Physiologic and Pathogenic Interactions Between Innate Immune Cells and Central Nervous System Axons

Gregory F. Wu, M.D., and Laura Piccio, M.D.

Funded in September, 2011: $300000 for 3 years
LAY SUMMARY .

LAY SUMMARY

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Using cellular imaging to see how immune cells damage nerves in the animal model of multiple sclerosis

This study will use two-photon cellular imaging in an animal model of human multiple sclerosis (MS) to determine how neural-immune interactions may damage the nerve cells’ communication cables (axons) to produce disabling cognitive and motor disabilities. 

MS afflicts about 400,000 people in this country. It is an “autoimmune” disease in which the body’s immune cells mistake as foreign and attack some tissues in the brain and especially in the spinal cord (central nervous system, CNS). MS specifically targets a nerve cell’s axon and the myelin sheath that covers it. Axons carry nerve cell messages from one cell to another. Just how immune cells inflict damage to axons, however, is not yet known. The investigators hypothesize that “innate” immune cells, the body’s first line of defense, ordinarily help maintain the equilibrium of axons. But in autoimmune inflammation, they turn deadly and fatally injure axons. Since it is not currently feasible to image nerve-immune cell interactions in MS patients, investigators will test their hypothesis in the MS animal model, called EAE (experimental allergic encephalitis). The results are anticipated to be directly related to human MS.

They will use two-photon cellular imaging to compare the actions of innate immune cells in three animal models: healthy mice, those with EAE, and those with spinal cord injury. They will use new imaging tools where different cell types of interest carry different colors of fluorochromes.  They anticipate that innate immune microglial cells and macrophages in normal mice will do what they usually do: virtually eat (think “Packman”) any injured or dead axons to remove them from the environment. In spinal cord-injured mice, the investigators anticipate that the immune cells will similarly eat dead cell debris and also help slow down inflammation. But in the autoimmune EAE animal model, they anticipate that innate immune dendritic cells, marked with a different color than the microglia, will mistake axonal cells as foreign, and that they and the microphages and microglia will initiate inflammatory axonal damage. They suspect that during autoimmune inflammation, the axons’ signals that ordinarily say, in effect, “don’t eat me,” weaken, leading the innate dendritic cells to go after them. They will accelerate this situation by fully blocking the axons’ “don’t eat me signal,” and seeing whether this results in a rapidly worsening clinical condition in the EAE mice. If so, this would demonstrate that the immune cells are injuring axons because the axons are failing to send strong signals warding them off.  

Significance:   If the MS animal model findings demonstrate that innate immune cells directly injure axons due to axonal signaling problems, the results could lead to new types of MS therapies.