In June 2010, Mauricio Vargas and colleagues from Stanford University School of Medicine reported research in Proceedings of the National Academy of Sciences showing that endogenous antibodies play an important role in repairing peripheral nervous system (PNS) damage. Antibodies are a principal part of the adaptive immune response to infection, but this research suggested that antibodies are also able to clear degenerating myelin which inhibits axon regeneration, akin to a homeostasis function. This repair was only present after PNS injury, whereas myelin debris remained in the central nervous system (CNS) white matter for years. The well known blood-brain barrier concurs with this separation in responses, as it is understood to be impermeable to large proteins such as antibodies.

Various new studies, however, have shown that behavior, mood, and memory can all be influenced by aspects of the immune system, suggesting that antibodies can somehow infiltrate the brain.

Sammy Maloney was a happy and outgoing 12-year-old boy. In 2002, however, his mother started to notice curious deviations in his personality. In six months, he underwent complete mental deterioration and was diagnosed with obsessive compulsive disorder and Tourette’s syndrome. Shortly afterwards, he was found to be harboring a streptococcal infection, although he exhibited no physical symptoms of one. Interestingly, when he started taking the prescribed antibiotics, his behavior markedly improved.

Madeline Cunningham at the University of Oklahoma has spent several years investigating various behavioral disorders associated with streptococcal infections. Cunningham has shown that antibodies against one group of streptococcal bacteria are able to bind to a site in the brain that controls movement, and consequently trigger the release of dopamine. This could explain the emotional disturbances associated with these types of disorders (1).

Studies also suggest that an activated immune system has other perceivable effects on the nervous system. For example, Jonathan Kipnis of the University of Virginia and his colleagues have shown that learning triggers a stress response in the brain, which causes CD4 cells, a type of T lymphocytes, to gather at the meninges and release interleukin-4. IL-4 switches off the stress response and causes a release of brain-derived neurotrophic factor, which facilitates memory formation. Interestingly, cancer patients treated with chemotherapy drugs often experience various cognitive defects and some memory loss.  This is commonly called “chemobrain”, and these studies raise the possibility that it is a consequence of immunosuppression. Finally, an immune response against Mycobacterium vaccae has been shown to improve mood by causing neurons in the prefrontal cortex to release excess seratonin.

So it could be that the blood-brain barrier is kind of leaky after all. Understanding the connections between the immune system and the brain could lead to all sorts of ingenious treatments for various disorders. Perhaps those scientists at Stanford will utilize antibodies to develop a treatment for central nervous system repair. Perhaps we’ll one day be faced with immuno-emotive treatments for depression. Who knows? Anything is possible when a long-standing “truth” turns out not to be absolute – I’m optimistic since scientific advancement is often built on the refinement of prior knowledge.

Happiness is Catching – New Scientist

Endogenous Antibodies Promote Rapid Myelin Clearance and Effective Axon Regeneration after Nerve Injury – Proceedings of the National Academy of Sciences

Previous The Nerve Blog post About PNAS Article

Footnote:

(1) Antibodies raised against the Streptococcal M protein and human myocardial tissue, and Guillain-Barre syndrome in response to Campylobacter infection, are well studied examples of cross-reactivity between anti-pathogen antibodies with host tissues.

August 25, 2009 marked the day that America, and most importantly Massachusetts, lost one of its greatest senators, Ted Kennedy. Kennedy was diagnosed with a type of brain cancer called glioblastoma multiforme (GBM) in May 2008 after suffering from a seizure. GBM is a tumor formed in the glial, or supportive, brain cells; there is no current evidence for a genetic predisposition to this type of cancer. The American Cancer Society believes that 21,000 Americans are diagnosed with brain tumors, and about 10,000 are GBMs. They are the most aggressive and common type of brain tumor, which are resistant to many types of treatments. Only 3% of patients diagnosed with these tumors generally survive five years after diagnosis.

Almost two years after Kennedy’s death, doctors are using the drug Avastin to treat GMBs. Avastin blocks the growth of new blood vessels, a necessary component for the survival of tumors. In one study conducted on Dennis Sugrue, physicians thread a fine tube through his blood vessels and into his head to spray the drug on the location where the tumor had been cut out. They did this experiment because the tumor began growing back even after treatment with surgery, radiation, and chemotherapy. The FDA has approved the use of this drug on GMB, based on the results of 2 phase II clinical trials that showed reduced tumor size in the patients, but it can only be administered after a prior treatment is performed on the tumor.

One of the biggest challenges facing the treatment of GBM is the blood-brain barrier, a separation of the circulating blood and the brain’s extracellular fluid. It occurs along the capillaries and prevents the diffusion of many cells into the brain. Dr. John Boockvar, a brain surgeon at New York-Presbyterian/Weill Cornell, is administering the Avastin to Mr. Sugrue by first injecting mannitol, a drug that opens the blood-brain barrier, and then flooding the tumor with the drug. In the future, other drugs may be combined with Avastin to combat GBM. Although it is unknown whether it improves disease-related symptoms or survival in people under this treatment, it is promising.  Mr. Sugrue’s tumor has decreased in size and his treatment is still an ongoing process.

Although the survival rate for GBM is very low, it is unfortunately the reason why there is a push to try more treatments and expand experimental trials. One can only hope that this treatment leads to more breakthroughs, and more patients like Mr. Sugrue will be able to live longer, healthier lives.