Neuroimmunology
Encyclopedia
Neuroimmunology is a field combining neuroscience
, the study of the nervous system
, and immunology
, the study of the immune system
. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology
. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including but not limited to the physiological functioning of the two systems in both health
and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.
, behavior
, sleep
, and mood
can be affected by pro-inflammatory cytokine
s which are released by activated macrophages and monocytes during infection. Within the central nervous system
production of cytokines has been detected as a result of brain injury, during viral
and bacterial infections, and in neurodegenerative processes.
From the US National Institute of Health:
"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 signaling 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.
"Neuroinflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurological disorders such as stroke, Parkinson's and Alzheimer's disease, multiple sclerosis
, pain
, and AIDS-associated dementia
. However, cytokine
s and chemokine
s also modulate CNS function in the absence of overt immunological, physiological, or psychological challenges. For example, cytokines and cytokine receptor inhibitors affect cognitive and emotional processes. Recent evidence suggests that immune molecules modulate brain systems differently across the lifespan. Cytokines and chemokines regulate neurotrophins and other molecules critical to neurodevelopmental processes, and exposure to certain neuroimmune challenges early in life affects brain development. In adults, cytokines and chemokines affect synaptic
plasticity and other ongoing neural processes, which may change in aging brains. Finally, interactions of immune molecules with the hypothalamic-pituitary-gonadal system indicate that sex differences are a significant factor determining the impact of neuroimmune influences on brain function and behavior."
Recent research demonstrates that reduction of lymphocyte populations can impair cognition in mice, and that restoration of lymphocytes restores cognitive abilities.
, neuronal and network plasticity and homeostasis, senescence
, the etiology
of diverse neurological diseases and neural regenerative processes. This new study is leading to the discovery of environmental stressors that dictate initiation of specific neurological disorders and specific disease biomarkers. The goal of this is to “promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous
regional neural stem cells .” Understanding epigenetic medicine is important to understanding possible future pharmacological treatments. Many of the immediate gaps in knowledge
are attributed to basic lack of understanding of gene expression
and regulation and are thus the limiting factors for creating advanced treatments or cures to many diseases. To better understand these processes, neuroimmunological experiments are being created and tested to once and for all amass a more complete anthology
of knowledge pertaining to the complex interactions between the nervous and immune systems along with that of gene expression. While some disorders may affect the nervous and immune systems independently of one another, it is impossible to truly understand neuroimmnulogical science without a complex understanding of how each system works independently and also how they work together.
, traumatic brain injury
, communication
, speech and language disorders, genetic disorders such as fragile-X syndrome, Down syndrome
, epilepsy
, and fetal alcohol syndrome
. Studies have shown that autism spectrum disorders (ASDs) may in fact be due to basic disorders of epigenetic regulation . Other neuroimmunological research has shown that deregulation of correlated epigenetic processes in ASDs can alter gene expression and brain function without causing classical genetic lesions which are more easily attributable to a cause and effect relationship . These findings are some of the numerous recent discoveries in previously unknown areas of gene misexpression.
. Throughout development and adult life, the immune system detects and responds to changes in cell identity and neural connectivity . Deregulation of both adaptive and acquired immune responses, impairment of crosstalk between these two systems, as well as alterations in the deployment of innate immune mechanisms can predispose the central nervous system (CNS) to autoimmunity and neurodegeneration . Other evidence has shown that development and deployment of the innate and acquired immune systems in response to stressors on functional integrity of cellular and systemic level and the evolution of autoimmunity are mediated by epigenetic mechanisms . Autoimmunity has been increasingly linked to targeted deregulation of epigenetic mechanisms, and therefore, use of epigenetic therapeutic agents may help reverse complex pathogenic processes . Multiple sclerosis
(MS) is one type of neuroimmunological disorder that affects many people. MS features CNS inflammation, immune-mediated demyelination and neurodegeneration, and may represent an emerging class of epigenetic disorders .
Basic understanding of neuroimmunological diseases has changed significantly during the last ten years. New data broadening the understanding of new treatment concepts has been obtained for a large number of neuroimmunological diseases, none more so than multiple sclerosis, since many efforts have been undertaken recently to clarify the complexity of pathomechanisms of this disease. Accumulating evidence from animal studies suggests that some aspects of depression and fatigue in MS may be linked to inflammatory markers .
