Interview with Neuroimmunology Expert Prof. Malu Tansey

Malú Gámez Tansey is a tenured professor at Emory University School of Medicine in Atlanta and a member of the Center for Neurodegenerative Diseases (CND). She obtained her B.S/M.S in Biological Sciences from Stanford University in Palo Alto, CA, and her Ph.D. in Cell Regulation from UT Southwestern Graduate School of Biomedical Sciences in Dallas, TX, where she studied the role of MLCK phosphorylation in regulation of smooth muscle contraction in the laboratory of Dr. James T. Stull in the Department of Physiology.

The general interests of her laboratory include investigating the role and regulation of neuroinflammatory and immune system responses in modulating the gene-environment interactions that determine risk for development and progression of neurodegenerative and neuropsychiatric disease.


The following has been paraphrased from an interview with Prof. Malu Tansey on June 27th, 2018.

(Click above to listen to the full audio version or click here for a downloadable version)


How much variability is there between each of our immune systems and how much complexity does this variability add when trying to design immune based therapies?

There is a fair amount of variability between people that is biologically normal. There are normal ranges in levels of monocytes, neutrophils, T-cells, etc., and if someone is outside those ranges, that could signal immune dysfunction or infection. To determine those ranges we make sure to examine enough healthy people to see what the normal variability is in a certain age and sex. But even healthy individuals may be stressed or have an infection that is challenging their immune system and which could skew results, so we also use questionnaires to help us interpret results.

The human immune phenotype project is working on optimizing and designing antibodies for certain cell markers that can be used to establish a normal percentage of cells of each type in a milliliter of blood. That should give us a better understanding of our immune system, as well as better tools and markers to measure the health of an individual’s immune system.

Another challenge is in deciding on the exclusion criteria in the design of immune based trials and studies. If we decide that people with other immune related disorders are excluded from a particular study, that may preclude us from being able to observe links, for example, between PD and IBD or Crohn’s disease.

How quickly can our immune systems go from helping us to harming us?

There has been strong evolutionary pressure, because of infectious diseases, for gene variants in the immune system that can protect against infection and launch a very robust immune response. This is typically very effective when you are young so you can get through the reproductive stage and pass on your genes. But, as we age we get a chronic antigenic load from all that we are exposed to throughout our life. This load becomes burdensome to maintain as the immune system and the brain ages. Most degenerative diseases have a component of immune dysfunction which needs to be looked at in the context of immuno-senescence (the aging of the immune system).

There are a few other things that happen as we age that weaken our immune system. One is a loss of diversity in the T-cell and B-cell receptors that can recognize stimuli. Another is an increase in the production of cytokines (signaling proteins) that increase inflammation and can lead to chronic low grade inflammation that your system doesn’t even recognize. Also, the immune system’s ability to recognize your own cells decreases as we age, which means small modifications in certain proteins may then stimulate an immune response.

So, in this perfect storm of less diversity and less ability to recognize self, inflammation may make the immune system work against you. As you age and accumulate damage, your immune system’s ability to differentiate healthy neurons from disease neurons diminishes, along with its ability to decide if no neuron is better than a dysfunctional neuron. Potentially this could happen in days if you turn on or off the right pathways, though in the context of age related neurodegeneration, this usually takes decades.

How close are we to getting a reliable biomarker for neuroinflammation?

There have been a lot of conflicting results reported for various markers. We think these inconsistencies came from sampling people’s blood and cerebral spinal fluid (CSF) at different times of the day. So, we took a group of 12 people with Parkinson’s disease and 6 controls, and took blood and spinal fluid samples from them every 2 hours over a 24 hour period. We measured 30 or so biomarkers to see if they were stable throughout the day and to look for a signature of inflammation from the PD subjects that could help us tell if blinded samples were from people with PD or not.

The ideal biomarker would be steady throughout the day, with clear differences between healthy and diseased individuals, and would show up reliably across different populations of people. But, a lot of the inflammatory levels in the blood are very low, which makes it tough to reliably detect them. We tried to be very agnostic by looking at all the levels and see how they could relate to levels of degeneration. We saw that when we compared the peptides from alpha-synuclein (protein that produces harmful build ups in PD) with inflammatory markers we could come up with a profile that distinguished PD samples from healthy controls. Now we are trying to take this further and see how early in PD we can detect these changes and if they predict trajectory.

