Biochemically altered myelin triggers autoimmune demyelination

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 an...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 21; pp. 5528 - 5533
Main Authors Caprariello, Andrew V., Rogers, James A., Morgan, Megan L., Hoghooghi, Vahid, Plemel, Jason R., Koebel, Adam, Tsutsui, Shigeki, Dunn, Jeffrey F., Kotra, Lakshmi P., Ousman, Shalina S., Yong, V. Wee, Stys, Peter K.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 22.05.2018
Subjects
Arginine
Biochemistry
Biological Sciences
Brain
Central nervous system
Cuprizone
Demyelination
Encephalitis
Immune response
Immune system
Inflammation
Inflammatory diseases
Lesions
Multiple sclerosis
Myelin
Pathogenesis
Pathology
Splenocytes
myelin
cuprizone
immunopathogenesis
multiple sclerosis
citrullination
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Summary: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.
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Author contributions: S.T. was involved in experiment conception; A.V.C., J.A.R., S.T., S.S.O., V.W.Y., and P.K.S. designed research; A.V.C., J.A.R., M.L.M., and V.H. performed research; J.R.P., A.K., L.P.K., and P.K.S. contributed new reagents/analytic tools; A.V.C., J.A.R., M.L.M., J.F.D., and P.K.S. analyzed data; S.S.O. and V.W.Y. oversaw the design and execution of immunological experiments; A.V.C. and P.K.S. contributed to all stages of the study, including idea conception and data analysis; and A.V.C. and P.K.S. wrote the paper.
Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved April 6, 2018 (received for review December 5, 2017)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1721115115