Research into the link between smell, depressive behavior, and autoimmunity has turned up interesting findings including the facts that inflammation is common in all of the diseases analyzed, depressive symptoms appear early in the course of most diseases, smell impairment is also apparent early in the development of neurological conditions, and all of the diseases involved the amygdale and hippocampus. Better understanding of how the immune system functions and what factors contribute to responses are being heavily investigated along with the aforementioned coincidences.
(Written for the highly technical reader)
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
, the study of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, and immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
, the study of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including but not limited to the physiological functioning of the two systems in both health
Health
Health is the level of functional or metabolic efficiency of a living being. In humans, it is the general condition of a person's mind, body and spirit, usually meaning to be free from illness, injury or pain...
and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.
Background
Neural targets that control thermogenesisThermogenesis
Thermogenesis is the process of heat production in organisms. It occurs mostly in warm-blooded animals, but a few species of thermogenic plants exist.-Types:...
, behavior
Behavior
Behavior or behaviour refers to the actions and mannerisms made by organisms, systems, or artificial entities in conjunction with its environment, which includes the other systems or organisms around as well as the physical environment...
, sleep
Sleep
Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
, and mood
Mood (psychology)
A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event....
can be affected by pro-inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s which are released by activated macrophages and monocytes during infection. Within the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
production of cytokines has been detected as a result of brain injury, during viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
and bacterial infections, and in neurodegenerative processes.
From the US National Institute of Health:
"Despite the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
's status as an immune privileged site, an extensive bi-directional communication takes place between the nervous and the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
in both health and disease. Immune cells and neuroimmune molecules such as cytokines, chemokines, and growth factors modulate brain function through multiple signaling pathways throughout the lifespan. Immunological, physiological and psychological stressors engage cytokines and other immune molecules as mediators of interactions with neuroendocrine, neuropeptide, and neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
systems. For example, brain cytokine levels increase following stress exposure, while treatments designed to alleviate stress
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
reverse this effect.
"Neuroinflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurological disorders such as stroke, Parkinson's and Alzheimer's disease, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, and AIDS-associated dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. However, cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s also modulate CNS function in the absence of overt immunological, physiological, or psychological challenges. For example, cytokines and cytokine receptor inhibitors affect cognitive and emotional processes. Recent evidence suggests that immune molecules modulate brain systems differently across the lifespan. Cytokines and chemokines regulate neurotrophins and other molecules critical to neurodevelopmental processes, and exposure to certain neuroimmune challenges early in life affects brain development. In adults, cytokines and chemokines affect synaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
plasticity and other ongoing neural processes, which may change in aging brains. Finally, interactions of immune molecules with the hypothalamic-pituitary-gonadal system indicate that sex differences are a significant factor determining the impact of neuroimmune influences on brain function and behavior."
Recent research demonstrates that reduction of lymphocyte populations can impair cognition in mice, and that restoration of lymphocytes restores cognitive abilities.
Overview
Epigenetic medicine encompasses a new branch of neuroimmunology that studies the brain and behavior. This new branch has already provided unique insights into the mechanisms underlying brain development, evolutionEvolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
, neuronal and network plasticity and homeostasis, senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
, the etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
of diverse neurological diseases and neural regenerative processes. This new study is leading to the discovery of environmental stressors that dictate initiation of specific neurological disorders and specific disease biomarkers. The goal of this is to “promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
regional neural stem cells .” Understanding epigenetic medicine is important to understanding possible future pharmacological treatments. Many of the immediate gaps in knowledge
Knowledge
Knowledge is a familiarity with someone or something unknown, which can include information, facts, descriptions, or skills acquired through experience or education. It can refer to the theoretical or practical understanding of a subject...
are attributed to basic lack of understanding of gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
and regulation and are thus the limiting factors for creating advanced treatments or cures to many diseases. To better understand these processes, neuroimmunological experiments are being created and tested to once and for all amass a more complete anthology
Anthology
An anthology is a collection of literary works chosen by the compiler. It may be a collection of poems, short stories, plays, songs, or excerpts...
of knowledge pertaining to the complex interactions between the nervous and immune systems along with that of gene expression. While some disorders may affect the nervous and immune systems independently of one another, it is impossible to truly understand neuroimmnulogical science without a complex understanding of how each system works independently and also how they work together.
