Ikezu Tsuneya, Gendelman Howard E. (eds.) Neuroimmune Pharmacology

2nd ed. — Springer, 2017. — 1045 p. — ISBN: 978-3-319-44020-0.In the past three decades, enormous strides have been made in our understanding of the relationships between inflammation, immune responses, and degenerative human diseases. Neuroinflammation has grown from a tiny beginning to its current status as the largest field of brain research. Its growth continues to be rapid so this dominance will continue to expand. The field commenced with the obscure identification of activated microglia in the brains of Alzheimer’s disease cases. A grant application of ours to the Canadian government to explore the ramifications of this finding was turned down with the terse comment: “This hypothesis is ridiculous!”
To grasp the dimensions of growth in tis field, and to gain a perspective of future opportunities, today’s neuroscientists only need to read this volume from cover to cover. The developing information has mostly appeared in specialty journals that have dealt only with isolated aspects of these tightly related fields. As a result, contemporary scientists have had a difficult time finding sources, even in review articles, that provide an integrated picture. This updated volume, by assembling chapters that demonstrate the relationship between these historically separated fields, overcome that difficulty. There are 56 chapters which cover a broad spectrum of topics on immunology of the nervous system. Included are diseases that result from immunological dysfunction, current therapeutic approaches, and prospects for the future. Overall, it integrates cutting-edge neuroscience, immunology, pharmacology, neurogenetics, neurogenesis, gene therapy, adjuvant therapy, nanomedicine, pharmacogenetics, biomarkers, proteomics, and magnetic resonance imaging. It is a rich harvest and readers will gain a perspective that has not previously been so readily available. Exposure to such a wealth of ideas is bound to inspire readers to undertake new and productive research initiatives.
The modern era of research into neuroinflammation and its relationship to neurodegenerative diseases began in the 1960s with the elaboration by Ralph van Furth of the monocyte phagocytic system. He injected labeled monocytes into animals and followed their migration and maturation into resident phagocytes in all body tissues. This provided a closure between Metchnikoff’s 1882 discovery of mesodermal attack cells in starfish larvae, which he named phagocytes, and del Rio Hortega’s 1919 discovery of phagocytic mesodermal cells entering the brain, which he named microglia. Hortega’s results had always been questioned, and for more than two further decades, the controversy continued as to whether microglia were truly phagocytes of mesodermal origin or were merely typical brain cells of epidermal origin. Resolving the controversy required development of the techniques of immunohistochemistry and monoclonal antibody production. These tools for exploring brain biochemistry at the cellular level opened new vistas for understanding brain functioning and the pathogenesis of human disease. Using these tools, our laboratory and that of Joseph Rogers in Sun City at that time demonstrated that HLA-DR was strongly expressed on activated microglia. The identification of HLA-DR, a well-known leukocyte marker displayed by antigen-presenting cells, on these cells vindicated both Hortega and van Furth. The way was paved for many productive investigations exploring the properties of microglial cells and their relationship to inflammation and immune responses. This example of a conjunction between a fundamental concept and technical advances to establish its validity has been repeated many times since, as the chapters in this volume illustrate.
For a time, the concept that the brain is immunologically privileged held sway among neuroscientists.
This was based on a narrow view that only the invasion of brain by lymphocytes could be taken as evidence of an inflammatory response. But immunohistochemistry, coupled with newly developed molecular biological techniques, revealed that a spectrum of inflammatory mediators, including many known to cause tissue damage, was produced within the brain by resident brain cells. These discoveries required entirely new interpretations as to the nature of neuroinflammation and its relationship to immune responses. The innate immune system, operating at the local level in brain, has clearly proved to be the first line of defense. Indeed, the basic discoveries from studying the response of the brain in a variety of neurological diseases are causing a reevaluation of a number of peripheral degenerative disorders where innate immune responses, which had previously been ignored, have been shown to play a critical role in their pathogenesis. In other words, those studying the brain are providing immunologists with revolutionary new concepts regarding classical peripheral diseases. The insights of this volume need to be interpreted in this broader context.
Major neurologic disorders and details of their pathobiology are presented as individual chapters. They involve disorders where innate immune responses predominate, as in Alzheimer’s disease, to others such as multiple sclerosis, where adaptive immune responses predominate, and others which seem to involve both. We have suggested that diseases involving self-damage generated by innate immune responses be defined as autotoxic to differentiate them from classical autoimmune diseases where self-damage is generated by adaptive immune responses. The common theme, however, is the involvement of microglia as the effector cells. Genetics is well covered. It is a rapidly moving field. The methodology for linking familial disease to DNA mutations commenced in the late 1970s through identification of restriction fragment-linked polymorphisms. By 1983, when James Gusella and his colleagues demonstrated a linkage of the G8 fragment to Huntington disease, only about 18 markers were known. Now over 1,500,000 single-nucleotide polymorphisms have been localized so that every centimorgan of the human genome can be explored. This advance has been coupled with rapid methods for sequencing DNA. The report on genetics must be regarded as the tiny tip of a giant iceberg where much below the surface will soon be revealed.
The ultimate objective of neuroscientists studying human disease is to find more effective treatments. Part 3 covers the pharmacology of existing drugs, as well as describing approaches now in clinical evaluation, and those still at the bench level. Some of these include concepts that depart from established therapeutic approaches, giving the reader much food for thought.
There is an important chapter on the new field of biomarkers. Biomarkers have established that neurodegenerative disorders such as Alzheimer’s disease commence at least a decade before clinical signs develop. A window of opportunity is opened up where early anti-inflammatory intervention can arrest disease progression and abort disease development. This can be combined with brain imaging to measure objectively the effects of therapeutic agents in diseases where progressive brain degeneration occurs.
In summary, this is a volume not to be put on the shelf as a reference text, but to be read cover to cover by aspiring neuroscientists.