TY - JOUR
T1 - Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination
AU - Lee, Nathanael J.
AU - Ha, Seung Kwon
AU - Sati, Pascal
AU - Absinta, Martina
AU - Luciano, Nicholas J.
AU - Lefeuvre, Jennifer A.
AU - Schindler, Matthew K.
AU - Leibovitch, Emily C.
AU - Ryu, Jae Kyu
AU - Petersen, Mark A.
AU - Silva, Afonso C.
AU - Jacobson, Steven
AU - Akassoglou, Katerina
AU - Reich, Daniel S.
N1 - Publisher Copyright:
© Published by Oxford University Press on behalf of the Guarantors of Brain 2018. This work is written by US Government employees and is in the public domain in the US.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen - A marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.
AB - Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen - A marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.
KW - blood-brain barrier
KW - common marmosets (Callithrix jacchus)
KW - experimental autoimmune encephalomyelitis
KW - fibrinogen
KW - multiple sclerosis
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U2 - 10.1093/brain/awy082
DO - 10.1093/brain/awy082
M3 - Article
C2 - 29688408
AN - SCOPUS:85048041784
SN - 0006-8950
VL - 141
SP - 1637
EP - 1649
JO - Brain
JF - Brain
IS - 6
ER -