Dissecting NMOSD pathogenesis through animal models: a mechanism-oriented systems perspective

Area of Science:

• Neuroimmunology
• Autoimmune Diseases
• Demyelinating Disorders

Background:

• Neuromyelitis optica spectrum disorder (NMOSD) is a CNS demyelinating disease driven by autoimmune inflammation.
• Antibody-mediated injury of astrocytes, targeting aquaporin-4 (AQP4), is a key pathogenic mechanism in NMOSD.
• Developing accurate animal models for NMOSD is challenging due to immune tolerance limitations.

Purpose of the Study:

• To review and analyze experimental systems modeling NMOSD pathogenesis.
• To evaluate how well current models recapitulate key pathological features of NMOSD.
• To identify limitations of existing models and propose priorities for next-generation models.

Main Methods:

• Survey of experimental systems across four mechanistic themes: immune tolerance breakdown, T-B cell collaboration, antibody-mediated injury, and pro-inflammatory milieus.
• Evaluation of model design rationale, pathological feature representation, and interpretational limitations.
• Discussion of how animal study findings inform therapeutic target discovery.

Main Results:

• Existing NMOSD models capture complementary, partially overlapping aspects of pathogenesis.
• These platforms provide a mechanism-oriented framework for understanding disease drivers.
• Significant discrepancies remain between experimental systems and the heterogeneous, dynamic course of human NMOSD.

Conclusions:

• Animal models are crucial for NMOSD research but do not fully replicate human disease complexity.
• Understanding model limitations is key to advancing therapeutic development for NMOSD.
• Future research should focus on developing next-generation models with enhanced translational relevance for NMOSD.