(Above Image: Nerve Cells And Glial Cells, Sem is a photograph by Thomas Deerinck, Ncmir: Source)

“Science is often described as an iterative and cumulative process, a puzzle solved piece by piece, with each piece contributing a few hazy pixels of a much larger picture. But the arrival of a truly powerful new theory in science often feels far from iterative. Rather than explain one observation or phenomenon in a single, pixelated step, an entire field of observations suddenly seems to crystallize into a perfect whole. The effect is almost like watching a puzzle solve itself.” ― Dr. Siddhartha Mukherjee, The Emperor of All Maladies: A Biography of Cancer. Pg. 362

The blossoming field of neuroimmunology is radically transforming how we study and understand our brains. Though the role of the brain’s immune system in various functions had long been suspected, it is only in the last decade, thanks to a suite of new tools and markers, that we have begun to understand just how critical it is to keeping us alive and healthy.

It is also where I personally derive a lot of hope from for improved therapies in the future. Recent insights from the field have already given us a variety of promising new targets for a number of brain diseases, along with a much better understanding of how these diseases start and develop. And we have only begun to tap its potential.

Glia and Beyond: A (very) brief overview of recent discoveries

Traditionally the neuroimmune system’s role was believed to be limited to maintaining the barriers between the brain and the outside world (most notably the blood-brain-barrier), controlling neuroinflammation, maintaining the health of neurons, and defending the brain from pathogens. But the last few years have shown that there is much much more going on:

All of these insights have led to new understandings of how the brain does all that it does and what goes wrong along the way…

(* A note on Ben Barres: He sits for me with Oliver Sacks at the top of the list of neuroscientists I would have liked to meet but who passed just before my interest in the brain was piqued. He will likely go down as one of the early pioneers of neuroimmunology as his fingerprints are everywhere. He is widely revered as a proponent of all things glia, and his ideas permeate through all the students and post-docs that went through his lab. But his reach extends beyond just this field as he was a champion of equal opportunity in science, placed great importance on the responsibility inherent in mentoring the next generation of scientists, and was a powerful advocate for an individual’s right to self-determination. Click here to learn more about his life and contributions to neuroscience or here to pre-order his forthcoming autobiography.)

In The Beginning…

“What attracted me to immunology was that the whole thing seemed to revolve around a very simple experiment: take two different antibody molecules and compare their primary sequences. The secret of antibody diversity would emerge from that. Fortunately at the time I was sufficiently ignorant of the subject not to realize how naive I was being.” — César Milstein From Nobel Lecture (8 Dec 1984), collected in Tore Frängsmyr and Jan Lindsten (eds.), Nobel Lectures in Physiology Or Medicine: 1981-1990 (1993), 248.

It is important to stress that what we don’t know about the neuroimmune systems far exceeds what we do know. New discoveries are frequently being made that force us to tweak our models and reexamine what we thought we knew about the brain. (Just last week it was reported (though in preprint) that microglia in a specific region of the brain look and behave very different from other microglia.) The field is just beginning to comprehend all of the ways that the neuroimmune system contributes to both health and disease. But what we have learned so far is enough to unequivocally state that it will be an essential part of humanities quest to understand our brains and rid ourselves of the diseases that ail it.

With so much going on, and so much still to be uncovered, I decided to reach out to some of the people who know it best to try and get some insight on where the field is and where it is going…

Survey Participants

Prof. David Sulzer – Professor at Columbia University Medical Center in the Departments of Psychiatry, Neurology, and Pharmacology. Co-discovered the first direct evidence that autoimmunity plays a role in Parkinson’s disease and that adult human neurons can present antigens, particularly the dopamine and norepinephrine neurons that die in Parkinson’s.

Prof. Malu Tansey – Professor of Physiology at Emory University School of Medicine. Her laboratory investigates 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.

Prof. Ashley Harms – Assistant professor in the Department of Neurology at the University of Alabama at Birmingham. Her research is on the role of innate and adaptive immune system in alpha-synuclein models of Parkinson’s disease and in animal models of multiple system atrophy.

Prof. Shane Liddelow – Assistant professor at the Neuroscience Institute at New York University Langone. He discovered that there is a close associated between astrocytes, microglia and abnormal neuron function.

Dr. Megan Duffy – Research scientist in the Department of Translational Science and Molecular Medicine at Michigan State University. Her research focuses on reactive microglial activation in rodent models of Parkinson’s disease.

