MS & Epstein-Barr Virus Update – Part 2

Research Summary: EBV Infection and Multiple Sclerosis: Lessons from a Marmoset Model

Earlier in the week, we discussed the background information about the potential role of Epstein-Barr Virus (EBV) and multiple sclerosis (MS).  Today, we are going to expand on this by discussing some new research that has been conducted by the University of Groningen (Netherlands) and the University of Nottingham School of Medicine (UK).  The work was published in Trends in Molecular Medicine.

The Marmoset Model of MS 

We have previously talked at length about studies that have used an animal model of MS, known as EAE.  However, in most of these studies, the animals used have been rodents (mice or rats).  In this study, the researchers have used a primate model of MS, where they have induced EAE in marmosets.

The authors of the publication argue that there are a number of reasons why this is a valuable model for MS research.  In particular, they highlight the fact that these primates are very similar to humans, especially in key genetic aspects of the immune system.  The other key difference that separates this from rodent models of MS is that the marmosets are exposed to a similar environment to humans.

Often with rodent models, the animals are kept in clean conditions, guaranteed to be free of specific pathogens.  Unlike that situation, the environmental exposure of the marmosets leads to many of them carrying lifelong infections with herpesviruses – similar to that of humans with EBV.

Evidence From Marmoset EAE

As more evidence to the usefulness of this primate model, experiments have shown that B cell based treatments have similar effects in marmosets to humans.  For this, two different types of B cell medications have been tested:  ones that block the function of B cells and ones that attempt to deplete B cells.

In both humans and the marmoset model, the function blocking medications have shown clinical benefits, whereas those that attempt to kill the B cells have no benefits or worsen the disease.  There is a suggestion, based on other results, that infected B cells (such as with EBV) don’t rely on the same factors for survival and so aren’t destroyed by the second class of drug.  This has not yet been proven though.

In another interesting point, the researchers noted the following about the myelin damage that they observed in their marmoset model:

“Although requiring further validation, our recent work seems to indicate that MS-like lesions in white and cortical grey matter display serious oxidative injury, iron redistribution, and mitochondrial defects. These are features that, to our knowledge, have not been observed in any of the existing rodent EAE models”.

This is particularly relevant considering our recent feature week on MitoQ and mitochondrial dysfunction in MS.  You may recall that we also wrote a summary about a publication from their research teams regarding the use of this in a mouse model of MS, which indicated similar thoughts to those expressed in this current paper.

A Hypothesised EBV Mechanism in MS

Through their research, the authors have proposed a potential way that EBV may be a cause of MS.  This mechanism is summarised in the image below.

Essentially, the hypothesis is this.  In the individual, T cells exist that are capable of reacting against myelin (shown in orange).  At this stage, they are not activated and so will not cause damage.  For this activation to occur, B cells have to display the target of the T cells on their surface.  In B cells that aren’t infected, this doesn’t happen and instead the target gets destroyed before it is displayed (green pathway).

In B cells that are infected, however, this is altered (red pathway).  The infection leads to the protein becoming modified (called citrullination), which changes how the protein is processed.  This results in the T cell target being displayed by B cells, which causes the autoreactive T cells to become active and begin to attack the myelin.

It is important to realise that these results are very preliminary and require much further validation.  As the authors themselves state in the article, there are many outstanding questions that are still to be answered.  This does, however, suggest that more research into treatments that target EBV infected B cells is worthwhile and could provide a more targeted therapeutic option.

The abstract for this article can be viewed here.