminal points of tissue destruction. Such view conceptualizes pathogenesis as a dynamic, multiscale process and offers the roadmap to creating next-generation, mechanism-informed interventions.