While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production, and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.
Immune system
Melatonin
Melatonin | Immune system
An antiinflammatory effect seems to be the most relevant. An antiinflammatory effect seems to be the most relevant. While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant. It has an anti-inflammatory effect.
the primary high energy molecule in human metabolism is
user
Adenosine triphosphate (ATP)
assistant
what is catabolism?
user
It is the set of metabolic processes that breaks down large molecules.
assistant
which hormones are related to it?
user
Cortisol, glucagon, adrenaline, cytokines, orexin and melatonin.
assistant
what is the emotional response due to the third one?
user
Fear.
assistant
how does the first hormone related to metabolism of glucose?
user
Cortisol stimulates the synthesis of 'new' glucose from non-carbohydrate sources; this is known as gluconeogenesis..
assistant
is process resisted by insulin?
user
Yes.
assistant
when was this substance which resists the process discovered?
user
1921.
assistant
can it be extracted?
user
Yes.
assistant
from where?
user
Pancreas.
assistant
can we find in plants the last hormone in the list of hormones mentioned above?
user
Yes.
assistant
is it responsible for any memory related disease?
user
No.
assistant
how does it affect immune system?
user
While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production, and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.
Melatonin | Immune system
This increase in melatonin reduces the ability to learn and facilitate new memories. The ability for melatonin to suppress memory formation is very significant, however. The melatonin would work in conjunction with the LTD during slow oscillations during sleep, to keep individuals from potentiating unwanted, or unneeded, information from their day.
Metaplasticity | What else may be involved
The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep. Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep. When suffering from sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual.
Immune system | Sleep and rest
This milieu is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.
Immune system | Sleep and rest
In addition to the formed antibodies in the body there remains a small number of memory T and B cells that make up the cellular component of the immunological memory. They stay in the body in a resting state and at the second or next encounter with the same antigen these cells are able to respond immediately and eliminate the antigen. Memory cells have a long life and last up to several decades in the body. Immunity to chickenpox, measles, and some other diseases lasts a lifetime. Immunity to many diseases eventually wears off. The immune system's response to a few diseases, such as dengue, counterproductively makes the next infection worse (antibody-dependent enhancement).
Immunological memory | Development of immunological memory
Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. This increased production of IL-12 causes increased T-cell immune response.
Morphine | Effects on the immune system
When B cells and T cells are activated some become memory B cells and some memory T cells. Throughout the lifetime of an animal these memory cells form a database of effective B and T lymphocytes. Upon interaction with a previously encountered antigen, the appropriate memory cells are selected and activated. In this manner, the second and subsequent exposures to an antigen produce a stronger and faster immune response. This is "adaptive" in the sense that the body's immune system prepares itself for future challenges, but is "maladaptive" of course if the receptors are autoimmune. Immunological memory can be in the form of either "passive" short-term memory or "active" long-term memory.
Adaptive immune system | Immunological memory
Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and our circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation, shift work, etc. As a result, these disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma. In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both the innate and the adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine induce increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin.
Immune system | Sleep and rest
These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions such as immune cells activation, proliferation, and differentiation. It is during this time that undifferentiated, or less differentiated, like naïve and central memory T cells, peak (i.e. during a time of a slowly evolving adaptive immune response). In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) support the interactions between APCs and T-cells, a shift of the T1/T2 cytokine balance towards one that supports T1, an increase in overall T cell proliferation, and naïve T cell migration to lymph nodes.
Immune system | Sleep and rest
The circadian rhythm taking hold is responsible for the feeling of fatigue. Our body naturally starts to shut down, around the time that the sun starts to take its dip into the horizon. The primary chemical for this happening is melatonin, so it would seem natural to wonder if melatonin has some effect on learning and memory formation as well. Every animal that sleeps also exhibits some bodily concentration of melatonin. When studying the effects of sleepiness on fish, it was found that any significant amount of melatonin causes a "dramatic decrease" in learning and memory formation. This study was performed at night under bright lights, to inhibit the release of natural amounts of melatonin and learning behaviors were conducted.
Metaplasticity | What else may be involved
When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.
Immune system | Immunological memory
The pineal gland secretes the hormone melatonin "directly into the systemic circulation", thus melatonin is not affected by the blood-brain barrier.
Blood–brain barrier | Structure
Overnutrition is associated with diseases such as diabetes and obesity, which are known to affect immune function. More moderate malnutrition, as well as certain specific trace mineral and nutrient deficiencies, can also compromise the immune response. Foods rich in certain fatty acids may foster a healthy immune system. Likewise, fetal undernourishment can cause a lifelong impairment of the immune system.
Immune system | Nutrition and diet
Low-doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect, but instead appear to cause drowsiness for a longer period of time. Melatonin can cause nausea, next-day grogginess, and irritability. In the elderly, it can cause reduced blood flow and hypothermia. In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation. Melatonin can lower follicle-stimulating hormone levels. Melatonin's effects on human reproduction remain unclear.
Melatonin | Adverse effects
Inflammasomes are multiprotein complexes (consist of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1) that form in response to cytosolic PAMPs and DAMPs, whose function is to generate active forms of the inflammatory cytokines IL-1β and IL-18.