Neural stem cell fate
Several studies have shown that regulation of stem cell maintenance and the subsequent fate determinations are quite complex. The complexity of determining the fate of a stem cell can be best understood by knowing the “circuitry employed to orchestrate stem cell maintenance and progressive neural fate decisions .” Neural fate decisions include the utilization of multiple neurotransmitter signal pathways along with the use of epigenetic regulators. The advancement of neuronal stem cell differentiation and glial fate decisions must be orchestrated timely to determine subtype specification and subsequent maturation processes including myelination .Neurodevelopmental disorders
Neurodevelopmental disorders result from impairments of growth and development of the brain and nervous system and lead to many disorders. Examples of these disorders include Asperger syndromeAsperger syndrome
Asperger's syndrome that is characterized by significant difficulties in social interaction, alongside restricted and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development...
, traumatic brain injury
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
, communication
Communication
Communication is the activity of conveying meaningful information. Communication requires a sender, a message, and an intended recipient, although the receiver need not be present or aware of the sender's intent to communicate at the time of communication; thus communication can occur across vast...
, speech and language disorders, genetic disorders such as fragile-X syndrome, Down syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, and fetal alcohol syndrome
Fetal alcohol syndrome
Fetal alcohol syndrome is a pattern of mental and physical defects that can develop in a fetus in association with high levels of alcohol consumption during pregnancy. Current research also implicates other lifestyle choices made by the prospective mother...
. Studies have shown that autism spectrum disorders (ASDs) may in fact be due to basic disorders of epigenetic regulation . Other neuroimmunological research has shown that deregulation of correlated epigenetic processes in ASDs can alter gene expression and brain function without causing classical genetic lesions which are more easily attributable to a cause and effect relationship . These findings are some of the numerous recent discoveries in previously unknown areas of gene misexpression.
Neurodegenerative disorders
Increasing evidence suggests that neurodegenerative diseases are mediated by erroneous epigenetic mechanisms. Neurodegenerative diseases include Huntington’s disease and Alzheimer’s disease. Neuroimmunological research into these diseases has yielded evidence including the absence of simple Mendelian inheritance patterns, global transcriptional dysregulation, multiple types of pathogenic RNA alterations, and many more . In one of the experiments, a treatment of Huntington’s disease with histone deacetylases (HDAC), an enzyme that removes acetyl groups from lysine, and DNA/RNA binding anthracylines that affect nucleosome positioning, showed positive effects on behavioral measures, neuroprotection, nuclesome remodeling, and associated chromatin dynamics . Another new finding on neurodegenerative diseases involves the overexpression of HDAC6 suppresses the neurodegenerative phenotype associated with Alzheimer’s disease pathology in associated animal models . Other findings show that additional mechanisms are responsible for the “underlying transcriptional and post-transcriptional dysregulation and complex chromatin abnormalities in Huntington’s disease .”Neuroimmunological disorders
The nervous and immune systems have many interactions that dictate overall body health. The nervous system is under constant monitoring from both the adaptive and innate immune systemInnate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
. Throughout development and adult life, the immune system detects and responds to changes in cell identity and neural connectivity . Deregulation of both adaptive and acquired immune responses, impairment of crosstalk between these two systems, as well as alterations in the deployment of innate immune mechanisms can predispose the central nervous system (CNS) to autoimmunity and neurodegeneration . Other evidence has shown that development and deployment of the innate and acquired immune systems in response to stressors on functional integrity of cellular and systemic level and the evolution of autoimmunity are mediated by epigenetic mechanisms . Autoimmunity has been increasingly linked to targeted deregulation of epigenetic mechanisms, and therefore, use of epigenetic therapeutic agents may help reverse complex pathogenic processes . Multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
(MS) is one type of neuroimmunological disorder that affects many people. MS features CNS inflammation, immune-mediated demyelination and neurodegeneration, and may represent an emerging class of epigenetic disorders .
