Hi Leonard--the integin receptor mentioned in the abstract is shown within the context of finding a pharmacological method of blocking fibrinogen from crossing the BBB.
Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis. However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown. Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease.
This lab at UCSF has been working for over a decade on looking for a pharma solution to limit the damage from fibrinogen leakage into the brain.
http://labs.gladstone.ucsf.edu/akassoglou
What Dr. Zamboni suggested in 2006 was that this fibrinogen leakage was also seen in chronic venous disease of the legs, and the way to stop it
was to treat the underlying venous disease. Then, no fibrinogen leakage.
I guess it's the difference between searching for a molecular answer, as opposed to an underlying mechanical answer.
Or treatment vs. aetiology.
In any event, this research is still important, because it's focusing in on the order of destruction in the CNS in MS. And because fibrinogen appears to be the first invader, before the immune system and inflammation are activated---it further defines the link to the vascular theory.
cheer