Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination

Abstract

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.

Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis

“…Fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in OPCs, thus suppressing remyelination . Fibrinogen was recently detected at the edge of chronic active but not inactive lesions of MS cases and was demonstrated to stimulate a unique transcriptional signature in CD11b+/CD18+ microglia that activate a cascade of pro‐inflammatory events, including the recruitment and central nervous system (CNS) activation of myelin antigen‐specific Th1 cells and reactive oxygen species (ROS), TNF and IL1 β release . Chronification of these pathological events may contribute not only to tissue damage and neurodegeneration, but also to inhibition of potential repair mechanisms.…”

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

“…EAE was induced in marmosets by injecting human white matter homogenate emulsified in complete Freund’s adjuvant (Difco Laboratories, BD, Franklin Lakes, NJ, USA) (Absinta et al, 2016, Lee et al, 2018). For EAE induction, intradermal injections were divided over four areas around the inguinal and axillary lymph nodes.…”

Chronic inflammation in multiple sclerosis — seeing what was always there

“…Evidence of chronic BBB impairment, such as abnormal tight junctions, also can be found in normal-appearing grey matter 32 . Furthermore, fibrinogen can be seen around vessels at the edges of mixed active-inactive lesions, an observation that, in association with histopathological evidence of ongoing demyelination and inflammation, suggests that blood proteins leak into the CNS and help to sustain chronic inflammation 33,34 .…”

“…After careful spatial alignment of the serially acquired images, small brain signal changes over time after injection of contrast agent into the blood can be fitted to a diffusion model that quantitatively reflects the permeability of the BBB to the contrast agent. These measures are sensitive to small impairments of venule barrier function that are believed to lead to the leakage of fibrinogen and other proteins seen in neuropathological studies 33,34 . In this way, multiple } lesions in a single brain can be differentiated on the basis of differences in permeability to gadolinium contrast agent 85 .…”