Molecule Strikes Balance in Immune System and May Be Key to Autoimmune Attack in MS

Researchers funded by the National MS Society and others report that a molecule called the aryl hydrocarbon receptor – which helps the immune system respond to environmental toxins – seems to regulate the balance between inflammatory and anti-inflammatory cells in MS-like disease in mice. The results may eventually help tease out the effects of environmental factors that may trigger the launch of autoimmune attacks against the nervous system in MS. 
Francisco J. Quintana, PhD, Howard Weiner, MD (winner of the 2007 Dystel Prize for MS Research) and colleagues at Havard Medical School, Boston, report their findings in Nature (2008 May 1;453[7191]:65-71). This study was funded by the National MS Society and the National Institutes of Health among others. Marc Veldhoen, PhD (MRC National Institute for Medical Research) and colleagues report similar findings in a separate article, funded by the Medical Research Council UK (2008 May 1;453[7191]:106-9).

Background: Multiple sclerosis occurs when the immune system attacks the brain and spinal cord. The disease is thought to occur when individuals whose genes make them susceptible encounter some unknown triggering factor in their environment. Numerous cells and proteins participate in the immune attack. Immune cells called T helper 17 (Th17) cells incite inflammation, whereas T reg cells are regulatory cells that can suppress the attack. In people with MS, however, T reg cells fail to do their jobs, and the attack goes unchecked. A molecule called aryl hydrocarbon receptor (AHR), best known for regulating the immune response to toxins such as dioxin, exists on the surface of both Th17 cells and T reg cells; previous research indicates that it may play a role in their interaction.

These Studies: Working separately, the two research teams studied AHR in mice with EAE, an MS-like disease. Dr. Veldhoen’s group found that inducing EAE in mice lacking AHR reduced the number of Th17 cells, without increasing the number of T reg cells. Dr. Quintana’s group showed that the results of activating AHR in EAE depended on the toxin used for activation. In mice given dioxin, T regs increased their regulatory activity, decreasing the capabilities of Th17 cells and suppressing EAE. In mice given FICZ (another toxin), Th17 cells increased their activity and EAE worsened.

Conclusions: Taken together, the results may eventually help tease out the effects of environmental factors that may trigger the launch of autoimmune attacks against the nervous system in MS. In an accompanying editorial, Drs. Emily Stevens and Christopher Bradfeld (University of Wisconsin, Madison) explain that the therapeutic ramifications of these findings, although intriguing, are still unclear. The key may lie in discovering why different chemicals affect AHR differently, which may mimic cues that a developing T cell receives from the environment. This understanding is crucial to applying these findings to therapeutic strategies for autoimmune diseases such as MS.

Long-Term Study Yields Clues for Predicting Future Course of MS

A long-term study that has been tracking individuals for over 20 years provides important clues that may help doctors predict the clinical course of some individuals’ multiple sclerosis, a notoriously unpredictable disease. Among their findings, the United Kingdom investigators reported that those with relatively rapid increases in brain lesion volume, as detected with MRI scans, during the first five years after their initial neurological episode were more likely to develop long-term disability than those with slower rates of lesion accumulation. The study, supported by the MS Society of Great Britain and Northern Ireland, appears in the March 2008 issue of the journal Brain (L. K. Fisniku et al, 131, 808-817).

Details: For this study, Drs. Leonora Fisniku, David Miller (University College London Institute of Neurology, Queens Square, London) and colleagues followed up on a group of patients who had originally developed a first neurological episode (clinically isolated syndrome, or CIS), such as optic neuritis, in the 1980s. CIS can be a harbinger of future MS, but not all of those with CIS go on to develop definite MS. Researchers have been seeking ways to predict who of those experiencing a first episode will go on to develop MS to aid treatment decisions, and they are also searching for ways to predict the highly variable course of MS itself. One method employed is the use of periodic magnetic resonance imaging (MRI). The Queens Square research team previously conducted follow-ups on members of this group of patients after 5 years, 10 years, and 14 years.

Results: Of the original 140 patients who had had MRI and clinical workups for CIS, the researchers were able to follow up on 107 individuals after an average of 20 years. Of the 107, 67 (63 %) had developed definite MS. Definite MS developed in 82% of those whose MRI scans showed abnormalities at the beginning of the study, and it also developed in 7 out of 34 (21%) of those whose original MRI scans were normal.

One of the most important findings relates to long-term changes experienced by the patients. After the 20 years, 58% still had a relapsing-remitting course of MS (characterized by clearly defined flare-ups followed by complete or partial remissions), some quite mild, while 42% had developed secondary-progressive MS (characterized by an initial period of relapsing-remitting MS, followed by a steadily worsening disease course with or without occasional flare-ups or minor recoveries). Those individuals with secondary-progressive MS at the 20-year follow-up tended to have a steep increase in the total volume of brain lesions over the first five years of disease compared with those whose disease course remained relapsing-remitting.
This finding, in the longest study to date of patients starting with CIS, suggests that steep increases in an individual’s MRI lesion load during the first five years of disease may predict a likelihood of a progressive, disabling course of disease. The authors point out that only four of the 107 patients had been on any approved MS therapies during the study, so the results represent for the most part what can be predicted when there is no intervention. What the study cannot predict is whether therapeutically preventing relapses can ultimately change the expected course of disability progression. Further research is needed to answer this very important question.

“This study adds significant information to the complex effort to find ways to predict the course of MS and CIS in individuals,” explained John R. Richert, M.D., executive vice president of the National MS Society’s research and clinical programs department. “We need benchmarks like these that can help guide doctors in making treatment recommendations, and to speed clinical trials of new MS therapies,” he added.