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Brain Sci. 2013, 3(4), 1417-1444; doi:10.3390/brainsci3041417

Potential for Cell-Mediated Immune Responses in Mouse Models of Pelizaeus-Merzbacher Disease

Received: 24 July 2013 / Revised: 13 August 2013 / Accepted: 18 September 2013 / Published: 30 September 2013
(This article belongs to the Special Issue Myelin Repair)
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Although activation of the innate and adaptive arms of the immune system are undoubtedly involved in the pathophysiology of neurodegenerative diseases, it is unclear whether immune system activation is a primary or secondary event. Increasingly, published studies link primary metabolic stress to secondary inflammatory responses inside and outside of the nervous system. In this study, we show that the metabolic stress pathway known as the unfolded protein response (UPR) leads to secondary activation of the immune system. First, we observe innate immune system activation in autopsy specimens from Pelizaeus-Merzbacher disease (PMD) patients and mouse models stemming from PLP1 gene mutations. Second, missense mutations in mildly- and severely-affected Plp1-mutant mice exhibit immune-associated expression profiles with greater disease severity causing an increasingly proinflammatory environment. Third, and unexpectedly, we find little evidence for dysregulated expression of major antioxidant pathways, suggesting that the unfolded protein and oxidative stress responses are separable. Together, these data show that UPR activation can precede innate and/or adaptive immune system activation and that neuroinflammation can be titrated by metabolic stress in oligodendrocytes. Whether or not such activation leads to autoimmune disease in humans is unclear, but the case report of steroid-mitigated symptoms in a PMD patient initially diagnosed with multiple sclerosis lends support.
Keywords: cytokines; chemokines; myeloid; lymphoid; microarrays; rumpshaker; myelin synthesis-deficient cytokines; chemokines; myeloid; lymphoid; microarrays; rumpshaker; myelin synthesis-deficient
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Southwood, C.M.; Fykkolodziej, B.; Dachet, F.; Gow, A. Potential for Cell-Mediated Immune Responses in Mouse Models of Pelizaeus-Merzbacher Disease. Brain Sci. 2013, 3, 1417-1444.

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