Dr. Arun Varadhachary: A conversation on mitochondrial dysfunction in autoimmune and inflammatory disorders
Dr. Arun Varadhachary, MD, PhD, is Professor of Neurology and Chief of Neurohospitalist Medicine at Washington University, St. Louis, Missouri. He also serves on the Scientific Advisory Board of Blue Oak Nutraceuticals, Inc. Dr. Varadhachary has published 24 peer-reviewed publications.
Note: The content has been lightly edited for readability and conciseness.
Your current research explores the interaction between autoimmune and inflammatory disorders and mitochondrial dysfunction. Tell us more about your discoveries.
Dr. Vardhachary: We often try to categorize diseases based upon what we think is causing the problem. And in neurology, we typically will divide disorders into several broad categories, such as degenerative immune, metabolic, toxic or traumatic. That categorization works reasonably well at the highest or most superficial level of understanding a disorder. But when we dig deeper, we understand that these categories have a great deal of overlap between one category of potential disease, pathogenesis and another.
When we think of autoimmune disorders, we typically think of it as the immune system attacking our own tissue. However, when we dig a little deeper, we also can see that in the setting of inflammation, there is often a metabolic perturbation that accompanies the disease state. We have observed and others have observed that many autoimmune disorders will have dysfunction of the energy producing systems.
In the case of inflammatory myopathy, we can see when we look at pathology that there is evidence of mitochondrial dysfunction in addition to evidence of inflammation. And so what we have to try to understand is how those two pathologic findings are actually related and how those two findings contribute to the disease state that would be located in the center. And if you want to do that, think just the weight of the mechanism. Basically, the interaction between autoimmune and taurine disorders and controls.
So in neurologic disorders, we frequently categorize diseases based upon what we presume to be their underlying pathophysiologic activity. And so disorders can be divided into being immune mediated or degenerative or due to a toxicity or a traumatic type of an event.
However, we understand that these different types of pathogenic features of a disorder overlap with one another. When we typically think of an autoimmune disease, we typically think of the immune system attacking our own tissue and thereby causing tissue injury damage and then symptoms. However, when we look at that tissue under the microscope and look to see what those pathologic features are, not only do we often see the inflammation or the immune activation itself, we often see markers of abnormal metabolism.
This pathologic finding is, of course curious because our disorders are typically not categorized as being immune and metabolic. But as we look at disorders in greater detail, we see that there’s a great deal of overlap.
Trying to understand how the immune system and metabolic dysregulation can coexist and co-contribute to a disease state is something that is quite fascinating.
In neuromuscular disorders, we frequently take care of patients that have autoimmune muscle diseases, the so-called inflammatory myopathy or myositis. There are types of myositis where we have observed and others that mitochondrial pathology is as prominent a feature of those conditions as any frank, inflammatory or immune markers that we see on the pathology.
So over the last number of years we’ve been curious and have tried to investigate how metabolism and autoimmunity interact to create a disease state.
Tell us more about your work in mitochondrial pathology in immune and inflammatory myopathy
Dr. Vardhachary: This is an observation that had been made quite a number of years ago when inflammatory myopathy, these were first being categorized back in the mid seventies, and some of the early categorization of inflammatory myopathy had recognized that there are two broad classes of inflammatory myopathy that have mitochondrial pathology.
The first class of inflammatory myopathy that has mitochondrial pathology is a condition called dermatomyositis, which is frequently seen in the pediatric population, but then is also observed in the older population, frequently in association with malignancy.
A second class of immune or inflammatory myopathy is a condition called Inclusion Body Myositis. This is a condition which is slow moving, typically seen in an older patient population, but is also characterized by immune pathology as well as mitochondrial pathology.
What’s interesting is that these two different disorders respond very differently to immuno modulation. In the case of Dermatomyositis patients frequently do very well in response to immuno modulation, where in the setting of inclusion body myositis patients do not do nearly as well, suggesting that although the pathologic features may have some semblance of resemblance to each other, what’s actually driving the disorder may be very different
And so looking using these two disorders as case examples, we can try to parse apart the difference between what the immune contribution is to the disease state versus what the mitochondrial or metabolic dysfunction is contributing to the disease state.
What, in your opinion, is the impact of autoimmune and inflammatory disorders of the central nervous system and metabolic and degenerative neurological disorders and other systemic diseases?
Dr. Vardhachary: I think that’s a fascinating question because most typically in disease states, we have thought of it as being a unique directional relationship, but it is becoming more and more appreciated that the relationship between the immune system and the nervous system is reciprocal, meaning that abnormalities in the immune system will result in neurologic disorders.
For example, multiple sclerosis or demyelinating neuropathies would be an example of the immune system negatively impacting the nervous system. On the flip side, we also know that the nervous system plays a huge role in being able to regulate the immune system, so our autonomic nervous system will help control and attenuate immune responses by regulating how immune cells are being turned on and turned off in the peripheral immune compartment
The role of metabolism in all of this is, of course, an area of investigation. We don’t fully understand that relationship, but we do know that the immune system as well as the nervous system, are very attuned to what the metabolic state of an organism or a person is at any given point in time. And then how metabolism or dysregulation of metabolism can turn on or turn off the immune or the nervous system is an area of investigation.