Immune system | Inflammasomes
Melatonin serves a variety of functions throughout the body. While its role in sleep promotion is its most well known, melatonin has its hands in a wide range of biological processes. In addition to sleep promotion, melatonin also regulates hormone secretion, rhythms in reproductive activity, immune functionality, and circadian rhythms. Further, melatonin functions as a neuroprotective, pain-reducer, tumor suppressor, reproduction stimulant, and antioxidant. Melatonin has an anti-excitatory effect on brain activity which is exemplified by its reduction of epileptic activity in children which is to say that it is an inhibitory transmitter. The functional diversity of the melatonin receptors contribute to the range of influence that melatonin has over various biological processes.
Melatonin receptor | General
Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally these are secondary, tertiary and other subsequent immune responses to the same antigen. Immunological memory is responsible for the adaptive component of the immune system, special T and B cells — the so-called memory T and B cells. Immunological memory is the basis of vaccination.
Immunological memory | Introduction
Remodeling of immune response and reduced ability to protect individuals from infectious diseases is observed in relation to age. Especially in the elderly, long-term CMV infection leads to a rapid increase the number of CMV-specific T cells. The number of CMV memory CD8 + T lymphocytes then predominate and the total number of available naïve T lymphocytes decrease. CD8+T cells form up to 50 % of all peripheral blood memory cells in HCV-positive elderly individuals. The same effect on the immune system has been described in herpes viruses and parvoviruses.
Memory T cell inflation | Immunosenescence
The neuro-immune system, and study of, comprises an understanding of the immune and neurological systems and the cross-regulatory impacts of their functions. Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Cytokines have also been implicated in the coordination between the nervous and immune systems. Instances of cytokine binding to neural receptors have been documented between the cytokine releasing immune cell IL-1 β and the neural receptor IL-1R. This binding results in an electrical impulse that creates the sensation of pain. Growing evidence suggests that auto-immune T-cells are involved in neurogenesis. Studies have shown that during times of adaptive immune system response, hippocampal neurogenesis is increased, and conversely that auto-immune T-cells and microglia are important for neurogenesis (and so memory and learning) in healthy adults.
Neuroimmune system | Cellular physiology
Other immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol, are dendritic cells, keratinocytes and macrophages. It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals. Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity. The age-related decline in immune function is also related to decreasing vitamin D levels in the elderly. As people age, two things happen that negatively affect their vitamin D levels. First, they stay indoors more due to decreased activity levels. This means that they get less sun and therefore produce less cholecalciferol via UVB radiation.
Immune system | Vitamin D
A 2016 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease. A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's it has little to no effect. Melatonin may, however, help with sundowning.
Melatonin | Dementia
Melatonin is discharged by the Pineal Gland as a neurohormone. Melatonin is a central hormone in the treatment of patients with Alzheimer’s disease as it adjusts sleep patterns that are abnormal, which occurs in over forty five percent of patients. Melatonin affects type 3 diabetes by reducing harm caused by beta amyloid, regulating hyperglycaemia and insulin resistance in patients with diabetes and stopping blood brain barrier disruption caused by hyperglycaemia. Through these processes, melatonin has been shown to lessen the progression of type 3 diabetes.
Type 3 diabetes | Melatonin administration
Non-specific immunity results in no immunologic memory. There are mechanical, chemical, and biological factors affecting the effectiveness and results of the non-specific immune response. These factors include the epithelial surfaces forming a physical barrier, fatty acids that inhibit the growth of bacteria, and the microflora of the gastrointestinal tract serving to prevent the colonization of pathogenic bacteria. The non-specific immune system involves cells to which antigens are not specific in regards to fighting infection. The non-specific immune cells mentioned above (macrophages, neutrophils, and dendritic cells) will be discussed regarding their immediate response to infection.
Nonspecific immune cell | Cells of the Innate Immune System
Wound healing has been shown to be affected by sleep. It has been shown that sleep deprivation affects the immune system. It is now possible to state that "sleep loss impairs immune function and immune challenge alters sleep," and it has been suggested that sleep increases white blood cell counts. A 2014 study found that depriving mice of sleep increased cancer growth and dampened the immune system's ability to control cancers. The effect of sleep duration on somatic growth is not completely known. One study recorded growth, height, and weight, as correlated to parent-reported time in bed in 305 children over a period of nine years (age 1–10).
Neuroscience of sleep | Restoration
Her lab has focused on two main mechanisms with which the immune system signals to and interacts with the central nervous system: the first is through leukocytes infiltrating the brain and the second is through cytokines and chemokines directly affecting neuronal function. Her lab has extensively explored how cytokines and chemokines affect blood brain barrier permeability and her lab has discovered a novel role for cytokines and chemokines in the regulation of blood-brain barrier permeability to arboviruses, and protective versus pathogenic leukocytes. For example, since West Nile Virus has been shown to cause significant brain damage leading to memory loss, Klein’s lab researches ways to prevent this from occurring.