Prof. Sarkis Mazmanian – Professor of microbiology in the Division of Biology and Biological Engineering at the California Institute of Technology. He was among the first to link the microbiome to various diseases and he is leading research into how the gut microbiome impacts and communicates with the immune and nervous systems.

How similar do you believe your mental model of the brain is with that of your colleagues?

David Sulzer – “I think one relevant point for this discussion is how isolated the brain is from the cells of the peripheral immune system. I would agree with the prevailing view that most of the time these are walled off, but suspect that this can change under conditions associated with disease.”

Malu Tansey – “My neuroscientist colleagues are coming around to the idea that the brain is an immune-specialized rather than an immune-privileged organ and are slowly but surely developing an appreciation for the role of the immune system in brain health. My model is one in which a healthy immune system protects neurons, clears debris and misfolded proteins, and prevents propagation of aggregated toxic proteins in the brain; and therefore, aging of the immune system is likely to contribute to age-related neurodegenerative conditions like Parkinson’s and Alzheimer’s disease.”

Ashley Harms – “I believe that my mental model of the brain in terms of steady state and disease is probably a bit different than most of my colleagues. I think in neurodegenerative disease models, each person’s working hypothesis is heavily influenced by their research interests, so it is no surprise my working model of the brain is heavily focused on non-cell autonomous or glial driven mechanisms. With that said, I believe that working and collaborating with others that have a different brain or working model interpretation is key to pushing the field (myself included) to think more broadly about neurodegenerative disease mechanisms”.

Shane Liddelow – “As a glial biologist I always place the non-neuronal cells at the peak of importance for the function of the brain – but residing academically in a neuroscience department means I interact on a daily basis with many people who have ignored glia and the immune system for most of their careers! What is most exciting however is to sit down and meld our two different models together to produce an ever more complex but infinitely more exciting concept of how the brain works.”

Megan Duffy – “I think it’s safe to say we all agree on our mental model of how the healthy brain works. In the field of neurodegenerative disease however, it’s very easy to get into a niche or attached to a certain story and lose sight of other angles. For example, microglia often get a bad reputation when it comes to neurodegenerative diseases but we have to remember they have many beneficial functions as well. That balance is important when designing therapeutics to target inflammation – we’re likely to be more successful long-term by trying to restore the balance of the immune response in the brain, rather than trying to outright inhibit it altogether.”

Sarkis Mazmanian – “Our research suggests a radically different model for the etiology (cause) of Parkinson’s disease (PD) than mainstream research. While there are several perspectives for genetic and environmental factors that cause or contribute to PD, most research focuses on studying events in the brain. However, since many PD patients also have constipation, we and a few other groups have proposed that perhaps in some cases, PD orientates in the gut and spreads to the brain. While more research is needed to validate this concept, emerging data lend support for Braak’s hypothesis that PD may be caused by an insult in the gastrointestinal tract, which is a departure from current principles in neuroscience.”

What do you believe the first neuroimmune based or glial targeted therapy will be?

David Sulzer – “It could be a way to assist in the helper cells that decrease unwanted immune responses.”

Malu Tansey – “Because I believe that immunocompetence (the ability of the body to produce a normal immune response following exposure to an antigen) is lost as one ages, the key will be to restore the basic (homeostatic) function of immune cells rather than try to dampen the aging immune system further with immunosuppressive therapies. Therefore, therapies that boost immune function to a more ‘younger’ state would be beneficial.”

Ashley Harms – “This is a tough question to answer. I think that alpha-synuclein antibody therapy is probably the closest, but still has a very long way to go before being useful in the clinic. It really is also hard to predict what neuroimmune based therapy will be the first as we are still looking for the best animal model to understand disease mechanisms. There are multiple anti-inflammatory therapeutics in use for autoimmune disorders such as anti-TNF or T cell targeted therapies, so perhaps one of those could be re-purposed and tested in PD.”

Shane Liddelow – “I often joke with my students that it will be something we already have had for decades – like aspirin! I honestly believe however, that the first neuroimmune/glial targeted therapy will be effective – and we will find that it will make so many of the currently failed therapeutics viable again. These drugs that may be exceptional at improving (say) neuronal firing may have little effect when neurons keep dying, but by targeting glial/immune-derived neurotoxicity with a combination therapy that can improve neuron function we will have a very formidable treatment.”

