Biochemically altered myelin triggers autoimmune demyelination

Area of Science:

• Neuroimmunology
• Demyelinating Diseases
• Autoimmunity

Background:

• Multiple sclerosis (MS) involves immune attacks on central nervous system (CNS) myelin, but its cause remains unknown.
• Peptidyl arginine deiminases (PADs) alter myelin structure and correlate with MS lesion severity.

Purpose of the Study:

• To investigate if subtle biochemical myelin alterations can trigger pathological immune responses.
• To explore the role of PADs in mediating these responses and their potential as therapeutic targets.

Main Methods:

• Induced subtle myelinopathy in mice using abbreviated cuprizone treatment followed by immune stimulation.
• Administered PAD inhibitors during the myelin-altering phase to assess their impact on pathology.
• Assessed splenocyte reactivity against myelin isolates from treated and untreated donors.

Main Results:

• Subtle myelin injury, but not minimal or excessive damage, elicited inflammatory demyelination resembling MS lesions.
• PAD inhibition significantly mitigated the induced pathology.
• Splenocytes showed reduced reactivity to myelin from PAD inhibitor-treated donors.

Conclusions:

• A primary biochemical myelinopathy can initiate secondary pathological inflammation, offering a potential explanation for MS pathogenesis.
• Targeting myelin, particularly PAD activity, presents a promising strategy for early, preventative MS therapies.