Robyn S. Klein | Career and research
Immunological memory occurs after a primary immune response against the antigen. Immunological memory is thus created by each individual, after a previous initial exposure, to a potentially dangerous agent. The course of secondary immune response is similar to primary immune response. After the memory B cell recognizes the antigen it presents the peptide: MHC II complex to nearby effector T cells. That leads to activation of these cells and rapid proliferation of cells. After the primary immune response has disappeared, the effector cells of the immune response are eliminated. However, there remain antibodies previously created in the body that represent the humoral component of immunological memory and comprise an important defensive mechanism in subsequent infections.
Immunological memory | Development of immunological memory
The immune system then builds a memory of that antigen, which enables it to recognize the antigen quicker in the future and be able to combat it quicker and more efficiently. The more the system is exposed to the antigen, the quicker it will build up its responsiveness.
Immunopathology | Introduction
Adaptive (or acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination. Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms.
Immune system | Introduction
Naturally acquired active immunity occurs when a person is exposed to a live pathogen and develops a primary immune response, which leads to immunological memory. This type of immunity is "natural" because deliberate exposure does not induce it. Many disorders of immune system function can affect the formation of active immunity such as immunodeficiency (both acquired and congenital forms) and immunosuppression.
Immunity (medical) | Naturally acquired
A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive. A 2005 review of unblinded clinical trials found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.
Melatonin | Cancer
Thus, CD32B plays an important role in both antibody and memory immune responses. The balance between CD32B and its activating counterparts is crucial to appropriate cell function. Having too little CD32B has been associated with dysregulated antibody function, as well as increased antibody-dependent inflammatory cell responses. Some individuals inheriting mutated, inactivate CD32B genes have a reduced risk of contracting malaria; this is attributed to an enhancement of FcR-dependent phagocytic functions. CD32B imbalance is also associated with autoimmunity. CD32B-deficient mice have been found to be more susceptible to immune-complex-mediated autoimmunity. Likewise, systemic lupus erythematosus (SLE) in humans is associated with a decrease in CD32B on the surface of memory B cells.
CD32 | "CD32B"
Immune system undergoes profound changes during ageing. Adaptive immune response becomes less effective as lymphocyte numbers are reduced in the elderly. This is the result of the decline of generation of new naive T lymphocytes as a consequence of thymic involution. Furthermore, as we age T-lymphocyte population comprises more and more of memory cells at the expense of naive cells. While effectiveness of adaptive immune system declines, innate immune mechanisms become more active. This is represented by increased number of natural killer cells and increased production of pro-inflammatory cytokines. This chronic activation of innate immune system results in a low-grade chronic inflammation development in the elderly.
Inflammaging | Characteristics
Ader (a psychologist) and Cohen (an immunologist) directly tested this hypothesis by deliberately immunizing conditioned and unconditioned animals, exposing these and other control groups to the conditioned taste stimulus, and then measuring the amount of antibody produced. The highly reproducible results revealed that conditioned rats exposed to the conditioned stimulus were indeed immuno suppressed. In other words, a signal via the nervous system (taste) was affecting immune function. This was one of the first scientific experiments that demonstrated that the nervous system can affect the immune system. In the 1970s, Hugo Besedovsky, Adriana del Rey and Ernst Sorkin, working in Switzerland, reported multi-directional immune-neuro-endocrine interactions, since they show that not only the brain can influence immune processes but also the immune response itself can affect the brain and neuroendocrine mechanisms.
Psychoneuroimmunology | Origins
They found that the immune responses to innocuous antigens triggers an increase in the activity of hypothalamic neurons and hormonal and autonomic nerve responses that are relevant for immunoregulation and are integrated at brain levels (see review). On these bases, they proposed that the immune system acts as a sensorial receptor organ that, besides its peripheral effects, can communicate to the brain and associated neuro-endocrine structures its state of activity. These investigators also identified products from immune cells, later characterized as cytokines, that mediate this immune-brain communication (more references in ). In 1981, David L. Felten, then working at the Indiana University School of Medicine, discovered a network of nerves leading to blood vessels as well as cells of the immune system.
Psychoneuroimmunology | Origins
In humans there are two subtypes of melatonin receptors targeted by melatonin agonists, MT and MT. They are G protein-coupled receptors and are expressed in various tissues of the body, together or singly. MT receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus (SCN) of the hypothalamus, hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes.
Melatonin receptor agonist | Melatonin receptors
In epigenetics there are various mechanisms for cells to pass on "memories" of stressors to their progeny. Strategies include Msn2 nucleo-cytoplasmic shuttling, changes in chromatin, partitioning of anti-stress factors, and damaged macromolecules between mother and daughter cells. In adaptive immunity there is a functional CM that enables the immune system to learn to react to pathogens through mechanisms such as cytoxic memory mediation in bone marrow, innate immune memory in stromal cells, fungal mediation of innate and inherited immunological response, and T and B-cell immune training. In this regard CM is essential for vaccine and immunity research.
Body memory | Current usage and research
With normal aging comes a gradual diminishing of the body's immune system. This phenomenon called immunosenescence is largely due to a decline of T cell function, including the capacity for T cells to properly support germinal center responses. This may be in part due to lower CD40L levels on the cell surface of T cells in the aged.
Follicular B helper T cells | Controlling age-related immune decline
Mice without individual NF-κB proteins are deficient in B- and T-cell activation and proliferation, cytokine production and isotype switching. Mutations in RELA is found responsible for inflammatory bowel disease as well.
