Authors: Lauren Pulling
As part of our Spotlight on neuroimmunology, we spoke to our Expert Panel member Katerina Akassoglou about her pioneering work on the interactions of the immune and nervous systems in neurologic disease: Dr Akassoglou’s work centers on the leakage of the blood–brain barrier in disease and injury, and the mechanisms by which blood proteins subsequently activate immune cells that attack the brain. Of particular note is her work on the role of the blood protein fibrinogen in multiple sclerosis – research that she hopes will one day lead to an effective treatment for patients. In this interview, Dr Akassoglou discusses her research, as well as the key challenges in this exciting area of neuroscience and her hopes for the field.
Dr Akassoglou is primarily a Senior Investigator at the Gladstone Institutes (CA, USA) and a Professor of neurology at the University of California, San Francisco (UCSF; CA, USA). She is also an Associate Adjunct Professor of Pharmacology at the University of California, San Diego (CA, USA), and directs the Gladstone/UCSF Center for In Vivo Imaging Research.
First, could you tell us a little about your background? How did you come to work in neuroimmunology?
I became interested in neuroimmunology early on. I pursued my PhD in an immunology lab at the Hellenic Pasteur Institute (Athens, Greece), studying the cytokine tumor necrosis factor (TNF), under the direction of George Kollias and Lesley Probert. The lab had made several transgenic mice expressing TNF, and all these mice developed arthritis. However, there was one transgenic line that was paralyzed without any symptoms of arthritis. My PhD project was to find out why TNF caused paralysis in this line. I made the unexpected discovery that, in this particular line, TNF was expressed only in the brain and spinal cord. With the expert guidance of Hans Lassmann at the University of Vienna (Austria), we discovered that expression of TNF in the brain was sufficient to activate brain immune cells and cause MS-like symptoms, such as leakage of blood in the brain and loss of myelin. It was an eye-opener that autoimmunity is not the only way to induce loss of myelin, but other mechanisms like activation of brain immune cells appeared to be potent drivers of disease. In 1998, I was fortunate to receive the Women In Neuroimmunology Award by Cedric Raine and the International Society for Neuroimmunology for my PhD work. It truly was an unexpected honor for a graduate student like myself.
“The blood protein fibrinogen was already recognized as a marker of disruption of the BBB, but no one had actually asked about its role in brain diseases. Was it a cause of the disease or a consequence?”
Neuroimmunology is perhaps one of the most multidisciplinary fields of study that requires training in multiple fields. During my PhD training, I made the observation that activation of brain immune cells strongly correlated with leakage of blood in the brain. I was curious as to whether blood in the brain could be responsible for activating the brain immune cells and cause damage. To obtain training in blood proteins, I pursued my postdoctoral studies at The Rockefeller University (NY, USA) under the guidance of Sidney Strickland. The blood protein fibrinogen was already recognized as a marker of disruption of the BBB, but no one had actually asked about its role in brain diseases. Was it a cause of the disease or a consequence? We made the unanticipated discovery that fibrinogen was required for regeneration of the peripheral nerve. This was the first time that fibrinogen knock-out mice had been tested for their neurological functions. After having completed training in immunology, neurobiology and hematology, I was ready to study in my own lab how fibrinogen affects brain functions. Indeed, we showed that, when fibrinogen gets into the brain, it activates microglia, the brain’s immune cells, to become pro-inflammatory cells, promoting autoimmune responses and neuronal damage.
What are your lab’s current research focuses?
We focus on the molecular mechanisms that control communications among the brain, immune system and blood vessels. We continue to study fibrinogen and other blood proteins and their effects on microglia in mouse models of MS that we developed. We want to understand those interactions in mouse brains and spinal cords and learn what happens when the BBB is disrupted and as the process of demyelination and neurodegeneration begins. We recently found a way that we might be able to block the effects of fibrinogen in the brain. We made other significant discoveries, including a fascinating relationship between astrocyte activation and neuronal activity and remodeling of the nuclear pore complex. We are also looking beyond fibrinogen to its downstream pathways directly linked to neurodegeneration. For example, we are using state-of-the-art genomic and proteomic technologies to discover new pathways that damage neurons.
We have also invested a great deal in imaging, particularly high resolution in vivo imaging. We knew the microglia were dynamic cells, but we needed the ability to see them in action in living animals. So we developed methods to image the neurovascular interface in vivo in transgenic mice. We use high-resolution two-photon microscopy and fluorescently labeled microglia, T cells and fibrinogen. With this procedure, we can watch the whole disease process as it moves from a normal brain to full-blown autoimmune disease. We’ve made some surprising discoveries. For example, in MS, microglia change shape and cluster around blood vessels early on in the disease course. This finding supports the theory that disruption of the BBB and leakage of blood into the brain may occur before other symptoms of disease.
Could you talk us through your work on the role of fibrinogen in MS?