Fig. 10: Integrated hypothesis.

a Physiological neurovascular unit and central nervous system (CNS) tissue organization. Under normal conditions, discrete CNS regions receive preferential nutrient flow from adjacent capillary beds. Nutrient exchange occurs mainly at capillaries, whereas immune cell transmigration into CNS tissue typically occurs at post-capillary venules, where slower blood flow facilitates interactions between endothelial adhesion molecules and migrating leukocytes. While the immune cells and mechanisms triggering blood–brain barrier (BBB) opening in multiple sclerosis (MS) remain unclear, evidence suggests Epstein–Barr virus (EBV)-latently infected B cells may occasionally infect CNS endothelial cells during transmigration. The white background represents physiological extracellular matrix (ECM) and neuropil (dense networks of unmyelinated axons, dendrites, synapses, and glial processes). b Formation of contrast-enhancing lesions (CELs) and associated CNS injury. If EBV contributes to BBB disruption in MS, it may occur via lytic reactivation in endothelial cells, similar to EBV behavior in nasopharyngeal epithelium. BBB opening initiates ECM degradation, complement and coagulation cascade activation, immune infiltration, and activation of resident CNS cells (astrocytes, microglia, endothelial cells, pericytes, fibroblasts). Inflammatory mediator diffusion (cytokines, granzymes, reactive oxygen/nitrogen species, serum extravasation) visualized on magnetic resonance imaging (MRI) as CEL following intravenous contrast causes demyelination and axonal damage. Although antiviral CD8+ T cells clear EBV, residual CNS injury remains as non-enhancing T2 lesions, contributing to cumulative T2 lesion load (T2LL). c Effective repair response and functional recovery. Recovery depends not only on the initial injury but also on repair quality. Successful repair involves axonal preservation, remyelination, synaptogenesis, and restoration of CNS architecture. Data suggest CNS stromal cells interact with myeloid cells, neurons, and glia to remodel ECM, with stromal cell phenotype determining repair outcome. Restoration of endothelial integrity and neurovascular stoichiometry appears essential for pro-regenerative responses. d Failed repair leading to fibrosis, EBV persistence, and neurodegeneration. Maladaptive repair drives stromal cells toward myofibroblast or follicular dendritic cell-like phenotypes, producing non-physiological fibrosis and tertiary lymphoid follicles (TLFs) that harbor EBV-infected B cells. Cycles of reactivation sustain local inflammation. Fibrotic ECM impairs nutrient diffusion (hypoxia), fosters a hostile microenvironment, and drives glial activation, axonal degeneration, and progressive disability accumulation. Created in BioRender. Kosa, P. (2025) https://BioRender.com/9jnhnts.