RELA | Role in immune system
Rapamycin has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but are not yet well understood.
Sirolimus | Effects on longevity
The phase response curve for melatonin is roughly twelve hours out of phase with the phase response curve for light. At spontaneous wake-up time, exogenous (externally administered) melatonin has a slight phase-delaying effect. The amount of phase-delay increases until about eight hours after wake-up time, when the effect swings abruptly from strong phase delay to strong phase advance. The phase-advance effect diminishes as the day goes on until it reaches zero about bedtime. From usual bedtime until wake-up time, exogenous melatonin has no effect on circadian phase. The human body produces its own (endogenous) melatonin starting about two hours before bedtime, provided the lighting is dim.
Phase response curve | Melatonin
One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection). This regulation of cytokines appear to occur via the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway.
Morphine | Effects on the immune system
Memory T cells undergo different changes and play different roles in different life stages for humans. At birth and early childhood, T cells in the peripheral blood are mainly naive T cells. Through frequent antigen exposure, the population of memory T cells accumulates. This is the memory generation stage, which lasts from birth to about 20-25 years old, when our immune system encounter the greatest number of new antigen. During the memory homeostasis stage that comes next, the number of memory T cells plateaus and is stabilized by homeostatic maintenance. At this stage, the immune response shifts more towards maintaining homeostasis since few new antigens are encountered.
Memory T cell | Lifetime overview
The authors also gave a drug to the fish to help block the effects of melatonin and then studied their behavioral patterns on memory formation and retrieval. It was found that in the daytime when melatonin was artificially administered, the fish's ability to learn new material was at its lowest. As one stays awake for a long time, so much extra potentiation has already happened from the waking day, and trying to force more LTP isn't going to help anything. Too much extra information is floating around, and the neurons can't handle all of the extra activity. In addition, however, as the night starts to loom, the circadian rhythm begins to take effect and the body naturally begins to release stores of melatonin.
Metaplasticity | What else may be involved
A key concept in the adaptive immune system, and the foundational science behind vaccines, is that some elements of the immune system recognizes antigens it has seen before in a process called as immunological memory. Dr. Blish and colleages have identified a potential mechanism through which NK cells may also display immune memory. This is unusual and shifts the accepted paradigm because NK cells are typically considered part of the innate immune system, not the adaptive immune system. Dr. Blish and colleagues demonstrate antigen-specific recognition, and memory of viruses and viral antigens by NK cells in mice and primates.
Catherine Blish | Natural Killer cell immune memory
Neural targets that control thermogenesis, behavior, sleep, and mood can be affected by pro-inflammatory cytokines 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.
Neuroimmunology | Background
The potential for immune memory may mean that the treatment effect is long-lasting (by contrast antibodies have a short half-life – that of Herceptin is only 12 days – meaning that the patient has to have infusions every 1–3 weeks). The vaccine would be available intra-muscularly, where Herceptin and Perjeta have to be given by regular infusions.
Imugene | HER-Vaxx
Melatonin was originally discovered by Aaron Lerner, a Yale dermatologist, and colleagues, who had hoped it could be used to treat vitiligo. Although melatonin did not prove to be relevant to dermatology treatments, it was quickly confirmed to be secreted by the pineal gland to affect the brain. Further research found that circadian melatonin rhythms persisted under constant darkness, which suggested that light alone is not responsible for the cycle of melatonin secretion. Rather, endogenous melatonin serves to internalize light cues, making melatonin responsible for modulating neuroendocrine functions. The suprachiasmatic nucleus, or SCN, is a small region within the anterior hypothalamus of the brain that is responsible for orienting the organism’s internal measurement of time to external time cues like daylight.
Chronobiotic | History
Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive. Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.
Immune system | Hormones
Therefore it is not subject to tolerance mechanisms of the immune system. Since the mutated gene product is only expressed in tumors, but not on healthy cells, neoepitopes may evoke vigorous T cell response.
Mutanome | Neoantigens and neoepitopes
They may include somnolence (sleepiness), headaches, nausea, diarrhea, abnormal dreams, irritability, nervousness, restlessness, insomnia, anxiety, migraine, lethargy, psychomotor hyperactivity, dizziness, hypertension, abdominal pain, heartburn, mouth ulcers, dry mouth, hyperbilirubinaemia, dermatitis, night sweats, pruritus, rash, dry skin, pain in the extremities, symptoms of menopause, chest pain, glycosuria (sugar in the urine), proteinuria (protein in the urine), abnormal liver function tests, increased weight, tiredness, mood swings, aggression and feeling hungover. Its use is not recommended during pregnancy or breastfeeding or for those with liver disease. In animals (including humans), melatonin is involved in synchronizing the circadian rhythm, including sleep–wake timing, blood pressure regulation, and seasonal reproduction.
Melatonin | Introduction
The test mice were also less able to recognize an object that had been moved from its previous location, showing a decrease in spatial reference memory. As in humans, there is a decrease in vision spatial task ability. Within the hippocampus (area of brain responsible for memory and learning), changes in gene expression occur, and infection presents a change in the pathways of immune cell functioning and antigen processing. It has been suggested that this possibly indicates an immune system response to the ACTV-1 virus causing inflammation which may be the cause for the cognitive impairments. The symptoms presented may also suggest hippocampus and medial prefrontal cortex interference from ACTV-1 infection.
