探索狼疮对脑的损伤

EXPLORING THE EFFECTS OF LUPUS ON THE BRAIN

Michael Carroll, PhD, from Boston Children's Hospital, is a leading scientific investigator who has been interested in lupus since he was a post-doctorate fellow at Oxford. In the intervening years, he has honed his focus in on lupus and the brain.



"Along the way, I became aware that lupus was not only affecting the immune system — but that there was a Central Nervous System (CNS) component," said Dr. Carroll. Because his expertise is in immunology, not neurobiology, Dr. Carroll recruited Dr. Allison Bialas to his lab as a postdoctoral fellow. Dr. Bialas, who received her PhD in Neurobiology at Harvard, wanted to learn more about the peripheral immune system.

Lupus patients can experience a variety of neuropsychiatric symptoms, including anxiety, depression, mood disorders, and cognitive decline. In rare cases, patients may experience psychosis and seizures. Drs. Carroll and Bialas want to discover why.

Referring back to his earlier work, Dr. Carroll's investigation with Dr. Bialas builds on his research involving the complement system — an essential part of the body’s immune response. This important inquiry — entitled Investigating the Mechanisms of Lupus-associated CNS Dysfunction — is being funded by the ALR.

The complement system is composed of more than 20 proteins that work together to destroy foreign invaders (such as bacteria and viruses), trigger inflammation, and remove debris from cells and tissues.

"The complement system is intricately involved in the normal development of the brain," said Dr. Carroll. "Defects may underlie a number of neurological conditions and there may be an association with lupus."

What is this association? Drs. Carroll and Bialas noted that 60% of lupus patients will experience neuropsychiatric symptoms within the first year of diagnosis. "This number may reflect changes in brain chemistry — in particular, in those patients who have shown elevations of cytokines in their cerebral spinal fluids," said Dr. Bialas.



Cytokines are proteins that increase inflammation in the body. Drs. Carroll and Bialas believe that cytokinedependent changes influence normal brain function.

"It is possible that the behavior of these cytokines is, in turn, influenced by lupus-specific components of the immune system," said Dr. Carroll. "These components or autoantibodies mistakenly work against patients' own tissues or cells."

With ALR funding, Drs. Carroll and Bialas will investigate the hypothesis that cytokines induced by lupus-specific autoantibodies trigger nerve dysfunction. They will also explore the impact of an early event in lupus development — the breakdown of B cell tolerance on the nervous system.

"Knowing the underlying mechanisms can lead to a cure for lupus," said Dr. Carroll. "From murine models, we already know that we can block or slow down the activity of cytokines."

Dr. Carroll is quick to point out that his investigation may not have gotten off the ground without ALR funding. "The ALR makes it possible for a novel idea like ours to get some exposure. If we are on the right track, the ALR will have set us up for a larger NIH-funded grant to push the research further," he concluded.