Inside-Out or Outside-In? Rethinking the Origins of Multiple Sclerosis
Introduction Multiple Sclerosis (MS) is a complex, immune-mediated neurodegenerative disease affecting the central nervous system (CNS), primarily targeting the myelin sheath. Despite extensive research, the precise mechanisms driving MS remain elusive. The article discusses two primary paradigms—the "outside-in" and "inside-out" models—that propose different origins and pathways leading to MS. This editorial explores these paradigms and the associated experimental evidence, arguing that an integrated approach may best explain MS pathology.
The Outside-In Paradigm
The outside-in hypothesis posits that MS originates from an external autoimmune response. This theory suggests that peripheral immune cells infiltrate the CNS, targeting myelin as a foreign entity, leading to the observed demyelination. Key studies, including Titus et al., provide insights into this paradigm, demonstrating how immune responses can target myelin and proposing animal models that replicate this peripheral attack on CNS structures.
The Inside-Out Paradigm
Conversely, the inside-out paradigm suggests that MS begins with intrinsic CNS damage, such as neurodegeneration or myelin breakdown, which subsequently triggers an immune response. Sen et al. examined the cuprizone (CPZ) mouse model, which supports this view by showing that early neurodegenerative changes occur prior to immune involvement, highlighting the potential for primary neurodegeneration to drive disease onset and progression.
Genetic Factors in MS
Genetics play a crucial role in MS susceptibility, progression, and treatment response. Ferrè et al. reviewed current genetic research, which predominantly points to immune-related genes. However, emerging evidence suggests that genes involved in oligodendrocyte maturation might also contribute to MS, supporting a dual role of immune and intrinsic CNS factors in disease etiology.
Cellular and Molecular Mechanisms
The article addresses cellular processes that support both paradigms, such as autophagy and complement activation, which could either result from immune attack or respond to CNS degeneration. Autophagy dysfunction and complement activation are implicated in myelin breakdown, mitochondrial instability, and oxidative stress, all of which are key features in MS pathology. Studies by Bergaglio and Poertoawmodjo indicate that mitochondrial dysfunction might serve as a primary trigger of CNS damage, aligning with the inside-out model but also providing a basis for autoimmune responses.
An Integrated Perspective
The editorial concludes that MS likely involves both outside-in and inside-out mechanisms, depending on the genetic and environmental context. This integrative view encourages the development of multi-faceted models and biomarkers that can capture the heterogeneity of MS. As new experimental models and genetic insights emerge, understanding how these pathways converge could reveal novel therapeutic targets and improve patient outcomes.
Conclusion
This collection of studies emphasizes the need for a balanced approach in understanding MS etiology. Future research must continue to explore both paradigms, integrating genetic, cellular, and clinical data to fully understand this multifactorial disease.
References:
Luchicchi, A., Preziosa, P., & 't Hart, B. (2021). “Inside-Out” vs “Outside-In” paradigms in multiple sclerosis etiopathogenesis. Frontiers in cellular neuroscience, 15, 666529.