Chlorovirus | Effects of infection
Immunosenescence refers to the gradual deterioration of the immune system brought on by natural age advancement. The adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory, especially by vaccination. This age-associated immune deficiency is ubiquitous and found in both long- and short-living species as a function of their age relative to life expectancy rather than chronological time. It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly. Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely repeat an evolutionary pattern and most of the parameters affected by immunosenescence appear to be under genetic control.
Immunosenescence | Introduction
Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response.
Neuroinflammation | Introduction
Activation of MT receptors mediates vasoconstriction and the activation of MT receptors mediates vasodilation. Melatonin is involved in regulating immune responses in both human and animals through activation of both MT and MT receptors. MT and MT receptors are widespread in the eye and are involved in regulating aqueous humor secretion, which is important for glaucoma, and in phototransduction. This is not a complete list since many of the possible processes need further confirmation.
Melatonin receptor agonist | Mechanism of action
Hoffmann noted many similarities between the immune system and the brain, including that: The analogy resulted in the discovery of a neural network in which neurons exhibit hysteresis and thus can learn without synaptic modification. He also discovered, with Davenport, a way to add hidden neurons to Hopfield neural networks and thus extend their associative memory capacity.
Geoffrey W. Hoffmann | Neural networks
There is also initial evidence that major depression and stress can alter the permeability of the blood-brain barrier, allowing substances which would normally not be able to pass through enter the brain, thereby increasing the ways peripheral inflammation can affect the brain. Once peripheral cytokines initially communicate the existence of inflammation outside of the CNS, microglia and astrocytes within the CNS are activated and release additional cytokines and chemokines, which then results in the production of neurotransmitters that can contribute to sickness behavior or depression. Although the possibility of maladptive outcomes due to dysregulation, this connection is largely thought to be adaptive due to the benefits of coordinating the CNS with broader immune processes and due to the role immune function in the brain has in facilitating learning and memory.
Depression and immune function | Link between symptoms
When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening. Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60 minutes of administration, and is then eliminated. Melatonin has a half life of 35–50 minutes. In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva. The bioavalibility of melatonin is between 10 and 50%.
Melatonin | Pharmacokinetics
Kellis, Li-Huei Tsai, and others at MIT used epigenomic markings in human and mouse brains to study the mechanisms leading to Alzheimer’s disease. They showed that immune cell activation and inflammation, which have long been associated with the condition, are not simply the result of neurodegeneration, as some researchers have argued. Rather, in mice engineered to develop Alzheimer’s-like symptoms, they found that immune cells start to change even before neural changes are observed
Manolis Kellis | Alzheimer's disease
In current research, the significant relationship between immune factors and hangover severity is the most convincing among all factors so far studied. An imbalance of the immune system, in particular of cytokine metabolism has been identified as playing a role in the pathophysiology of the hangover state. Especially the hangover symptoms nausea, headache, and fatigue have been suggested to be mediated by changes in the immune system. The concentration of several cytokines have been found to be significantly increased in the blood after alcohol consumption. These include interleukin 12 (IL-12), interferon gamma (IFNγ) and interleukin 10 (IL-10). Some pharmacological studies such as on tolfenamic acid and "Opuntia ficus-indica" (OFI) have also indicated an involvement of the immune system.
Hangover | Immune system
Memory T and memory B cells are also produced in the case that the same pathogen enters the organism again. If the organism does happen to become re-exposed to the same pathogen, the secondary immune response will kick in and the immune system will be able to respond in both a fast and strong manner because of the memory cells from the first exposure. Vaccines introduce a weakened, killed, or fragmented microorganism in order to evoke a primary immune response. This is so that in the case that an exposure to the real pathogen occurs, the body can rely on the secondary immune response to quickly defend against it.
Immune response | Introduction
This is caused by the measles virus wiping out parts of the body's immune system's memory. "Two months after the unvaccinated children recovered from measles, the team found that the virus had erased 11–73% of their antibodies against other bacteria and viruses. ...The kids who received the MMR vaccine showed no reduction in these antibodies."
Melanie's Marvelous Measles | The scientific data
Some viruses evade this by producing molecules which interfere with IFN production. For example, the Influenza A virus produces NS1 protein, which can bind to host and viral RNA, interact with immune signaling proteins or block their activation by ubiquitination, thus inhibiting type I IFN production. Influenza A also blocks protein kinase R activation and establishment of the antiviral state. The dengue virus also inhibits type I IFN production by blocking IRF-3 phosophorylation using NS2B3 protease complex.
Innate immune system | Viruses
According to this theory, the effector function of the immune response is mediated by the glycans (polysaccharides) displayed by the cells and humoral components of the immune system. Individuals with autoimmunity have alterations in their glycosylation profile such that a proinflammatory immune response is favored. It is further hypothesized that individual autoimmune diseases will have unique glycan signatures.
Autoimmune disease | Altered glycan theory
This exacerbates the inflammatory environment of the brain and contributes to chronic neuroinflammation and neurodegeneration.