Sarkis Mazmanian – “Many studies have implicated inflammation, both in the brain and systemically, as coincident with PD symptoms. There are some studies that suggest inflammation may not simply be a consequence, but may indeed be a driver of disease. Specifically, brain resident immune cells known as microglia are activated in PD brains and mouse models of PD. I believe that targeting microglia, using a number of therapeutic modalities, to dampen inflammation may be a viable approach to preventing, slowing or halting symptoms and pathology.”

What do you think will be the first reliable biomarker(s) of neuroinflammation?

David Sulzer – “I think the jury is out on this. It could be by identifying particular T cell types, and we are working towards this, but the research is so new that we don’t know at this time.”

Malu Tansey – “Because inflammatory proteins play complex roles in the brain and our group and others have shown their levels fluctuate throughout the day, I don’t believe it will ever be a single biomarker but rather alterations in an inflammatory profile of a number of markers that demonstrate an imbalance in the numbers or function of the immune cells that produce them.”

Ashley Harms – “I believe there has been a lot of success surrounding neuroimaging ligands, particularly the translocator protein or peripheral benzodiazepine receptor. These ligands have been successful in showing evidence of neuroinflammation in PD patients in areas of neurodegeneration. However, more studies are needed to determine how neuroinflammation evolves over time, and if it can be correlated with active disease state, and optimized for use.”

Shane Liddelow – “Due to most glial/immune cell functions having localized effects, and largely by secreted factors, I would presume that an extremely targeted ligand-based imaging technique will be the most effective biomarker for the highly heterogeneous neuroinflammatory responses (e.g. reactive astrocyte subtype positron emission tomography, PET, ligands). As these non-neuronal cells respond in a variety of different ways, with each having vastly different functional changes, a broad-spectrum biomarker approach with no spatial context will likely be insufficiently informative.”

Megan Duffy – “I think that the first reliable biomarker will be some combination of inflammatory cytokines and disease-implicated protein (e.g. alpha-synuclein for PD, tau for AD, etc..) measured in the CSF. Plasma would be more ideal and less invasive for patients, but it is much farther removed from what’s going on in the brain and likely won’t provide an accurate picture of what’s going on.”

Sarkis Mazmanian – “There are imaging approaches that are being developed to measure microglial activation and aSyn aggregation, which may represent biomarkers. Further, there are efforts to identify small molecule metabolites that correlate with disease symptoms, which may represent blood or urine biomarkers.”

How big of a factor do you believe autoimmunity is in neurodegenerative diseases?

David Sulzer – “I suspect that autoimmune steps are downstream in neurodegeneration, even in multiple sclerosis which is accepted to be autoimmune, but still important as a link in the chain of the disease. Breaking the immune link in the chain might provide very important therapy, particularly if we can do so during the early stages of the disease. The inflammatory steps might be the driver of much of the stress on dopamine synapses and could be driving the neuronal death, at least in some forms of PD. This direction might work best if we can stratify the different types of PD progression and determine who will best respond to particular therapies, including cytokine, cellular, and other immune based approaches. The good news is that multiple sclerosis is far better treated than it once was due to multiple immune based therapies that work for particular patients, and so there is a reason for optimism that this will happen in PD too. ”

Malu Tansey – “Gronzy and colleagues at Stanford have described the Janus-head of immune aging in humans which consists of an age-related inflammatory syndrome and age-related immunodeficiency. They state “the aged immune system is prone to autoimmune responses and many autoimmune diseases increase in incidence with age or are even preferentially encountered in the elderly.” I believe that both of these processes are likely to play a key role in the aggregation and propagation of misfolded toxic proteins as individuals age, so Parkinson’s and Alzheimer’s may turn out to be age-related autoimmune conditions. Experiments are underway in our lab and others to test this hypothesis.”

Ashley Harms – “I think it is actually a big factor and the research and literature surrounding this idea is starting to really catch on (it has been a very slow process). As far as we know, age is one of the greatest risk factors for neurodegenerative disease, and it is well established that immune system response is greatly affected by age. Whether inflammation is the cause, the driving force, or the result of active disease is still up for debate. I think that we are getting closer to developing better tools and technologies to study and get a definitive response to these questions.”

Shane Liddelow – “Outside my area of expertise, but I think that immune dysfunction (and glia dysfunction) is the biggest factor contributing to neurodegenerative disease. The mounting evidence that immune, glial, and microbiome changes are actively driving the initiation and progression of neurodegenerative diseases is too large to ignore. Once we have the ability to target these factors in a specific manner, I predict a rapid and sweeping redesign in the way we detect, treat, and cure such diseases.”

