Neuro Immune Interactions In Neurologic And Psychiatric Disorders

The idea that the brain is an "immune-privileged site" has perhaps served to slow our realization that the intact brain can generate its own inflammatory reactions. These responses can be to peripheral infection, or they can arise from local, internal causes, for instance as a response to stress or to the se vere changes in neuronal activity in seizure or the loss of oxygen in stroke. We are also becoming increasingly aware of the contribution of local inflam matory reactions to certain neurodegenerative diseases such as Alzheimer's In fact, evidence is accumulating that inflammatory processes disease (AD). contribute to the progression of AD, suggesting the possibility of using cur rently available or novel anti-inflammatory agents to interfere with this terri ble disease. Correlations are also being made between inflammatory signs and mental illness, which is a new frontier of research. This book presents the current state of knowledge in a variety of areas relevant to neuro-immune interactions, with particular attention to AD.

It is now well appreciated that the immune system, in addition to its traditional role in defending the organism against pathogens, communicate in a well-organized fashion with the brain to maintain homeostasis and regulate a set of neural functions. Perturbation in this brain-immune interactions due to inflammatory responses may lead to psychiatric and neurological disorders. Microglia are one of the essential cells involved in the brain-immune interactions. Microglial cells are now not simply regarded as resident tissue macrophages in the brain. These cells are derived from myeloid progenitor cells in the yolk sac in early gestation, travel to the brain parenchyma and interact actively with neurons during the critical period of neurogenesis. Microglia provide a trophic support to developing neurons and take part in the neural wiring through the activity-dependent synapse elimination via direct neuron-microglia interactions. Altered microglial functions including changes in the gene expression due to early life inflammatory events or psychological and environmental stressors can be causally related to neurodevelopmental diseases and mental health disorders. This type of alterations in the neural functions can occur in the absence of infiltration of inflammatory cells in the brain parenchyma or leptomeninges. In this sense, the pathogenetic state underlying a significant part of psychiatric and neurological diseases may be similar to “para-inflammation”, an intermediate state between homeostatic and classical inflammatory states as defined by Ruslan Medzhitov (Nature 454:428-35, 2008). Therefore, it is important to study how systemic inflammation affects brain health and how local peripheral inflammation induces changes in the brain microenvironment. Chronic pain is also induced by disturbance in otherwise well-organized multisystem interplay comprising of reciprocal neural, endocrine and immune interactions. Especially, early-life insults including exposure to immune challenges can alter the neuroanatomical components of nociception, which induces altered pain response later in life. Recently the discrete roles of microglia and blood monocyte-derived macrophages are being defined. The distinction may be further highlighted by disorders in which the brain parenchymal tissue is damaged. Therefore, studies investigating the dynamics of immune cells in traumatic brain injury and neurotropic viral infections including human immunodeficiency virus, etc. as well as neurodegenerative diseases such as amyotrophic lateral sclerosis are promising to clarify the interplay between the central nervous and immune systems. The understanding of the histological architecture providing the infrastructure of such neuro-immune interplay is also essential. This Frontiers research topic brings together fourteen articles and aims to create a platform for researchers in the field of psychoneuroimmunology to share the recent theories, hypotheses and future perspectives regarding open questions on the mechanisms of cell-cell interactions with chemical mediators among the nervous, immune and endocrine systems. We hope that this platform would reveal the relevance of the studies on multisystem interactions to enhance the understanding of the mechanisms underlying a wide variety of neurological and psychiatric disorders.

Increasing evidence indicates that inflammatory cells and immunological cytokines can enter into the brain and modulate a number of biological and cognitive functions. Under physiological conditions, only a few immune cells, such as: macrophages, lymphocytes and dendritic cells can cross the blood-brain barrier and gain access to neural tissue. For many years, these findings supported the notion that the brain was an immunologically privileged organ. To date, increasing evidence strongly challenges this conjecture. In fact, neuroinflammation triggers a significant infiltration of immune cells into the cerebral parenchyma. The infiltration of inflammatory cells is accompanied by the release of a number of cytokines that target neurons, astrocytes and microglia. This interaction between the immune system and the central nervous system modulates many cerebral functions, such as: neural remodelling, synaptic plasticity, neurotransmitter releasing, stress-associated response, cognitive and mental disease progression, and others. The book summarises the latest discoveries, from basic to clinical science, regarding the interactions between the immunological mediators and the neural tissue under physiological and pathological conditions. In this book, it is discussed the influence of immune cells and cytokines in neural-regulated systems. Herein, the readers can find comprehensive descriptions in diverse fields, such as: lipids and obesity, neuronal activity, neurotransmission, stress pathogenesis, rheumatologic diseases, spinal cord injuries, regulation of neural stem cells, neural control of reproduction, and others. To ensure that most of readers obtain clear and complete information, all chapters have been written by prominent experts in their respective fields, who explain these topics with a very accessible language. In summary, this book represents a highly-updated compendium about the interactions between the central nervous system and the immune system that could be very useful for undergraduate students, postgraduate students, academic educators or trainers, basic science researchers and clinical physicians.

