Promising news for keeping the motor neurone neighbourhood safe

There was standing room only in the first of the dedicated scientific sessions of the Symposium last week. All had gathered to hear Prof Stan Appel inform them of the latest chapter of this story on the role of inflammation in MND.

Listening to his presentation I got the gist of the overall positive message – a real step forward in MND research – but to report in any more detail of how and why was a step too far for my brain when I was in Sydney! Reading through my notes when I got back to the office, I was determined to get to the bottom of this science. It helped me to write a non-technical summary of it as I went. It’s perhaps a bit more technical than our normal blog posts – but I couldn’t resist the opportunity to (try and) share my new found knowledge. So here goes:

Inflammation is one response of the immune system. The immune system is a community of cells that exist within your body to protect it from damage and to maintain its status quo. Given its important function, it is perhaps reassuring to know that how it works is mind-blowingly complex!

In the brain and spinal cord, a slightly different defence system exists in comparison to the rest of the body. It is now common knowledge that motor neurones are surrounded by cells that support their function – known as glial cells. Within the community of these glial cells there are ‘police’ cells called microglia. Prof Appel’s lab has contributed many elegant studies to a consensus of research showing that in MND these police cells operate a delicate balance between protecting the environment around motor neurones and triggering a toxic atmosphere. Gradually the toxic atmosphere prevails.

In Sydney, Prof Appel discussed another component of this defence system, ‘regulator T-cells’. Continuing the police analogy, T-cells patrol the blood, rather than the brain and spinal cord tissue of microglia. As their name suggests, regulator T cells regulate the response rate of removing toxins and maintaining a healthy environment, in particular they regulate microglia by sending out specific chemical signals.

Prof Appel wanted to know how the interaction of T-cells with microglia is affected in MND. He found that a large ‘police presence’ (or high numbers) of regulator T-cells influence microglia to maintain their protection of motor neurones. In other words, large numbers of regulator T-cells kept motor neurone death at low level, showing itself as a slower phase of disease progression. As the levels of regulator T-cells get lower, the microglia turn toxic and the rate of progression of the disease speeds up. These conclusions were based on studies in mice models of MND and in patients at different stages of MND – by analysing blood samples for the presence of regulator T-cells and comparing this with what they knew of their symptoms.

This information presents two opportunities to MND researchers – firstly if therapies can be developed to maintain the levels of these regulator T-cells they may slow down the disease; and in the meantime, chemical markers in the blood, used in these studies, may be a valuable biomarker to measure the rate of progression.

Mediating the delicate balance between protection and damage

The Opening Session theme on how the disease progresses within the Central Nervous System (CNS) continued with the presentation by Prof Stan Appel from Baylor College of Medicine, Huston on neuroinflammation.

Examination of post-mortem brain and spinal cords from people with MND shows clear evidence of inflammation (although Prof Appel was quick to point out that this is not the same as occurs in ‘primary’ inflammatory conditions such as multiple sclerosis). Similar patterns are seen in human MND spinal cord and in SOD1 mice, suggesting that at least for this aspect of the disease, SOD1 mice may be a good model of human MND.

He went on to explain how migroglia, the ‘innate’ immune cells of the CNS, help mediate a delicate balance between protection and damage. The speed of progression in MND appears to be dictated by this balance.

Prof Appel showed that SOD1 mice exhibit two phases of disease: an early slow phase, where the microglia release a series of protective factors, and a rapid secondary progressive phase where levels of these protective markers fall and are replaced by a rise in ‘pro-inflammatory’ toxic factors. Of course, strains of lab mice are so inbred that they are genetically very similar and develop the disease in a uniform manner. Humans on the other hand are very different, as is the way the disease progresses between one individual and the next, so the two stages of disease are not easy to demonstrate in MND patients. However, by examining the inflammatory factors present in patients with very rapid progression against those with slower progression, he was able to show that the factors associated with the second ‘rapid progression’ phase in mice were also present in the rapidly progressing patients. He suggested that this may assist clinicians in predicting how the disease is likely to progress in patients at an early stage in the disease.

It is relatively easy in cell culture studies to tilt this balance from protective to toxic, but could the balance be tilted the other way in patients, as a therapeutic strategy? Certainly, in response to a question from the floor, he suggested that greater attempts should be made in this direction, commenting, “The whole issue of immunosuppressant drugs in MND needs to be re-opened. But – you can’t just take down all immune responses in an uncontrolled way. You need drugs that are much more selective”.

Read our official day one symposium press release on our website.