Neuroinflammation | Peripheral immune response
Rolls has pioneered the use of CyTOF mass cytometry in the characterization of immune cell populations in the brain. She and her team recently characterized previously unknown populations of T, B, Dendritic, and NK Cells in the brain using this method and found that CD44 is a common marker of infiltrating immune cells. Using CyTOF analysis, Rolls and her team found that after sleep deprivation, B cells begin to infiltrate the brain parenchyma, highlighting the impacts of sleep deprivation on the immune environment in the brain.
Asya Rolls | Characterizing immune system in the brain
Another suggestion is that variation in neurotransmitter production or receptors may also play a role in one's risk of experiencing inflammation-based depression if certain combinations result in increased risk of inflammation, similarly putting them at risk of maladaptive changes in brain chemistry. However, findings that depression and pro-inflammatory responses do not require the presence of the other for one to develop have led others to argue that the two conditions are often distinct, something which has been suggested to reduce the explanation's appeal to psychiatrists.
Depression and immune function | From immune response
When memory helper T cells' CD4 receptors bind to the MHC class II molecules which are expressed on the surfaces of the target cells of the graft tissue, the memory helper T cells' T cell receptors (TCRs) can recognize their target antigen that is presented by the MHC class II molecules. The memory helper T cell subsequently produces clones that, as effector cells, secrete immune signalling molecules (cytokines) in approximately the cytokine balance that had prevailed at the memory helper T cell's priming to memorize the antigen. As the priming event in this instance occurred amid inflammation, the immune memory is pro-inflammatory.
Transplant rejection | Immune memory
Swain has investigated the cellular and molecular mechanisms by which CD4 T cells contribute to immunity. Her research topics include the function of T cell subsets at the effector stage; the generation of memory CD4 T cells and their role in protection against infection; and age-related defects in T cell function.
Susan L. Swain | Research
Immune priming is memory-like phenomenon described in invertebrate taxa of animals. It is evolutionary advantageous for an organism to develop a better and faster secondary immune response to pathogen, which is harmful and which it is likely to be exposed again. In vertebrates immune memory is based on adaptive immune cells called B and T lymphocytes, which provide an enhanced and faster immune response, when challenged with the same pathogen for a second time. It was assumed that invertebrates do not have memory-like immune functions, because of their lack of adaptive immunity. But in recent years evidence supporting innate memory-like functions were found.
Priming (immunology) | Immune priming (invertebrate immunity)
In 1986, Kelley developed a model to study the regulation of immune function based on the fact that the ability of animals and humans to withstand infections declines as they age. He reasoned that the decline in immune function might be directly correlated with the decline in the production and release of pituitary-derived growth hormone. His findings, published that year in the Proceedings of the National Academy of Sciences, demonstrated for the first time that the shrunken and atrophic key lymphoid organ, the thymus, could be rejuvenated by growth hormone. He subsequently showed that growth hormone overcomes a block in the development of T cells in the thymus gland of aged rats, allowing double negative immature thymocytes to complete growth and maturation.
Keith W. Kelley | Aging and decline of immune system function
In contrast to leukocytes which have monomeric Kv1.3 channels, macrophages have heterotetrameric Kv1.3/Kv1.5 channels. These heterotetramers plays a role in regulating the membrane potential of macrophages on different stages of macrophage activation by lymphocytes. Potassium channels are involved in leukocyte activation by calcium. The possible different conformations of these Kv1.3 and 1.5 complexes can affect the immune response. Margatoxin inhibits Kv1.3 channels, so no heterodimers can be formed. The effect of margatoxin is similar to the effect of DEX. DEX diminishes amount of K1.3 channels by binding to GC receptor, which leads to downregulating of expression of K1.3 channels. Both margatoxin and DEX lead to immune suppression.
Margatoxin | Immune system suppression
miR-155 is involved in immunity by playing key roles in modulating humoral and innate cell-mediated immune responses, for example, In miR-155 deficient mice, immunological-memory is impaired; making it fall prey to repetitive bouts of invasions by the same pathogen (Rodriguez et al. 2007), maturation and specificity of miR-155-deficient B-lymphocytes are impaired since the process relies on AID enzyme which has a miR-155 target in its 3′ UTR end. The phenotypic consequences involving deficiency of miR-155 in mice show later in life where the animals develop lung and intestinal lesions. Activated B and T cells show increased miR-155 expression, the same goes for macrophages and dendritic cells of the immune system.
MiR-155 | Immunity
Lewin's group has also studied immune reconstitution after antiretroviral treatment begins, exposing some of the factors associated with faster reconstitution and has demonstrated7 a link between immune reconstitution and variants in the IL-7R gene.
Sharon Lewin | Research and accomplishments
Because the TREX1 gene is identical in all of the cells in the body the ineffective enzyme allows the accumulation of “scrap” single strand DNA in all of the cells in the body. Eventually, the immune system has destroyed enough of the cells in the walls of the blood vessels that the capillaries burst open. The capillary bursting happens throughout the body but is most recognizable when it happens in the eyes and brain because these are the two places where capillary bursting has the most pronounced effect.
