Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 21, Pages 5528-5533Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1721115115
Keywords
multiple sclerosis; immunopathogenesis; citrullination; myelin; cuprizone
Categories
Funding
- Brain Canada Platform
- Alberta Innovates-Health Solutions postgraduate fellowship [20130980]
- Canadian Institutes of Health Research (CIHR) [MOP126040, PPP136719]
- Canada Foundation for Innovation
- Ontario Research Fund
- CIHR
- Multiple Sclerosis Society of Canada
- Brain and Mental Health Strategic Research Fund through the Hotchkiss Brain Institute of the University of Calgary
- Alberta Innovates-Health Solutions Collaborative Research and Innovation Opportunities (CRIO) Team program
Ask authors/readers for more resources
Although immune attack against central nervous system (CNS) myelin is a central feature of multiple sclerosis (MS), its root cause is unresolved. In this report, we provide direct evidence that subtle biochemical modifications to brain myelin elicit pathological immune responses with radiological and histological properties similar to MS lesions. A subtle myelinopathy induced by abbreviated cuprizone treatment, coupled with subsequent immune stimulation, resulted in lesions of inflammatory demyelination. The degree of myelin injury dictated the resulting immune response; biochemical damage that was too limited or too extensive failed to trigger overt pathology. An inhibitor of peptidyl arginine deiminases (PADs), enzymes that alter myelin structure and correlate with MS lesion severity, mitigated pathology even when administered only during the myelin-altering phase. Moreover, cultured splenocytes were reactive against donor myelin isolates, a response that was substantially muted when splenocytes were exposed to myelin from donors treated with PAD inhibitors. By showing that a primary biochemical myelinopathy can trigger secondary pathological inflammation, cuprizone autoimmune encephalitis potentially reconciles conflicting theories about MS pathogenesis and provides a strong rationale for investigating myelin as a primary target for early, preventative therapy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available