Potential For Cell-mediated Immune Responses In Mouse Models Of Pelizaeus-Merzbacher Disease.
Brain Sci
; 3(4): 1417-44, 2013 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-24575297
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Brain Sci
Year:
2013
Document type:
Article
Affiliation country:
United States
Publication country:
CH
/
SUIZA
/
SUÍÇA
/
SWITZERLAND