In the markers we measured, most went up and down in the CSF, yet were pretty flat in the blood, telling us that what is happening in the blood did not accurately reflect what is happening in the brain. It also tells us that maybe these factors are doing something more important in the brain that makes them change throughout the day. The only marker that correlated between the blood and the brain was C-reactive protein. But, we also found that looking at synuclein levels with TNF (tumor necrosis factor) levels told us which samples were from people with PD. We think that neurodegeneration and neuroinflammation people need to talk to each other and not look at these things in isolation, as the information each are getting could be much more informative when looked at together.

Additionally, we thought a better way to look for biomarkers is to examine the different cell types in a dish under very controlled conditions and give them very defined immunological challenges. When we did that we saw some huge differences between PD and control samples. We now think that this might be a better approach to help us find biomarkers.

How much opposition did you face to the link you proposed between the gut-brain axis and what experiments are being done to try to further establish this connection?

We weren’t the first to make this connection, but it seems that any barrier surface: gut, lungs, skin, olfactory bulb, anything that is in contact or sensing your environment, is a place where an insult can happen and immune cells can become activated. There the cells then try to deal with the situation, but it gets out of hand and propagates from there. That is a general way to think about the initiating mechanism we proposed.

When we started thinking about the gut, we thought about the fact that the LRRK2 gene, which has been implicated in PD, had already been studied for many years by people investigating Crohn’s disease and inflammatory bowel disease. They identified several variants on the gene that predispose people to these conditions. So we already knew that LRRK2 was involved in inflammatory responses, and when the connection to PD came out, we thought it couldn’t be a coincidence. The geneticists were slow to accept this, saying we would have many more cases of PD than we do if there was a direct connection. But, considering we are an over medicated society, and that everyone is on anti-inflammatories, that might have kept these inflammatory conditions under control. It is clear that there is a role for autoimmunity in the disease families where PD is clustering. It may turn out that the gut is one site where you are interacting with your environment and either there is an infection or pesticide that triggers inflammation and then up-regulates levels of synuclein in the surrounding nerve cells that are part of the enteric system (which is connected to the brain stem). So there is a potential highway for them to convey or transfer aggregated and pathogenic synuclein to the brain.

Also, there are gut macrophages whose job is to scavenge anything that leaks out of one cell into another. My favorite theory is that as these cells age, they don’t scavenge as well and that’s how synuclein spreads. We are testing this in non-human primates and hopefully soon in longitudinal studies in humans.

Do we know enough about the immune system to be able to meaningfully intervene?

We need to figure out the right species of alpha synuclein to target. The track record in Alzheimer’s tells us that you have to be sure you are actually engaging the right target. My concern with the immunotherapies underway is that we need to be very careful to consider the potential disadvantages of targeting a protein that we don’t know enough about yet. A lot of studies make synuclein look like the bad guy, but clearly it also has some important roles, so we can’t just knock it out. These immunotherapies are exciting, but we need to be cautiously optimistic and also make sure that in the trials we pick people that have the roughly the same levels of synuclein.

Could you explain some of the promise surrounding TNF inhibitors, particularly XPro1595?

We are finishing up some studies in non-human primates where we have seen some interesting effects on the gut and the heart. We also know that if we give these inhibitors to animal models and then expose them to compounds that typically kill 70% of dopamine neurons, we can get that number down to 30%, which in humans would be below the typical threshold where symptoms appear. Additionally, we know from an Alzheimer’s study in humans that it seems to slow cognitive decline. There are organizations eager to move XPro1595 into human clinical trials, but it is not quite ready because it has never been dosed in people and nobody wants to step up and be the first to do so. Designing the right trial is also tricky because it has to be pretty long and it has to measure inflammation in the brain and in the blood. I would also monitor the cells, the microbiome, and gut inflammation. However, there might be a cancer trial soon that uses XPro1595, if successful that should push the needle for it to be used in PD.

Click here to learn more about the work of Prof. Malu Tansey


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