ARTICLE IN BRIEF
Investigators reported that two lipids — phosphatidylserine and oxidized phosphatidylcholine derivatives — seem to quell myelin inflammation in a mouse model of multiple sclerosis (MS). They say that the lipids may serve as “natural brakes” on inflammatory responses in the CNS, and could be potential therapeutic targets in MS.
Their previous research predicted that administering lipid-specific antibodies in a mouse model of multiple sclerosis (MS) would aggravate symptoms, but in a new study, researchers at Stanford University discovered instead that certain saturated fatty acids appear to quell the inflammation of myelin, perhaps by bolstering the body's own natural defenses against the disease.
The research, published June 6 in the online edition of Science Translational Medicine, suggests that several phospholipids naturally present in the brain and CNS confer protection against the autoimmune attacks that produce the symptoms of MS, and promote recovery after attacks occur.
“Within 24 to 36 hours animals with hind-limb to four-limb paralysis were able to walk around,” said Lawrence Steinman, MD, chair of Stanford University's Program in Immunology, and professor of neurology and neurological sciences, pediatrics and genetics, and one of the lead authors of the paper. “That was very surprising. The conclusion I made was that in the myelin sheath we have lipids that protect us from attack by the immune system.”
Two lipids in particular — phosphatidylserine and oxidized phosphatidylcholine derivatives — may serve as “natural brakes” on inflammatory responses in the CNS, according to the authors. These “guardian lipids,” they added, which are attacked by the immune system, “may have therapeutic potential in MS and other inflammatory diseases.”
In a 2006 paper in Nature Medicine, Dr. Steinman and colleagues reported they had developed microarrays to examine about 50 lipids derived from the myelin sheath of MS patients, and found lipid-specific antibodies against sulfatide, sphingomyelin, and oxidized lipids. Sulfatide-specific antibodies also were found in SJL/J mice with experimental autoimmune encephalomyelitis (EAE), a condition that produces MS-like symptoms. Immunization of the mice with sulfatide-specific antibodies exacerbated EAE symptoms, and produced a more severe course of the disease. This caused the authors to conclude that autoimmune responses to sulfatide and other lipids found in individuals with MS probably contributed to autoimmune attacks and demyelination in patients with MS.
In their more recent work, the researchers used lipid antigen microarrays and lipid mass spectrometry to identify lipid targets of autoimmune attacks in MS, and administered some of those lipids derived from human MS patients into SJL/J mice with EAE. This time, the symptoms displayed by the mice declined dramatically. Phosphatidylserine and oxidized phosphatidylcholine — two fatty acids targeted in MS — possess side chains that appear to confer protection by suppressing inflammation and inducing apoptosis of autoreactive T cells. “I look at these molecules as naturally occurring guardian molecules that sometimes are attacked by the immune system, and then can't do enough guarding,” said Dr. Steinman.
Augmenting the body's own supply of these fatty acids may help to ameliorate symptoms by protecting myelin from the immune system rather than by weakening the immune system, which fingolimod and other treatments achieve.
“When administered in high doses these fatty acids are protective,” said Dr. Steinman. “Since the paper was published we've started to administer them orally to paralyzed mice, and we've seen evidence of improvement. We're taking a material that's relatively rare in the body and merely giving the body more of it. We do this type of augmentation therapy all the time in medicine. I think this opens a potential medicine chest of new lipid-soluble, lipid-based natural drugs we might be able to use in diseases like MS.”
SIMILAR RESEARCH UNDER WAY
Francisco J. Quintana, PhD, assistant professor of neurology at Harvard Medical School, has been pursuing similar research. He and his colleagues are investigating the role of lipids in CNS inflammation, both as biomarkers and as regulators of microglia, macrophages, and CNS autoimmunity.
“We are trying to boost immune mechanisms that usually keep the pathogenic immune response under control,” he said. “Dr. Steinman and coworkers have used DNA vaccines before, and now they are using lipids to achieve this goal.”
Dr. Quintana believes the Stanford researchers may succeed in their efforts to use lipids or modified lipids to trigger immune changes. “Obviously they have to consider side effects or off-target effects of lipids, and how much gets to the CNS,” he said. “I'm sure they're working on that, but they're well-respected, so I'm sure if they want to do it they will get it done.”
Thomas Korn, MD, a Fellow in the department of neurology at Technical University in Munich, Germany, also has been studying CNS autoimmunity — particularly the role of T cell-associated cytokine networks in CNS autoimmunity. In the Feb. 21 issue of Neurology he co-authored an editorial highlighting an article by Dr. Quintana and colleagues that described an array platform used to detect serum and CSF antibodies against a large number of CNS antigens.
After reading the paper in Science Translational Medicine, Dr. Korn said the work suggests a way “to apply phosphocholine derivatives in EAE both in a preventative and a therapeutic setting,” and “opens a new avenue regarding T cell extrinsic cues — namely, lipid compounds — that are present in the local milieu of the CNS, and might modulate T cell responses in situ.”
IS THE DISEASE MODEL RELEVANT?
The use of EAE mice has been a source of concern among some researchers, including Hartmut Wekerle, MD, director of the Max Planck Institute of Neurobiology in Munich and chair of the neuroimmunology department. Some strains are so inbred and genetically homogeneous that they essentially mimic a single individual, and the inbred strains probably have accumulated genetic irregularities that don't occur in wild-type mice, he wrote in a January 2012 paper in Nature Medicine.
But he told Neurology Today that the EAE model used by Dr. Steinman's group is the best one available. “Among the classic EAE models, the SJL/J variant may be the best at representing human relapsing-remitting MS,” he said. “Upon initiation — by immunization or T-cell transfer — the disease proceeds in a relapsing-remitting course, quite reminiscent of the human disease. In contrast, EAE in C57BL mice or Lewis rats — the most popular models — is either monophasic self-limiting, or leads to irreversible spinal cord damage. Both of these courses are not found in human disease.” However, spontaneously developing EAE models such as the SJL/J mouse, “circumvent this particular problem,” he said.
• Ho PP, Kanter JL, Robinson WH, et al. Identification of naturally occurring fatty acids of the myelin sheath that resolve neuroinflammation. Science Transl Med 2012;4(137); E-pub 2012 6 Jun.
• Kanter JL, Narayana S, Robinson WH, et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nature Med 2006;12(1):138–143.
• Korn T, Tumani H. Patterns of intrathecal autoreactive antibodies in MS using antigen microarrays. Neurology
• Wekerle H, Flügel A, Serreze D, et al. Autoimmunity's next top models. Nature Med 2012;18(1):66–70.