Megan Duffy – “This concept has garnered a lot of interest in the last decade and I think it certainly fits, and at least plays a contributory role. Recent work has suggested that T-cells recognize certain a-syn peptides implicated in PD (Sulzer 2017) and that there is a shift in the T-cell repertoire in PD patients which is conducive to pro inflammatory cytokine production (Sommer 2017, Kustrimovic 2018). It’s likely that autoimmunity plays a detrimental role, but is a secondary response to a-syn modification, accumulation, and aggregation. TL;DR: it acts as an accomplice, but not the major culprit.”

Sarkis Mazmanian – “While research into a potential autoimmune component in PD is an exciting concept, it is a relatively new finding and requires further replication and discovery of mechanism of action. That being said, it does support a role for the immune system and inflammation in PD, but again the details require more research.”

The link between inflammation (peripheral and neuro) and neurodegenerative diseases is pretty well established, but given how variable and multifaceted the neuroimmune system is, do you think the use of anti-inflammatories as a preventative therapy might do more harm than good?

David Sulzer – “Certainly and I think that is a valid point in medicine in general regarding sets of drugs. Even aspirin can do harm. We need to study this pathway and understand it better.”

Malu Tansey – “First, let me say that it’s important to distinguish between acute and chronic inflammation and the opposing roles these two processes play: acute inflammation tends to be an adaptive (beneficial) response to injury while chronic inflammation damages tissue and is associated with maladaptive (harmful) responses by chronically activated immune cells that change the metabolic profiles of immune cells, neurons and many peripheral tissues. To the extent that anti-inflammatory therapies can shut down the chronic inflammation, these could be beneficial as long as they are not immunosuppressive (like corticosteroids are for instance).”

Ashley Harms – “I think it depends on the exact mechanism of the therapy and how it is administered. Other autoimmune diseases have used targeted anti-inflammatory therapies with great success and disease modifying outcomes. The idea of using peripheral immune based therapies in neurodegenerative disease is attractive as it is less invasive then a gene therapy or brain-targeted approach. With that said, there is no perfect therapy or treatment that would not have side effects that need serious consideration.”

Shane Liddelow – “Anti-inflammatory therapies as a preventative measure may be a cross too dangerous to bear. Though immune-modulatory drugs have been shown to be beneficial in multiple-sclerosis, they do have many potential dangerous side effects. Until we have anti-inflammatory therapies that can target with greater specificity, they may do more harm than good in attempts to prevent neurodegenerative diseases.”

Megan Duffy – “”Yes. While it has been suggested that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs, i.e. Ibuprofen) use can reduce the risk of developing PD, I don’t think this applies to everyone given the heterogeneity of the disease. Moreover, the risky nature of long-term NSAID use (i.e., side effects on on other organs) likely outweighs the potential for benefits.”

Sarkis Mazmanian – “A number of studies have tested anti-inflammatory therapies in PD, with mixed success to date. There is always however the possibility that any therapy may have severe side effects.”

Let’s say you find a magic lamp, you rub it and a genie pops up and says, “I know everything there is to know about the human brain, I will answer any one question you have.” What would you ask?

David Sulzer – “In my own lab we are trying to understand precisely what happens when you learn and unlearn as we think this is what makes us thinking organisms that interact with our environment and is responsible for our personalities. I think that understanding this not only contributes to appropriate brain function throughout life but will be fundamental to understanding what changes in diseases, including movement disorders and Parkinson’s.”

Malu Tansey – “OK that is an easy one! I would ask: “What are the key regulatory switches one must turn on or turn off to restore the dialogue between immune cells and neurons to a younger more functional state as an individual is aging to prevent age-related neurodegenerative diseases like PD and AD and improve the quality of life in the elderly and their families?””

Ashley Harms – “A big caveat of studying disease mechanisms in rodent models is that the immune system in a mouse is likely very different than that of a human. I would probably ask something along the lines of – what are the fundamental differences in immune responses or cell characterization that we would need to be aware of when targeting therapeutics?”

Shane Liddelow – “How does it work?”

Megan Duffy – “You know everything about the human brain…can you please write it down? ;)”

Sarkis Mazmanian – “Define brain health (so we know what goes wrong during disease).”