The nervous system plays an important role in the regulation of immunity and inflammation. On the other hand unbalanced immune responses in inflammatory and autoimmune conditions may have a deleterious impact on neuronal integrity and brain function. Recent studies have characterized neural pathways communicating peripheral inflammatory signals to the CNS, and brain- and spinal cord-derived circuitries controlling various innate and adaptive immune responses and inflammation. A prototypical neural reflex circuit that regulates immunity and inflammation is the vagus nerve-based “inflammatory reflex”. Ongoing research has revealed cellular and molecular mechanisms underlying these neural circuits and indicated new therapeutic approaches in inflammatory and autoimmune disorders. Pharmacological and bioelectronic modulation of neural circuitry has been successfully explored in preclinical settings of sepsis, arthritis, inflammatory bowel disease, obesity-driven disorders, diabetes and other diseases. These studies paved the way to successful clinical trials with bioelectronic neuronal modulation in rheumatoid arthritis and inflammatory bowel disease. Dysregulated release of cytokines and other inflammatory molecules may have a severe impact on brain function. Brain inflammation (neuroinflammation), imbalances in brain neuronal integrity and neurotransmitter systems, and cognitive impairment are characteristic features of post-operative conditions, sepsis, liver diseases, diabetes and other disorders characterized by immune and metabolic dysregulation. Derangements in cytokine release also play a pivotal role in depression. Characteristic brain reactive antibodies in autoimmune conditions, including systemic lupus erythematosus and neuromyelitis optica, significantly contribute to brain pathology and cognitive impairment. These studies, and the simultaneous characterization of neuro-protective cytokines, identified new therapeutic approaches for treating neurological complications in inflammatory and autoimmune disorders. This Frontiers Research Topic is a forum for publishing research findings and methodological and conceptual advances at the intersection of immunology and neuroscience. We hope that presenting new insight into bi-directional neuro-immune communication in inflammation and autoimmunity will foster further collaborations and facilitate the development of new efficient therapeutic strategies.

For many years, the immune and central nervous systems were thought to function independently with little or no interaction between the two. This view has und- gone dramatic changes over the past three decades. Indeed, we now know that there exists various feedback loops between the brain and immune systems that impact signi cantly upon different behavioral processes, including normal behavior and mental disorders. Pioneering efforts in generating this change were initiated by a number of early investigators. Included were those whose efforts were directed at establishing neuroimmune connections as well as others whose research focused upon the relationship between immunity, cytokines, and behavior. This book brings together outstanding scientists and clinicians who have made major contributions to the rapidly developing eld investigating the relationship between immunity and behavior. The book is divided into three parts. The rst part describes pathways by which the brain and immune systems communicate and int- act with each other. In the chapter “Cytokines and the Blood–Brain Barrier” p- vides insight into interactions between the blood–brain barrier and cytokines. Such interactions underlie basic communication between the immune system and brain that are present in normal as well as in disease conditions. In the chapter “Neu- chemical and Endocrine Responses to Immune Activation: The Role of Cytokines,” the neurochemical and endocrine consequences of immune challenge and cytokine administration on central neurotransmitter activity are discussed.

