Sam Pleasure, MD, PhD

You rely on your immune system to stay alive. Think about this: maybe, the person walking ahead of you rubs their itchy eyes and then opens the door, which you touch right after, and then of course you touch your face– this happens constantly, you are always being confronted with germs. You expect to be exposed to these particles and not get sick every time; you rely on your body not to succumb to every infectious particle it encounters… The same system activates when you hit your arm and get a bruise– your immune system will activate to clear away those broken blood vessels and dead blood cells, so your body isn’t covered in permanent bruises. These are all normal functions of the immune system that keep you alive. But what if this system doesn’t know when to stop? What if it doesn’t simply attack these foreign or dead cells, defeating the flu particles and clearing away the dead blood cells from your bruises. What if your immune system attacks the good cells, the things you need to function everyday. The consequences can be devastating. This is what happens with autoimmune autoantibody associated diseases.  

Antibodies are the workhorses of the immune system. Cleveland Clinic defines Antibodies as “proteins that protect you when an unwanted substance enters your body. Produced by your immune system, antibodies bind to these unwanted substances in order to eliminate them from your system.”  

Modern medicine has identified numerous autoimmune disorders, some of which may be familiar. Rheumatoid arthritis occurs when the immune system eats away at the joints in your body. Lupus is a broad autoimmune response that reacts to tissue of all kinds, a condition affecting popular musicians Seal and Selena Gomez (Wikipedia). Autoimmune disorders can also target the nervous system.  Unlike other tissues of the body, the central nervous system (your brain and spinal cord) cannot regenerate. Consequently, autoimmune disorders that attack the brain are particularly devasting.  

The most common autoimmune disease of the nervous system is Multiple Sclerosis (MS). Another auto-immune disorder that recently reached the popular press is termed Anti-NMDA receptor encephalitis, popularized in the book Brain on Fire: My month of Madness, by Susana Cahalan. This autobiographical book chronicles a woman in her early 20s who goes from living the life of a high-functioning journalist in New York City, to completely losing the ability to take care of herself. Her brain had become inflamed. She acquired a rare autoimmune response that led her immune system to attack synaptic connections in her brain. Synapses are sites of nerve-nerve communication. There are hundreds of trillions of synapses in the human brain, essential for every aspect of brain function. Special proteins, termed NMDA receptors, reside at many cortical synapses and mediate nerve-nerve communication. Susana Cahalan’s immune system began to attack her NMDA receptors.  

Sam Pleasure, MD, PhD, Glenn W. Johnson, Jr. Memorial Endowed Chair in Neurology at UCSF, knows all too well how ‘autoimmune autoantibody associated encephalitis’ can manifest with mysterious symptoms in his patients. At UCSF Dr. Pleasure runs both a clinic that sees patients and a laboratory that seeks to identify, characterize and treat patients with autoimmune autoantibody-associated encephalitis.  

There are approximately 20,000 -30,000 people diagnosed with encephalitis, but less than 50% of cases are infectious, the rest probably attributed to autoimmunity.  

Autoimmune autoantibody associated encephalitis can be extremely hard to diagnose. The disease can be “acute” (instantaneous onset), “subacute” (days to weeks to months) or “chronic” (months to years). If onset occurs in the patients 20s-40s, they can have a normal lifespan but health-span can vary dramatically. In autoimmune autoantibody associated encephalitis, there is usually an initiating event. The initiating event can be post infectious (such as after the flu), paraneoplastic (meaning it may have been caused by how the body reacts to the presence of a cancerous tumor), or sometimes it just comes out of the blue. In Brain On Fire Cahalan’s disease had subacute onset, and even years later doctors are still unsure what initiated her disease.   

 The Clinic:  

A particular challenge of autoimmune autoantibody associated encephalitis is diagnosis. Many types of autoimmune autoantibody associated encephalitis present with psychological symptoms  This can lead to mis-diagnosis. This makes sense. Autoimmune encephalitis is not the first thing a physician thinks of when their patients are experiencing some of these symptoms.   It took MANY doctors and months for Chalalan to get a proper diagnosis. She was accused of having an alcohol problem followed by a diagnosis of bipolar disorder. It wasn’t until she started having seizures that she was admitted to a hospital for deeper testing. Treatment is essential in all cases to mitigate long term effects. These include medications to suppress the action of the immune system. If you are intrigued, I encourage you to read Brain on Fire!  

The Lab:  

For the past 10 years, Pleasure’s lab has focused on understanding the biology of disorders associated with inflammation in the central nervous system and the production of harmful, self-directed antibodies.  

“It turns out there are a lot of people who appear to have autoimmune neurological conditions that do not fall into a category of known disease”  

One of the major goals of Pleasure and his lab is to identify and categorize “unknown” autoantibody diseases. To identify and categorize the previously unknown types of autoimmune antibody encephalitis, in collaboration with Dr. Michael Wilson and Dr. Joe DeRisi the lab has developed a large biobank of CSF specimens from patients. A biobank is a collection of biological material used for research. The Pleasure lab has samples of spinal fluid from over 2500 patients; They have found around 20% of these samples have evidence of autoimmune autoantibody associated diseases. From here, they try to identify these previously unknown antibodies, to examine what they do.  

There have been several recent success stories. An antibody was recently discovered that attacks a receptor that is necessary for taking up vitamin B12 into cells. So, patients with those antibodies become vitamin B12 deficient, even though they have B12 in their bodies. B12 is necessary for myelin and neuronal integrity, so B12 deficiency leads to a variety of profound neuropsychiatric deficits. This antibody mediated B12 deficiency is somewhat treatable, because there are other less effective ways your brain can take up B12. By oversupplying the system with B12 at least some of these consequences can be treated.  

Brain on Fire: A new chapter. 

One of the primary autoimmune autoantibodies associated encephalitis conditions that Pleasure’s lab looks at is NMDA receptor encephalitis (the same disease described in Brain on Fire). Dr. Pleasure was  trained as a developmental neuroscientist and he takes a unique approach, asking what happens when autoantibodies occur early in brain development. Are there permanent effects or can the brain recover? Could autoantibodies be responsible for some of the childhood disorders that are commonly diagnosed but currently without an obvious genetic or environmental cause? Fundamental research in the Pleasure lab may provide answers, but it will require years of hard work and ample support from the National Institutes of Health and private foundations that support research.  

Brain on Fire Book

Where is Chalan today

Pleasure comes from a family of Physicians, his mother was a physician, and his father was a physician scientist who still studies neuroscience to this day. While he was never pressured to become a scientist himself, medical curiosity was all around him. His very first “job in science” was creating leather harnesses for chickens when he was 13, to help his father with a neuroscience experiment. Initially he didn’t have a clear path to attend medical school, but the thought was always in the back of his mind because he enjoyed science. Upon graduating from University of Pennsylvania he was accepted into a tandem MD PhD program at UPenn. Eventually, Pleasure became a neurology resident at UCSF, followed by a three-year research fellowship performed jointly with Dan Lowenstien and Mark Tessier-Lavigne at UCSF. He became an assistant professor, establishing his own independent research lab in 2000.  

Read More about Sam Pleasure's Lab Here