Scientists Find Early Immune Trigger Of MS

Using advanced imaging to observe the early stages of nerve damage in mice with MS, scientists in the US believe they have found an important early trigger for the disease: the leakage of a clotting protein across the blood-brain barrier that activates an immune response and results in a toxic environment that damages nerve cells. Through genetic modification, they also found a way to stop the protein triggering the immune response without impairing its ability to clot blood.

A report of the study, led by the Gladstone Institute of Neurological Disease at the University of California - San Francisco (UCSF), was published online in Nature Communications on 27 November 2012.

Researchers Just Starting to Understand Causes and Processes of MS

There are 2 million people worldwide living with MS, a disease that develops when the body's immune system attacks the brain, spinal cord and optic nerve. The attack damages nerve cells, including the myelin sheath that ensures they can send signals to each other via connecting filaments called axons.

As the damage ensues, the nerve signals get weaker and weaker and eventually don't reach the other end, causing a host of symptoms such as numbness, fatigue, difficulty walking, paralysis and loss of vision.

There are drugs that delay the symptoms, but none that removes the underlying cause, which researchers are only just starting to understand.

A new study recently reported in Nature Biotechnology, describes how scientists used nanoparticles to stop MS in mice.

Real-Time Imaging

In this latest UCSF-led study, the team used a high-resolution, real-time imaging technique called "in vivo two-photon microscopy", to observe individual cells in the living brains and spinal cords of mice engineered to develop a disease that mimics the human form of MS.

Traditional imaging techniques only show "snapshots" of the damage that MS can do.

With their latest methods, senior author Katerina Akassoglou, a professor in neurology at UCSF, and her team could see what happens to nerve cells over different stages of the disease.

Akassoglou, who also directs the Gladstone Center for In Vivo Imaging Research, says in a press statement:

"To successfully treat MS, we must first identify what triggers the disease and what enables its progression."

Leakage of Fibrinogen Causes Neurotoxic Environment for Nerve Cells

Akassoglou and colleagues saw that when there is a disruption in the blood brain barrier, it allows blood proteins to seep into the brain.

One of these proteins is a blood-clotting protein called fibrinogen. When it arrives in the brain it immediately activates a strong immune response from microglia cells, the immune system's first line of defence.

The microglia release large amounts of chemically reactive molecules called "reactive oxygen species". These are what create a toxic environment in the brain that results in damage to nerve cells that is seen in MS.

"Here, we have shown that the leakage of blood in the brain acts as an early trigger that sets off the brain's inflammatory response - creating a neurotoxic environment that damages nerve cells," says Akassoglou.

Lead author Dimitrios Davalos, a Gladstone staff research scientist and associate director of the imaging center, says the in vivo imaging analysis let them observe in real-time which of the molecules crossed the blood-brain barrier, and notes:

"Importantly, this analysis helped us identify the protein fibrinogen as the key culprit in MS, by demonstrating how its entry into the brain through leaky blood vessels impacted the health of individual nerve cells."

Targeting Fibrinogen

The team also found a way to stop the leakage: they genetically modified the fibrinogen in the MS mice. The modified protein didn't trigger the microglia response, and so no toxic environment was created. However, the protein was still able to carry out its blood-clotting role.

The treated mice did not show the same progressive nerve cell damage seen with MS.

Akassoglou says "targeting the fibrinogen-microglia interactions to halt nerve-cell damage could be a new therapeutic strategy".

She and her team are currenlty investigating ways to specifically target the damaging effects of fibrinogen in the brain.

"We also continue to use in vivo imaging techniques to further enhance our understanding of what triggers the initiation and progression of MS," notes Akassoglou.

Funding for the study came from the National Multiple Sclerosis Society, the American Heart Association, the Howard Hughes Medical Institute, the Nancy Davis Foundation for Multiple Sclerosis, the Dana Program in Brain and Immuno-Imaging, H. Lundbeck A/S, the National Institutes of Health, and other sources.

Written by Catharine Paddock PhD
Source:MNT