Recent studies have provided clear evidence on the role of neural-immune interactions in normal brain function and neuropathological conditions. Neuroimmune factors, which play an essential role in neuroinflammatory response, have been implicated in the regulation of neuronal function and plasticity. Thus, neural-immune interactions provide a new frame work for understanding the role of the neuroimmune system in normal brain function, neurodevelopment, and a variety of neurological disorders. These advances have a far reaching impact on many areas of neuroscience, including alcohol research. Studies using human alcoholic brains, gene knockout mice, and gene expression profiling have established a clear link between alcoholism and an altered neuroimmune profile. This book integrates emerging knowledge on neural-immune interactions with key discoveries in alcohol research and provides a comprehensive overview of neural-immune interactions in brain function and behavior associated with alcohol use disorders. While Neural–Immune Interaction in Brain Function and Alcohol Related Disorders focuses on neural-immune interactions in areas directly related to alcohol use disorders, it is not intended to be all inclusive. Several areas, including sleep disorders, pain, and cholinergic anti-inflammatory pathways, are not covered as independent chapters but briefly mentioned in the text. The close relevance of these topics to neural-immune interactions and alcohol use disorders warrants future discussion and more research efforts.

In this volume, international experts critically review cutting-edge advances in neuroprogression research. The relevance of these findings to psychiatric and neurological disorders is clarified. Potential etiopathological mechanisms of neuroprogression are described in detail. Special emphasis is placed on the role of the immune system in stress and stress-related disorders and brain-immune interactions. The epigenetic consequences of adverse experiences in early childhood, which may prelude major psychiatric disorders, are also considered. Recent research has not only provided evidence of neuroprogression in psychiatric and neurological disorders, but has shown that pharmacologic interventions have the potential to arrest this process. Advances in testing and imaging will lead to timely diagnosis and earlier treatment. Identification of neurological mechanisms alongside (epi-)genetic vulnerability markers will create truly personalized treatment programs. This book is a valuable resource for everyone who wishes to gain insight into the essential features of the neuroprogressive course of major psychiatric and neurological disorders. In particular, psychiatrists, neuroscientists and neurologists ¬ as well as immunologists, pharmacologists and molecular biologists - will find very informative chapters of direct relevance to their field.

It is now well appreciated that the immune system, in addition to its traditional role in defending the organism against pathogens, communicate in a well-organized fashion with the brain to maintain homeostasis and regulate a set of neural functions. Perturbation in this brain-immune interactions due to inflammatory responses may lead to psychiatric and neurological disorders. Microglia are one of the essential cells involved in the brain-immune interactions. Microglial cells are now not simply regarded as resident tissue macrophages in the brain. These cells are derived from myeloid progenitor cells in the yolk sac in early gestation, travel to the brain parenchyma and interact actively with neurons during the critical period of neurogenesis. Microglia provide a trophic support to developing neurons and take part in the neural wiring through the activity-dependent synapse elimination via direct neuron-microglia interactions. Altered microglial functions including changes in the gene expression due to early life inflammatory events or psychological and environmental stressors can be causally related to neurodevelopmental diseases and mental health disorders. This type of alterations in the neural functions can occur in the absence of infiltration of inflammatory cells in the brain parenchyma or leptomeninges. In this sense, the pathogenetic state underlying a significant part of psychiatric and neurological diseases may be similar to "para-inflammation", an intermediate state between homeostatic and classical inflammatory states as defined by Ruslan Medzhitov (Nature 454:428-35, 2008). Therefore, it is important to study how systemic inflammation affects brain health and how local peripheral inflammation induces changes in the brain microenvironment. Chronic pain is also induced by disturbance in otherwise well-organized multisystem interplay comprising of reciprocal neural, endocrine and immune interactions. Especially, early-life insults including exposure to immune challenges can alter the neuroanatomical components of nociception, which induces altered pain response later in life. Recently the discrete roles of microglia and blood monocyte-derived macrophages are being defined. The distinction may be further highlighted by disorders in which the brain parenchymal tissue is damaged. Therefore, studies investigating the dynamics of immune cells in traumatic brain injury and neurotropic viral infections including human immunodeficiency virus, etc. as well as neurodegenerative diseases such as amyotrophic lateral sclerosis are promising to clarify the interplay between the central nervous and immune systems. The understanding of the histological architecture providing the infrastructure of such neuro-immune interplay is also essential. This Frontiers research topic brings together fourteen articles and aims to create a platform for researchers in the field of psychoneuroimmunology to share the recent theories, hypotheses and future perspectives regarding open questions on the mechanisms of cell-cell interactions with chemical mediators among the nervous, immune and endocrine systems. We hope that this platform would reveal the relevance of the studies on multisystem interactions to enhance the understanding of the mechanisms underlying a wide variety of neurological and psychiatric disorders.