The functional anatomy of organisms is maintained by the coordination of different systems, that often rely on particular interactions between specialized cells and between macromolecules. The immune system works with the circulatory and the lymphatic systems to protect most of the organs. However, some organs are considered immune privileged due to the presence of highly selective and regulated barriers, such as the blood-brain barrier (BBB) within the brain. The BBB controls periphery-brain molecule exchange and prevents immune effector cells from entering the homeostatic brain. BBB-associated elements, such as endothelial cells, pericytes, astrocytes, and microglia, potentially can function as antigen-presenting cells (APC). Pathological scenarios that induce dysfunction of the BBB and its associated cells may lead to the infiltration of lymphocytes crossing over from the blood to brain. Similarly, traumas can also enable B and T lymphocytes to pass bidirectionally between the CNS and the periphery, via the meningeal lymphatic vessels which drain into the cervical lymph nodes. Research in animals and in humans has revealed that B and T cells are involved in the progression of neurological diseases. It has been showed that under particular conditions, T cells establish themselves and become resident in the brain (T RM cells), from where they can either exert beneficial or detrimental effects on brain function. Amazing efforts have been made to further comprehend interactions between brain-specific cells and peripheral immune cells, and especially their roles and impact on the onset, progression, and eventual resolution of diverse brain pathologies.

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.

Immunology has developed quite impressively over the past decade and perhaps very few fields in medicine or biology have grown so explosively. Completely new fields have been elucidated in depth. We recall only the definition of the nature and function of RLA antigens at the molecular level. the chemical and functional identification of several cytokines. and the correlation to particular immunological functions of specific epitopes present on cellular mem branes. The extensive application of immunological techniques and concepts to the neurological sciences has led to the development of neuroimmunology. a disci pline in its infancy until few years ago. In these last years. neuroimmunology has developed researches in various fields. RLA antigens were studied at the cellular level in brain samples and in CSF cells in several diseases. Cytokines. such as interleukin 1 and 2. gamma- and alpha-interferons. and tumor necrosis factor alpha. were studied at the immunohistological level and with quantitative methods in serum and CSF. With these data. new relevant insights were obtained on the molecular mechanisms underlying CNS immunological diseases. Moreover. neuroimmunological researches were carried on through the development of new and more 'specific' technologies for the study of natural and experimental diseases. the most important of which seem to be. at present. the techniques of cell cultures for cell lines specific to the CNS (oligodendrocytes. astroglia. microglia. meningeal cells. brain capillary cells and tumor cells).

Experimental and clinical evidence demonstrates an intense crosstalk among the nervous, endocrine and immune systems. The central nervous system (CNS) not only has the capacity to affect peripheral immune function, but is also able to sense and process signals from the peripheral immune system. The bi-directional interaction between the CNS and the peripheral immune system has gained great interest as it can help better understand disease pathophysiology as well as improving health and treatment outcomes in patients. On the one hand, inflammatory factors are known to affect CNS functions and to induce neuropsychiatric symptoms, making immune-to-brain communication highly relevant for psychiatric diseases and their treatments. On the other hand, analyzing pathways of brain-to-immune communication will help to understand the pathophysiology of chronic inflammatory disorders and will form the basis for optimizing treatment of these diseases.

Accumulating evidence reveals both local and peripheral immune systems participated in the pathophysiology changes of acute and chronic neurological diseases. Immune cell activation facilitates inflammatory response in neurological diseases such as stroke, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. The immune response initiated by brain local cells (microglia and astrocytes) and peripheral blood cells (monocytes/macrophages, neutrophil, T cells, B cells), are now commonly thought to contribute “double-edged sword” effects to the progression of neurological diseases, which not only promoting repair and recovery, but also accelerating brain injury. Meanwhile, local and peripheral immune responses have complex crosstalk in the development of post-stroke injury and neurodegeneration disease.

Neuroimmunology is a rapidly-growing branch of biomedical science that studies of all aspects of the interactions between the immune system and nervous system. It deals with, among other things, the physiological functioning of the neuroimmune system in states of both health and disease; malfunctions of the neuroimmune system in disorders (autoimmune diseases, hypersensitivities, immune deficiency), the physical, chemical and physiological characteristics of the components of the neuroimmune system in vitro, in situ, and in vivo. Despite the brain's status as an immune privileged site, an extensive bi-directional communication takes place between the nervous and the immune system in both health and disease. Immune cells and neuroimmune molecules such as cytokines, chemokines, and growth factors modulate brain function through multiple signalling pathways throughout the lifespan. Immunological, physiological and psychological stressors engage cytokines and other immune molecules as mediators of interactions with neuroendocrine, neuropeptide, and neurotransmitter systems. For example, brain cytokine levels increase following stress exposure, while treatments designed to alleviate stress reverse this effect. This book presents leading research in the 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.