By: Helen Beilinson
At the end of the nineteenth century, Ilya Metchnikoff discovered phagocytes, a subset of cells that ingests and digests foreign particles and cells. This Nobel-winning finding spearheaded the study of immunobiology. The twentieth century brought innumerable basic biological discoveries in how the immune system works— from how it battles and eliminates unwanted invaders to what causes its functions to go awry and induce autoimmunity. The last decade has brought yet another layer into immunology research. Advances in studies of immunology and studies of other organ systems have become integrated to understand how these systems work together and influence each other. Each system is not isolated from the rest of the body; they function in unison, often with overlapping functions, to ensure the health of the whole body.
Phagocytes play a crucial role in immune responses as they work to remove invading pathogens before they are able to harm the host. They are also vital in eliminating debris that is formed during the development and day-to-day maintenance of an organism. Multicellular organisms often have to eliminate unwanted cells, and do so using a type of programmed cell death, termed apoptosis. Swift removal of dying and dead cells, also called apoptotic cells, is necessary for the maintenance of the health and homeostasis of the organism. As opposed to living cells, apoptotic cells display “eat me” signals on their surface as a label for phagocytes to distinguish which cell they should be eliminating. Numerous of these “eat me” signals have been identified and come in many forms, from changes to the sugars attached to surface proteins, to the exposure of new proteins or lipids (also known as fats). The signals can also be derived from the apoptotic cell itself or be attached to the cell after the induction of apoptosis.
One system that plays a notable role is tagging cells for elimination is called complement. The complement system is made up of numerous proteins that have a multitude of functions to strengthen the immune response against pathogens. One of its roles is to deposit specified proteins on bacterial cells to mark them as foreign for their enhanced uptake and elimination by phagocytes. Although complement has been traditionally thought to act in combating infectious agents, there has been an increased appreciation for its role in the removal of apoptotic cells. Throughout the course of apoptosis, the composition of a cell’s outer membrane changes, such that they gain the capacity to bind to complement proteins, marking them for uptake by phagocytes.
For many years, it was believed that certain organs are sites of immune privilege—free of inflammation and immune cells, including phagocytes. Too much uncontrolled inflammation can cause permanent damage to the tissues surrounding the inflamed location. Immune privilege was believed to be an evolutionary adaptation that added an extra layer of protection to critical sites, such as the brain, to prevent organ failure. Recently, the converged studies of neurological and immunological research have brought to light the intricate relationship between these two organ systems, revealing that, in fact, the brain is not a site of immune privilege. In fact, although neuroimmunological research is still in its adolescent stages, it has shown that the immune system plays a heavy role in the development, regulation, and maintenance of the nervous system, particularly of the brain.
Between birth and the onset of puberty, neurons undergo a process called synaptic pruning, or the targeted elimination of the structures that allow neurons to communicate to each other using electrical and chemical signals. Targeted pruning and apoptosis eliminate imperfect neuronal connections and those unnecessary for an adult organism, allowing for the maturation of neuronal circuitry. In complete opposition to the idea that the brain is immune privileged, both of these processes rely on brain-specific phagocytes, called microglia, to eliminate the unwanted synapses and dying cells.
Apoptotic neurons are marked, for the most part, the classic “eat me” signals that are traditionally associated with dying cells, mostly processes that are driven by the cell itself. The “eat me” signals of synapses were a bit more surprising. A finding made nearly a decade ago showed that complement proteins are deposited on synapses during synaptic pruning, targeting them for elimination by the microglia. This finding was unexpected, as it was one of the first papers showing the importance of the complement system in neuronal development. It also emphasized the extent of the complex relationship between the nervous and immune systems. The cells of the immune system provide an invaluable service in the proper maturation of the brain; however, growing research in neuroimmunology has revealed an unfortunate side effect of having immune cells involved heavily in the nervous system.
Scientific and anecdotal evidence has shown for centuries that the immune system loses its strength throughout aging, not only working less effectively, but also working in a less targeted manner, increasing the chance of immunopathology, or damage done to an organism by its own immune system. Immunopathology is caused when the immune cells of an organism begin to attack ‘self’ cells and molecules. Many aging-associated diseases are now believed to be driven, at least to some extent, by the loss of control of the immune system—including neurodegenerative diseases. For example, Alzheimer’s and Parkinson’s diseases have both been linked to increased and mistargeted neuroinflammation. Both have also been associated with elevation of complement proteins and inappropriate loss of mature synapses, as well as the loss of proper function of microglial cells, the phagocytic cells of the brain. Biomedical research has begun to explore how to target neuroinflammation in patients, in an attempt to target the source of the disease, as opposed to current medications, which predominantly work to alleviate symptoms.
Fascinatingly, psychiatric diseases, diagnosed in significantly younger patients than most neurodegenerative diseases, have been increasingly linked to increased neuroinflammation as well. Schizophrenia is a serious psychotic disorder affecting a patient’s cognition, behavior, and perception. Its age of onset is, on average, 18 in men and 25 in women, much younger ages than most neurodegenerative diseases associated with aging. Although there is a strong heritability associated with schizophrenia, the specific genes involved in the disease, and the mechanism by which they do this, has for a long time been only speculative and correlative. In 2011, a Scandinavian study linked complement control-related genes to the heritability of schizophrenia. These genes are involved in regulating the level of complement activity. The study found that schizophrenic patients were more likely to have variants of these genes that were unable to control the level of complement proteins, such that, those patients would have increased levels of complement proteins in their brains. This research, however, was correlative, looking only at the genetics of the patients.
A paper published a few months ago, however, sought to find whether this correlation, and other correlations with similar findings found by other labs, had a biological basis. The authors looked at the presence of complement proteins in human patients with schizophrenia. They first confirmed other groups’ findings that there is a correlation of increased complement activity and schizophrenia. Further, they found that the genetic correlation also manifested in an increase in complement protein expression in the brains of schizophrenic patients. Human complement proteins localized specifically to neuronal synapses and neurons. In mice, they found that the same complement proteins found to be highly elevated in their human patients were responsible for synaptic pruning and neural development. Schizophrenia, as well has other psychiatric diseases, is an incredibly difficult disease to replicate in mice, making it difficult to definitively prove that complement-mediated synaptic pruning and neuron elimination by microglia is the major mechanism driving disease. However, the evidence for this has only been increasing.
Millions of years of evolution have driven our neuronal and immune systems to be dependent on each other. Unfortunately, as regulated as these systems are, imperfections in their regulation can lead to many diseases. Neuroimmunology research is a quickly expanding field working to explore the relationship between these two fields to find new and innovative ways to treat not only neurodegenerative diseases, but also psychiatric diseases, both of which that have been surprisingly linked to a loss of immune regulation.