03/06/2012
Paul Muhlrad

Confession number (where were we?) four: 

Immunology was not my strongest subject in college.

Vance and Angela, if you didn’t catch all the science in the morning session … please don’t ask me to help you.  What I can say is that I’m incredibly gratified that the neuromuscular community has wonderful and brilliant scientists like Carrie Miceli, Stan Appel, Richard Barohn, and Steve Greenberg, who understand the immune system intimately.  Their talks this morning demonstrated how critical the immune system is, both to the underpinnings of many of the diseases we care about, as well as to the therapies being developed by our researchers.

Dr. Miceli’s talk was titled “The ABCs of the Immune System.”  From my college … ordeal, I remember that immunology is an alphabet soup of abbreviations (CD MCP, DEC NFkB LPS SOD, FoxP3, ikB Treg, IVIg, SMAD, FOXO …), so restricting a discussion of the subject to just the ABCs is an unenviable task! 

The immune system is our body’s main defense system against infection, but in many neuromuscular diseases, it’s a double-edged sword.  When muscle fibers degenerate, substances that normally remain ensconced within their cells tend to spill out into the bloodstream.  The immune system mistakenly recognizes these molecules as “foreign invaders” and mounts its defensive response, leading to the inflammation and fibrosis that is a hallmark of Duchenne muscular dystrophy and so many other neuromuscular diseases.  That’s why understanding the immune system is so important.  If we understand what triggers and perpetuates this immune response, we should be able to develop drugs that can forestall the process.  Dr. Miceli told us that researchers, including several of her colleagues at UCLA, are making great strides in that direction.

Dr. Stanley Appel, from the Methodist Neurological Institute in Houston (and the Chairman of MDA’s Medical Advisory Committee), continued the discussion of the immune system by telling us its critical role in the development of ALS (amyotrophic lateral sclerosis).  Someone must have told Stan about my immunology deficiency.  He graciously used terminology I can understand:  “good guys” and “bad guys.” 

Dr. Appel explained that a common feature of many, if not all, familial cases of ALS is that motor neurons accumulate “misfolded” proteins.  For ALS, the good guys and bad guys are cells in the nervous system called microglia.  Microglia seem to have a Jekyll and Hyde complex.  Unfolded proteins have the nasty effect of turning good guy microglia (which normally keep motor neurons happy and healthy) into bad guy microglia, which are toxic to motor neurons!  I’ll spare you with the details, but suffice it to say, Dr. Appel wants to figure out how to keep the good guys from going bad and to turn the bad guys back on the path toward righteousness.

Dr. Richard Barohn, from the University of Kansas Medical Center, spoke about myasthenia gravis, which is a true autoimmune disease.  In MG, the body produces destructive antibodies against an important protein on the surface of motor neurons, called acetylcholine receptors. 

There’s actually a lot of good news regarding MG therapy.  Fifty years ago, the prognosis for the myasthenia gravis was grave indeed.  Mortality rates were greater than 30 percent.  Now, due to advances such as mechanical ventilation, steroids and other drug therapies, the disease has a very low mortality rate.  Dr. Barohn told us about several drugs and other therapy choices for MG, but cautioned that there needs to be more well-controlled clinical studies to validate the efficacies of these therapies and develop new therapies.

Dr. Steve Greenberg, from Brigham and Women’s Hospital in Boston, told us about his studies to figure out the molecular underpinnings of inflammatory myopathies, such as dermatomyositis and  inclusion body myositis.  To do that, Dr. Greenberg and his colleagues are using some very high tech methods (gene expression microarrays, mass spectrophotometric profiling, laser-capture microdissection — wow!). 

The gist of all these fancy terms is that Greenberg’s team is using a “guilt by association” approach.  They are identifying exactly which genes and proteins seem to show up when these inflammatory myopathies strike.  To give you a sense of how much “evidence” they have collected in their detective work, they created a “Myositis Gene Expression Map” with more than two MILLION pieces of data.  The point of this heroic sleuthing effort, as in the previous talks, is to identify therapeutic targets.