Molecules in myelin quell inflammation
Lipids compose the bulk of myelin, yet proteins have commanded the bulk of researchers’ attention in the search for factors that underlie autoimmune responses in multiple sclerosis. However, a study published on June 6 in Science Translational Medicine might ratchet up interest in the fatty molecules, as it describes anti-inflammatory lipids associated with myelin that relieve MS symptoms in mice.
Lipids compose 70% of myelin, the casing that protects axons and helps them conduct messages—and that disintegrates as MS develops. Yet “the field of lipids in multiple sclerosis has been neglected,” says Edward Hogan, an emeritus neurologist and lipid biochemist at the Medical University of South Carolina in Charleston. “The reason that’s the case is that they are so damn hard to work with.”
Whereas proteins are relatively easy to manufacture by forcing single-celled organisms such as yeast and bacteria to produce them, lipids must be synthesized—often by laborious chemical techniques—or purchased. Furthermore, lipid studies require expertise and techniques that are not readily available in most labs.
In the past few years, however, improvements in lipid mass spectrometry and new tools such as lipid arrays have made working with lipids easier, and researchers have begun to take a closer look at their role in MS. In a 2006 study, Lawrence Steinman, a neuroimmunologist at Stanford University School of Medicine, and Stanford colleague William Robinson, along with other team members, identified autoantibodies that target lipids in the cerebrospinal fluid (CSF) of people with MS and in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of the disease (Kanter et al., 2006, and “Animal Arsenal”). In this new work, the duo and their colleagues further characterized the lipid targets of autoantibodies in MS and EAE—and they’ve discovered anti-inflammatory lipids in the mix.
“This is a promising study that opens up the field of the roles of lipids in multiple sclerosis,” Hogan says.
In the new study, Steinman and Robinson’s team tested more than 50 lipids that exist in the brain and identified 17 that react with autoantibodies in the CSF of individuals with MS (n = 33), people with other neurological disorders (n = 26), and healthy controls (n = 5)—as indicated by a high degree of binding and thus fluorescence. Then they divided the CSF samples into three groups based on binding potency. Half of the MS group and three controls contributed the most strongly fluorescent cluster; conversely, the majority of the controls and only five of the MS samples fell into the weakest cluster.
The team identified several lipids with particularly strong reactivity in the MS group. Within that subset, they zeroed in on one lipid, PGPC, which is closely related to the oxidized form of a phospholipid called phosphatidylcholine. The brain contains large quantities of phosphatidylcholine, and antibodies to its oxidized version have been detected in brain lesions, making PGPC particularly interesting. The researchers expected that the lipids, if injected into mice with EAE, would cause an immune response and worsen the animals’ paralysis. To their surprise, the exposure had the opposite effect. Lipid injection alleviated the mice’s symptoms; it also dampened T cell activation and reduced levels of proinflammatory cytokines. These observations suggest that PGPC calms inflammation.
To determine whether the autoreactive lipids they had identified show up in diseased tissue, the researchers analyzed lipids in MS lesions using mass spectrometry, a technique for characterizing molecules in biological samples. Lesion tissue contained significantly less PGPC and three additional lipids than did tissue from age-matched control brains. Steinman speculates that antibodies attacked the molecules, decreasing their quantities. Like PGPC, the other three lipids improved paralysis in mice with EAE and suppressed T cell responses. Further studies revealed that four of the molecules also promote apoptosis, or programmed cell death, of activated T cells in culture dishes, and two of them (although not PGPC) elicited the same effect in mice with EAE. Killing off the T cells might be one way these lipids fight inflammation, the authors say. Finally, the team showed that the fatty acid side chains of these molecules deliver the anti-inflammatory punch.
The findings suggest that “components of the myelin sheath are not only there to serve as insulators of electrical activity,” Steinman says. Along with that function, they also have “protective guardian properties” that mitigate inflammatory damage. The new observations add to a growing body of work that posits nonstructural roles for myelin.
“This is really novel,” says Charles Serhan, a biochemist at Harvard Medical School in Boston who studies the anti-inflammatory pharmacological potential of lipids. “I can’t think of any [previously known] circumstances where using an analog of a phospholipid can actually regulate inflammation—or any therapeutic endpoint,” he says.
Until recently, people generally considered lipids to be “bricks and mortar”—structural components of the nervous system—says Jerold Chun, a neuroscientist at Scripps Research Institute in La Jolla, California. ”But now it’s absolutely clear that many lipids are in fact signals: messengers that are being used by various cell types.” He notes that the recent approval of fingolimod (Gilenya), a mimic of the naturally occurring phospholipid sphingosine-1-phosphate—which is well known for regulating the movement of B and T cells into the bloodstream—sets a promising precedent for novel lipid therapeutics, and that others, perhaps identified by techniques such as those described in this study, are sure to follow. Francisco Quintana, an immunologist at Brigham and Women’s Hospital in Boston, notes that the antibodies Steinman’s group identified might serve as biomarkers that would categorize specific populations of MS patients, for example, those who are responding to drugs or undergoing a particular disease course. Quintana and his colleagues as well as other researchers are trying to identify lipids that reflect such clinical features (Quintana et al., 2012).
Steinman says that his group’s study, which was 6 years in the making, started as a biomarker effort, but the anti-inflammatory potential of the molecules piqued the researchers’ interest. Team members hope that these naturally occurring lipids can be developed as therapeutic supplements to molecules that are already in the brain. These particular molecules, he adds, can cross the blood-brain barrier and, according to his group’s still-unpublished work, can be administered orally—two big boons for their potential as a drug. The authors have filed patent applications for the approach and are considering licensing the lipids to pharmaceutical companies or starting their own company to pursue the discovery.
Some researchers caution, however, that this therapeutic promise remains to be determined. “It would certainly be fair to say that while this is interesting, it’s quite preliminary and it would be a long, long way to go before this would be translated into a clinical drug,” Hogan says.
He and others note that the mechanism by which these lipids exert their effect is not clear, that the paper reports results from just one dose, and that the improvement in EAE mice after they receive injections is modest. Glyn Dawson, a neurochemist at the University of Chicago who has examined whether some of the anti-inflammatory lipids described in the study could treat heart disease, notes that what aids mice with EAE is far from certain to help people with MS. “We’ve been here before,” he says, referring to compounds that have alleviated symptoms in mice but then failed in humans. “Now they have to show that this is relevant for MS.”
Steinman, however, counters that the effect in mice was robust, comparing it to the equivalent of an MS patient “going from a wheelchair to a cane.” The group is continuing to explore the mechanism, he says. The researchers are also searching for a receptor through which these lipids might be signaling, providing a second potential therapeutic target that could bring them from obscurity to fame.
Key open questions
- What is the molecular mechanism by which the lipids identified in the study fight inflammation?
- Do these lipids exert their power by acting through a receptor?
- Will the molecules be as effective in humans as they are in mice?
Thumbnail image on landing page. "Photomicrograph of a demyelinating MS-Lesion. Klüver-Barerra-Stain." Marvin 101, 2007. Released under a Creative Commons Attribution-Share Alike 3.0 Unported license.