Benign MS Expresses Itself
Patients who’ve received controversial diagnosis show unique gene-activity profile
Benign multiple sclerosis may sound like a contradiction in terms, but some patients live for decades with only mild symptoms. Whether neurologists can predict which people will develop this slow-motion form of MS remains controversial. Now, a new study reveals that individuals with benign MS show a distinct gene-activity pattern. In these people, a pathway essential for manufacturing proteins slows down and cell suicide climbs. The researchers, who reported their results online in PLoS ONE on October 12 (Achiron et al., 2012), suggest that the findings could inspire new tests for recognizing this much-debated variety of MS as well as new treatments.
The work is a good first step toward understanding why MS severity varies so much, says Richard Rudick, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio: “It’s a crucial topic, and I applaud them for doing it.” However, neuroimmunologist Timothy Vollmer of the University of Colorado, Denver, School of Medicine in Aurora says the authors didn’t do enough to establish that the patients have a temperate form of the disease.
Depending on which recent publication you read, benign MS is either “a distinct clinical entity with therapeutic implications” (Pittock and Rodriguez, 2008) or “an unwarranted conceptual hodgepodge” (Leray et al., 2012). Researchers don’t doubt that some people develop a form of the illness with few symptoms. The controversy is over doctors’ ability to identify those patients early in the course of their disease.
To recognize benign MS, neurologists rely on the Expanded Disability Status Scale (EDSS), which gauges a person’s degree of physical impairment. Although the values can vary, the standard criterion for benign MS is a low EDSS score—usually 3 or below, which means the patient shows some disability but can still walk—10 or more years after the MS diagnosis. The EDSS score can have a big impact on therapy choices. Because of the possible side effects of current drugs, some doctors counsel that individuals with benign MS defer treatment unless their health appears to deteriorate. However, critics knock the current definition of benign MS because it weighs only the amount of physical disability, overlooking other symptoms, including fatigue, depression, and cognitive faults such as memory lapses and inability to concentrate. Patients don’t view such problems as mild, Vollmer says: “If they call it benign MS, it needs to be in patients who would call their disease benign.” Other skeptics complain that the definition is flawed because a large percentage of patients with so-called benign disease eventually get worse—nearly 50% within 10 years, according to one paper (Leray et al., 2012).
In the new study, a team led by Anat Achiron of Sheba Medical Center in Israel tested whether benign MS patients are distinct in another way: their gene expression profile. The researchers nabbed blood cells from 36 subjects with relapsing-remitting MS and from 31 benign MS patients, who’d had the illness for an average of 17 years and whose EDSS scores were 3 or lower. When the investigators used microarrays to compare the two groups, they found differences in 406 genes, more than half of which were less active in the benign MS subjects.
The researchers noticed that many of the genes that eased off belonged to the RNA polymerase I (Pol I) pathway, which crafts most of the RNA components of the ribosome, the cellular organelle that synthesizes proteins. Not only was the gene for Pol I itself dialed down, but so was the gene for one of its key helpers, RRN3. Achiron and colleagues also discovered that the benign MS patients showed increased activity in the p53 pathway, which spurs cell death.
Although upsetting ribosomal RNA production might not sound like a good thing, this change could explain why benign MS patients suffer so few symptoms, the scientists propose. Previous studies have revealed that inhibiting the Pol I pathway spurs cells to commit suicide. Achiron and colleagues determined that B cells and macrophages from the benign MS contingent were more likely to undergo apoptosis than were cells from patients with relapsing-remitting MS. When the researchers used small interfering RNA to slash RRN3 production in white blood cells from the control patients, the amount of apoptosis shot up, supporting the idea that inhibiting the Pol I pathway predisposes these cells to die. The team suggests that benign MS is less severe because many self-reactive immune cells kill themselves.
Rudick says he finds this mechanism plausible. He and Vollmer say they would like to see further evidence that the patients had only minimal disease—MRI scans to check for neurological damage, for instance. The paper’s authors did not respond to MSDF’s requests for comment. For Vollmer, the team’s failure to go beyond EDSS scores to determine degree of disability undermines the paper’s findings. “It’s hard to know if there is a difference between patients in the study,” he says.
Achiron and colleagues suggest that gene-expression measurements could provide a new way to identify patients who will develop the low-impact version of MS. The RNA polymerase I pathway could also be a drug target, according to the authors. Cancer researchers might be able to offer advice, as they’ve been trying to design compounds that block Pol I, which is often hyperactive in tumor cells. Next year, cancer biologist Ross Hannan of the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues will begin clinical trials of one of these inhibitors, known as CX-5461, that destroys cancerous B cells in mice with lymphoma but spares normal B cells (Bywater et al., 2012). Hannan says that the results of the MS paper are worth following up on. However, he cautions, “I think it would be hard to use a Pol I inhibitor for chronic treatment in MS patients.” Eventually, “you will start to kill normal cells,” particularly fast-dividing cells like those in the gut.
Whether attacking the Pol I pathway will prove beneficial for MS patients remains to be seen. But in the meantime, Vollmer and Rudick say that they’d like to see further investigation of why some patients escape the worst effects of MS. “If we understood the biological basis for this extreme heterogeneity [in severity], we’d understand a lot more about how MS works,” Rudick says.
Key open questions
- Does inhibiting the RNA polymerase I (Pol I) pathway trigger selective apoptosis by self-reactive immune cells, or does it have broader effects on the immune system or other cell types?
- Do Pol I inhibitors reduce severity of MS symptoms? If so, how does Pol I connect mechanistically to MS?
- Does Pol I activity correlate with severity of MS symptoms in a larger patient cohort? If so, why do some people have lower Pol I activity than others?
Thumbnail image on landing page. "50S subunit of the ribosome" by Yikrazuul, 2010. Large ribosomal subunit (50S) of Haloarcula marismortui, facing the 30S subunit. The ribosomal proteins are shown in blue, the rRNA in ochre, the active site in red. Released under Creative Commons Attribution Share-Alike 3.0 Unported License (CC BY-SA 3.0)