Divergent complement system activation in two clinically distinct murine models of multiple sclerosis

Area of Science:

• Neuroimmunology
• Innate Immunity
• Neurological Disorders

Background:

• Multiple sclerosis (MS) is a neurological disease characterized by neuroinflammation and neurodegeneration, primarily affecting young adults.
• While research has focused on the peripheral immune system's role in MS relapses, the mechanisms of neurodegeneration in progressive MS remain unclear.
• The complement system, a key part of innate immunity, is increasingly implicated in neurological disorders, but its specific role in MS pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the involvement of complement system proteins in the central nervous system (CNS) in perpetuating chronic inflammation and neurodegeneration in MS.
• To compare the roles of the complement system in two distinct mouse models of MS: relapsing-remitting (PLP-induced experimental autoimmune encephalomyelitis, rEAE) and progressive (Theiler's murine encephalomyelitis virus-induced demyelinating disease, TMEV-IDD).

Main Methods:

• Gene expression of complement factors was quantified using real-time PCR in the spinal cords of rEAE mice, TMEV-IDD mice, and age-matched sham controls.
• Correlation analysis was performed to link complement factor expression with disease severity and outcome.
• Complement protein deposition (C1q, C3) was visualized in the spinal cords of TMEV-IDD mice.

Main Results:

• Both MS models showed significantly increased expression of complement factors including C1q, C3, CfB, and C3aR.
• In TMEV-IDD (progressive MS model), the classical complement pathway (C1q, C3, C3aR1) was significantly associated with worse disease outcomes, with observed C1q and C3 deposition in affected spinal cord regions.
• Conversely, classical complement activation appeared protective in rEAE (relapsing-remitting model), while the alternative pathway (CFb) correlated with worse outcomes in this model.

Conclusions:

• The complement system exhibits divergent roles in different forms of MS.
• The classical complement pathway is implicated in the pathogenesis of chronic-progressive MS, contributing to neurodegeneration.
• The alternative pathway may play a role in the relapsing-remitting form of MS, potentially exacerbating acute relapses.