Major themes of research
The interaction of the CNS and immune system are fairly well known. Burn-induced organ dysfunction using vagus nerve stimulation has been found to attenuate organ and serum cytokine levels. Burns generally induce abacterial cytokine generation and perhaps parasympathetic stimulation after burns would decrease cardiodepressive mediator generation. Multiple groups have produced experimental evidence that support proinflammatory cytokine production being the central element of the burn-induced stress response . Still other groups have shown that vagus nerve signaling has a prominent impact on various inflammatory pathologies. These studies have laid the groundwork for inquiries that vagus nerve stimulation may influence postburn immunological responses and thus can ultimately be used to limit organ damage and failure from burn induced stress.Basic understanding of neuroimmunological diseases has changed significantly during the last ten years. New data broadening the understanding of new treatment concepts has been obtained for a large number of neuroimmunological diseases, none more so than multiple sclerosis, since many efforts have been undertaken recently to clarify the complexity of pathomechanisms of this disease. Accumulating evidence from animal studies suggests that some aspects of depression and fatigue in MS may be linked to inflammatory markers .
Research into the link between smell, depressive behavior, and autoimmunity has turned up interesting findings including the facts that inflammation is common in all of the diseases analyzed, depressive symptoms appear early in the course of most diseases, smell impairment is also apparent early in the development of neurological conditions, and all of the diseases involved the amygdale and hippocampus. Better understanding of how the immune system functions and what factors contribute to responses are being heavily investigated along with the aforementioned coincidences.
Future directions
The nervous system and immune system require the appropriate degrees of cellular differentiation, organizational integrity, and neural network connectivity. These operational features of the brain and nervous system may make signaling difficult to duplicate in severely diseased scenarios. There are currently three classes of therapies that have been utilized in both animal models of disease and in human clinical trials. These three classes include DNA methylation inhibitors, HDAC inhibitors, and RNA-based approaches. DNA methylation inhibitors are used to activate previously silenced genes. HDACs are a class of enzymes that have a broad set of biochemical modifications and can affect DNA demethylation and synergy with other therapeutic agents. The final therapy includes using RNA-based approaches to enhance stability, specificity, and efficacy, especially in diseases that are caused by RNA alterations. Emerging concepts concerning the complexity and versatility of the epigenome may suggest ways to target genomewide cellular processes. Other studies suggest that eventual seminal regulator targets may be identified allowing with alterations to the massive epigenetic reprogramming during gametogenesis. Many future treatments may extend beyond being purely therapeutic and may in fact be determined to be preventative perhaps in the form of a vaccine. Newer high throughput technologies when combined with advances in imaging modalities such as in vivo optical nanotechnologies may give rise to even greater knowledge of genomic architecture, nuclear organization, and the interplay between the immune and nervous systems.See also
- Immune systemImmune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
- ImmunologyImmunologyImmunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
- Neural top down control of physiologyNeural top down control of physiologyNeural top down control of physiology concerns the direct regulation by the brain of physiological functions...
- Neuroimmune SystemNeuroimmune SystemBy definition the neuroimmune system is composed of the immune system and those components of the nervous system that modulate immune response. In practice, the neuroimmune system also includes hormonal signals and cytokines that participate in signalling between the immune and nervous...
- NeurologyNeurologyNeurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
- Psychosomatic illnessPsychosomatic illnessPsychosomatic medicine is an interdisciplinary medical field studying the relationships of social, psychological, and behavioral factors on bodily processes and well-being in humans and animals...
Further reading
(Written for the highly technical reader)
- Mind-Body Medicine: An Overview, US National Institutes of Health, Center for Complementary and Alternative Medicine
technical.
(Written for the general public)
External links
- Neuroimmunology, The Medical School, Birmingham University - Dr Abid Karim
- Neuroimmunolgy, McGill University
- Online Resources Psychoneuroimmunology, Neuroimmunomodulation
(6 chapters from this Cambridge UP book are freely available)] - More than 100, freely available, published research articles on neuroimmunology and related topics by Professor Michael P. Pender, Neuroimmunology Research Unit, The University of Queensland