Autosomal dominant retinal vasculopathy with cerebral leukodystrophy | immune system becomes part of the condition
The "D. melanogaster" immune system can be divided into two responses: humoral and cell-mediated. The former is a systemic response mediated in large part through the "Toll" and "Imd" pathways, which are parallel systems for detecting microbes. Other pathways including the stress response pathways JAK-STAT and P38, nutritional signalling via FOXO, and JNK cell death signalling are all involved in key physiological responses to infection. "D. melanogaster" has a fat body, which is analogous to the human liver. The fat body is the primary secretory organ and produces key immune molecules upon infection, such as serine proteases and antimicrobial peptides (AMPs).
Drosophila melanogaster | Immunity
The symmetrical network theory has been developed with the assistance of mathematical modeling. In order to exhibit immune memory to any combination of a large number of different pathogens, the system has a large number of stable steady states. The system is also able to switch between steady states as has been observed experimentally. For example, low or high doses of an antigen can cause the system to switch to a suppressed state for the antigen, while intermediate doses can cause the induction of immunity.
Immune network theory | The symmetrical immune network theory
Several genes, proteins and enzymes have been extensively researched for their association with memory. Long-term memory, unlike short-term memory, is dependent upon the synthesis of new proteins. This occurs within the cellular body, and concerns the particular transmitters, receptors, and new synapse pathways that reinforce the communicative strength between neurons. The production of new proteins devoted to synapse reinforcement is triggered after the release of certain signaling substances (such as calcium within hippocampal neurons) in the cell. In the case of hippocampal cells, this release is dependent upon the expulsion of magnesium (a binding molecule) that is expelled after significant and repetitive synaptic signaling.
Memory | Genetic underpinnings
In the late 1990s, Associate Professor Brendon Coventry noticed that some of his patients responded better to a Melanoma vaccine than other patients despite receiving identical treatment. When local cancer tumours where injected with the vaccine, cancers that had not been injected began to shrink as well, thus indicating an immunogenic relationship. These observations led him to speculate that the immune system operates in a cyclical manner, with peaks and troughs. Operating on this theory, Coventry was able to increase complete response rates to treatment of advanced melanoma from 7% to 17% and without noticeable negative side effects to chemotherapy and radiotherapy.
Immune cycle | History
Lymphocytes generate the immune repertoire by recombining the genes encoding immunoglobulins and T cell receptors through V(D)J recombination. Although there are only a few of these genes, all their possible combinations can result in a wide variety of immune repertoire proteins. Through selection, cells with autoreactive proteins (and thus may cause autoimmunity) are removed, while cells that may actually detect an invading organism are kept. The immune repertoire is affected by several factors:
Immune repertoire | Development
An age-related decline in intestinal immune response is common in elderly people. This immunosenescence has been hypothesized to be due to impaired homing of lymphocytes to the Peyers' patches found in the gut. This process is not unique to humans and is documented in other animals including rhesus macaques and rats. Research has shown older rats had reduced expression of the key gut-specific homing receptors α4β7; and MadCAM-1. These older rats had 30% less α4β7; and 17% less MadCAM-1 than juvenile rat equivalents. Whilst no causative relationship has been proved to date, it is speculated that the reduced expression of the receptors is responsible for overall loss in immune response.
Gut-specific homing | Health concerns
Vitamin A is essential to maintain intact epithelial tissues as a physical barrier to infection; it is also involved in maintaining a number of immune cell types from both the innate and acquired immune systems. These include the lymphocytes (B-cells, T-cells, and natural killer cells), as well as many myelocytes (neutrophils, macrophages, and myeloid dendritic cells).
Retinol | Immune system
She found that microglia, the brain’s innate immune cells, accumulate around neurons at the site of infection and complement protein is also highly expressed at the site of infection. Klein also found that these microglia remain active long after infection clears leading to post-infection inflammation and further synapse loss. These findings signify increased neuronal pruning and destruction by microglia leading to memory loss in patients with West Nile Virus infections. Since inflammatory cues during infection regulate central nervous system repair via the regulation of neural stem cells, this is yet another mechanism that the Klein Lab probes to understand how viral infections and demyelinating diseases cause impaired learning and memory.
Robyn S. Klein | Career and research
Release of corticotropin-releasing hormone (CRH) from the hypothalamus is influenced by stress. Furthermore, stressors that enhance the release of CRH suppress the function of the immune system; conversely, stressors that depress CRH release potentiate immunity.
Psychoneuroimmunology | Corticotropin-releasing hormone (CRH)
Melatonin may therefore be involved in the drowsy state associated with the sopite syndrome.
Sopite syndrome | Biochemicals
She probed how diet effects immune infiltration into the brain since previous studies had showed that it might lead to compromised blood brain barrier function and increased immune cell infiltration into the CNS. Conversely, her findings showed that high fat high fructose diets did not increase peripheral trafficking of immune cells into the CNS. Tansey also explored the sex-specific effects of stress on neuro-immune reactivity and found that early life chronic stress led to increased neuro-immune reactivity but via different mechanisms in male versus female rats.
