What starts the process of multiple sclerosis still is unclear. What is becoming clear, though, is that once the process does start, the immune system is grimly determined to finish it, attacking not just the myelin sheath that insulates axons and makes neural communication possible, but also the major protective molecule the body produces in response.
"To borrow from The Sopranos, the immune system whacks the protein brought in to suppress what's going on," Lawrence Steinman, professor of neurology and director of the program in immunology at Stanford University, told BioWorld Today.
In this case, the protein brought in to suppress what's going on is alphaB-crystallin, a stress-response protein that is not found in healthy brains but is highly expressed in multiple sclerosis.
AlphaB-crystallin starts being expressed very early in the course of the disease. As soon as it is expressed, though, it also is attacked by the immune system. It is one of the major T-cell targets in multiple sclerosis.
In the July 26, 2007 issue of Nature, senior author Steinman and his colleagues demonstrated that alphaB-crystallin protects neurons in multiple sclerosis through two mechanisms: it reduces both inflammation and apoptosis.
Steinman and his group found that cells from alphaB-crystallin knockouts secreted more inflammatory cytokines. AlphaB-crystallin seems to act as a brake on several inflammatory pathways, including the p38 map kinase and NF-kappaB pathways.
Astrocytes, a type of brain support cell, cultured from knockouts showed higher rates of cell death than those from wild-type animals. Treating knockouts with recombinant alphaB-crystallin lessened both the inflammation and the apoptosis observed in the knockouts.
When the researchers tested spinal fluid samples from multiple sclerosis patients, they found that the highest antibody response was once again against alphaB-crystallin. Steinman said that the connection to what actually is going on in patients is one of the strengths of the paper. "Otherwise, this would just be one of many very interesting things that people are doing in the EAE model," the most widely used mouse model of multiple sclerosis.
Steinman said the findings represent "the first real example" of the immune system attacking protective mechanisms in autoimmune disease, but thinks it won't be the last. His lab is investigating the role of alphaB-crystallin beyond multiple sclerosis, and he said the molecule "is probably going to be notable in a few other autoimmune diseases." Add that to the fact that it shows up in other brain diseases as well, and the therapeutic potential is fairly obvious.
Steinman cautions, though, that the fact that alphaB-crystallin acts on such broad cellular regulators as NF-kappaB also could be a drawback.
"I suspect there won't be a free lunch on this either," he said, pointing out that therapeutic application of alphaB-crystallin likely would have several effects at the cellular level, and the net effect could be "something very bad, or something very wonderful, or something in between."
The proof, he said, will come in the trenches. "I'm determined to get this into a clinical trial, and then we'll see what happens, for better or for worse."
Patents pertaining to the discoveries have been filed, and Stanford University is "just about ready to end the shopping period" and decide who to license the rights to.
Steinman would be happy to do the commercialization honors himself, and it wouldn't be the first time, either. He is the co-founder of enterprises ranging from publicly traded companies like Neurocrine Biosciences to newcomers like Bayhill Therapeutics, which was formed in 2002 and has been funded with a total of $65 million in its Series A and B rounds, and Nuon Therapeutics, which just received Series A funding last month for the development of autoimmune therapies. (See BioWorld Today, July 30, 2007.)