Multiple sclerosis (MS) is a devastating autoimmune disease, where the immune system attacks the white matter throughout the nervous system. While the cause for MS is currently unknown, epidemiological data so far suggests that the disease is likely triggered by both environmental and genetic factors. To pinpoint the molecular mechanism for MS, Sergio Baranzini and colleagues at UCSF conducted a recent twin study on multiple sclerosis using advanced tools such as genomic deep sequencing analysis. In their study published recently in Nature, Baranzini analyzed immune cells from identical twins where one of the twins has developed MS (Barazini et al., 2010). Much to their surprise, the study found no significant genomic differences between the twins.

Ironically, previous studies have long suggested a strong genetic link for MS. This was very well supported by a recent microarray study, where researchers have used genomic microarray technology to analyze the expression profile of serum and post-mortem brain tissue from healthy and MS individuals (Habek et al., 2010). The array has identified a number of immune biomarkers that could be associated with this disease, many of which have been used as targets for drug development.

In light of the above studies, it was expected that the MS twin would have accumulated genetic mutations that triggered the disease emergence later in life. But why are these genetic differences not detected in Baranzini’s study? One possibility is that the genetic difference between the twins is not in the genomic sequence per se, but rather in the subtle differences in gene expression. To that end, Baranzini and colleagues took the twin study to another level by looking for changes in the intrinsic gene expression regulation program, which is mediated by coordinated chemical modification of chromatin structure- a process known as "epigenetics". Using a genome-wide epigenetic analysis, they discovered much to their astonishment that the immune cells from the twins have completely identical epigenetic profile, suggesting that the emergence of MS probably has nothing to do with gene expression.

Could multiple sclerosis be a disease triggered only by environmental factors after all? The researchers themselves have addressed this question, suggesting that both twins have the same genetic predisposition to MS but only one of them have been exposed to the right combination of environmental triggers to drive the development of the disease. While genetics seem to play an important role in the development of the disease, the actual trigger may be complex array of environmental factors that remain to be identified.

Another interesting question is whether Baranzini and colleagues were looking in the right place anatomically. Specifically, the twin study was focused on looking for genomic differences in the twins’ immune cells, presumably because these cells could be easily isolated from the serum. A more scientific reason for looking at immune cells is because MS was thought to arise from autoimmune activation of the host’s immune system against the brain. As this widely accepted model for MS has not yet been directly proven, there remains the possibility that MS is not triggered in the host’s immune system. Moreover, since gene expression differences have been observed in the brains of healthy and MS individuals, it is very likely that MS could arise from genetic triggers in the brain (Habek et al., 2010).

Interestingly, genome array studies have shown that apoptotic genes are elevated in post-mortem MS brains (Habek et al., 2010), suggesting that the autoimmune aspect of MS could be initiated by spontaneous white matter degeneration. Since ample evidence demonstrate that brain injury and neurodegeneration produce cellular debris that triggers an immune response very much like MS (Yong&Marks, 2010; Alexander&Popivich, 2009; Glass et al., 2010), it is apparent that the autoimmune symptoms of MS could just as easily arise from cellular debris produced at the onset of spontaneous white matter degeneration (reviewed in Barnett & Sutton, 2006). Like the chicken or egg argument, the origin of MS is still undecided and very much debated.

As the origin/trigger of MS still remains obscure, it may still be premature to decide whether there is a genetic link for MS based on Baranzini’s study. Rather, the Baranzini study should be an example for future twin studies to search for the genetic component for MS not only in immune cells, but also in post-mortem brain samples.

Overall, this twin study is the first genomic/epigenomic study yielding compelling negative results that may redefine the understanding of MS, and hopefully drive research closer towards unveiling the elusive trigger of MS.


References:

Baranzini, S.E. et al., Nature. 2010. 7293, 1351-1356.
Habek M. et al., Clinic Neurol. 2010. (in press).
Yong V.W., Marks S., Neurology. 2010. 74, S9-S16.
Alexander J.K., Popivich, P.G., Prog Brain Res. 2009, 175, 125-37.
Glass C.K. et al., Cell. 2010, 6, 918-934.
Barnett, M.H., Sutton, I. Curr Opin Neurol. 2006. 19, 242-247.