Malú G. Tansey | Chronic inflammation and neurodegeneration
In 1994, Reppert cloned human and sheep Mel melatonin receptor, the first in a family of GPCRs that bind the pineal hormone melatonin, and localized its expression in the mammalian brain to the SCN and the hypophyseal pars tuberalis. Mel is believed to be responsible for the circadian effects of melatonin and the reproductive actions in seasonal breeding mammals. In 1995, Reppert cloned and characterized the Mel melatonin receptor. He and colleagues found that the receptor was predominantly expressed in the retina, where it is believed to modify light-dependent retinal functions. They identified outbred populations of Siberian hamsters that lacked functional Mel but maintained circadian and reproductive responses to melatonin; these data indicate that Mel is not necessary for the circadian and reproductive actions of melatonin, which instead depend on Mel.
Steven M. Reppert | Mammalian melatonin receptors
Passive memory is usually short-term, lasting between a few days and several months. Newborn infants have had no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. "In utero", maternal IgG is transported directly across the placenta, so that, at birth, human babies have high levels of antibodies, with the same range of antigen specificities as their mother. Breast milk contains antibodies (mainly IgA) that are transferred to the gut of the infant, protecting against bacterial infections, until the newborn can synthesize its own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies: It only borrows them.
Adaptive immune system | Passive memory
Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and '80s, evidence suggesting that opioid drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV/AIDS) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system. The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system.
Morphine | Effects on the immune system
DNA vaccination generates an effective immune memory via the display of antigen-antibody complexes on follicular dendritic cells (FDC), which are potent B-cell stimulators. T-cells can be stimulated by similar, germinal centre dendritic cells. FDC are able to generate an immune memory because antibodies production “overlaps” long-term expression of antigen, allowing antigen-antibody immunocomplexes to form and be displayed by FDC.
DNA vaccination | Maintenance of immune response
In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei from retinal photosensitive ganglion cells of the eyes rather than the melatonin signal (as was once postulated). Known as "the hormone of darkness", the onset of melatonin at dusk promotes activity in nocturnal (night-active) animals and sleep in diurnal ones including humans. Many animals use the variation in duration of melatonin production each day as a seasonal clock. In animals including humans, the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter.
Melatonin | Other animals
Despite cancer cells causing increased inflammation and angiogenesis, they also appear to be able to avoid interaction with the body's immune system via a loss of interleukin-33 immune system. (See cancer immunology)
The Hallmarks of Cancer | Evading the immune system
The researcher, along with his team, also found nerves in the thymus and spleen terminating near clusters of lymphocytes, macrophages, and mast cells, all of which help control immune function. This discovery provided one of the first indications of how neuro-immune interaction occurs.
Psychoneuroimmunology | Origins
The CNS regulates the immune system through neuroendocrine pathways, such as the HPA axis. The HPA axis is responsible for modulating inflammatory responses that occur throughout the body. During an immune response, proinflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and can pass through the blood brain barrier where they can interact with the brain and activate the HPA axis. Interactions between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression, and mood changes. Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
Hypothalamic–pituitary–adrenal axis | Immune system
In general, active immunity is long-term and can be acquired by infection followed by B cell and T cell activation, or artificially acquired by vaccines, in a process called immunization.
Adaptive immune system | Active memory
Immune cells of both the Innate immune system and adaptive immune systems frequently express the α2, α5, α6, α7, α9, and α10 subunits of nicotinic acetylcholine receptors. Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of immune function.
Nicotine | Immune system
Subsequently, after 2 to 4 weeks its response declines. After the germinal center reaction the memory plasma cells are located in the bone marrow which is the main site of antibody production within the immunological memory.
Immunological memory | Memory B cells
The molecular mechanism behind neurokinin's role as a chemoattractor is currently unclear. Neurokinin A has an inhibitory effect on the formation of myeloid cells, and appear to be involved in one specific receptor since the effect can be completely abolished by a NK-2 receptor-selective antagonist. The inhibitory effect of neuronkinin A is countered by the excitatory effect of a structurally similar compound: substance P. The opposite effects on myelogenesis by substance P and neurokinin A may represent an important feedback mechanism for maintenance of homeostasis.
Neurokinin A | Immune system
Mycotoxins in general can either stimulate or suppress immune responses. Liu et al. (2010) investigated the role of CTN on nitric oxide (NO) production, a proinflamatory mediator, in MES-13 (glomerular mesangial cells from an SV40 transgenic mouse) cells. It has been found that endotoxin LPS and inflammatory mediators as IFN-γ, TNF-α and IL-1β can induce iNOS (NO synthesis enzyme) gene expression by activating transcription factors including NF-κB and STAT1a. When exposed to CTN the NO production reduced in a dose-responsive manner and this was not due to reduction in cell viability as still 95% of cells were alive while the NO production dropped with 20 or 40% for 15 and 25 μM.
Citrinin | Effect on immune response
In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.
Immune system | Tumor immunology
After the BBB breakdown, the immune-mediated attack against myelin happens. T cells, are a kind of lymphocyte that plays an important role in the body's defenses. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called "autoreactive lymphocytes". Demyelination, further inflammation and axonal transection are the result. The attack of myelin starts inflammatory processes, which triggers other immune cells and the release of soluble factors like cytokines and antibodies. Further breakdown of the blood–brain barrier, in turn cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.
Lesional demyelinations of the central nervous system | Immune mediated attack