Neuroimmunology

NEUROIMMUNOLOGY

Immune regulation of neuroendocrine function :

neuroimmunology : immune reactions in the brain (see also CSF sampling and normal CSF constituents )

lack of intratechal class-switch recombination from IgM to IgG

cytokines are expressed in areas of the brain, e.g. glia, neurons, and macrophages, and play a role in both neuronal cell death and survival. CNS to blood efflux of cytokines has also been shown to occur, but the mechanism of passage is unclear.
peripheral blood-borne cytokines can ...

pass the blood-brain barrier (BBB) at leaky points, for example at the organum vasculosum lamina terminalis (OVLT) or median eminence. They may be actively transported across the BBB in small amounts. Saturable transport systems from blood to the CNS have been described for IL-1a, IL-1b, IL-1ra , IL-6 , and TNF-a. Blood-borne cytokines have been shown to cross the BBB to enter cerebrospinal fluid and interstitial fluid spaces of the brain and spinal cord. IL-2 does not cross the BBB by a saturable transport system. The blood-to-brain uptakes of IL-1a, IL-1b, and IL-1ra are interrelated for most brain sites, but the posterior division of the septum shows selective uptake of blood-borne IL-1a. The saturable transport systems for IL-6 and TNF-a are distinguishable from each other and from the IL-1 systems. The amount of blood-borne cytokines entering the brain is modest but comparable to that of other water-soluble compounds, such as morphine, known to cross the BBB in sufficient amounts to affect brain function.
rapidly signal the CNS through the vagus nerve.

Neuroendocrine regulation of immune function : is essential for survival during stress or infection and to modulate immune responses in inflammatory disease.

clickable summary of neuroendocrine regulation of immune system
autoimmune diseases are more prevalent in females than in males, whereas males have higher mortality associated with infectious diseases. After the onset of puberty, female mice showed a higher expression of adaptive immune response genes, while males had a higher expression of innate immune genes in splenocytes, suggesting a requirement for sex hormones. Using in vivo and in vitro assays in normal and mutant mouse strains, we found that reverse signalling through FasL was directly influenced by estrogen, with downstream consequences of increased CD8⁺T cell-derived B cell help (via cytokines) and enhanced immunoglobulin production. Sexual dimorphism in innate and adaptive immune genes is dependent on puberty and estrogen influences immunoglobulin levels in post-pubertal female mice via the Fas-FasL pathway^ref.
the pineal gland lies outside the BBB and has been studied extensively in recent years for its immuno-regulatory function^{ref1,
ref2, ref3,
ref4}. The gland secretes a potent hormone, melatonin, that tends to stimulate the immune system and its production of cytokines^{ref1,
ref2, ref3,
ref4}. Because the pineal gland's neuroendocrine functions are closely linked to the 24-hour light:dark cycle (Klein DC: Circadian rhythms in the pineal gland; In Endocrine rhythms. Edited by: Krieger DT. New York, Raven Press; 1979:203-223), these pineal-immune interactions are also thought to have a temporal component. Evidence for effects of the pineal gland on photoperiodic changes in the immune system has been collected in both birds and mammals^{ref1,
ref2, ref3,
ref4}. Interactions between the neuroendocrine and immune systems presume that feedback mechanisms are present from one system to the other via immune soluble factors. Antigenic stimulation^ref, inflammation^ref and treatment with cytokines^ref (Mucha S ZKZMSJSH, Zarek-Melen G, Swietoslowski J, Stiepen H: Effect of interleukin-1 on in vivo melatonin secretion by the pineal gland in rats.Edited by: Maestroni GJM CA Reiter RJ. , John Libbey and Co.; 1992:177-18) have all been shown to modulate the neuroendocrine functions of the gland, although the cellular and molecular mechanisms of this feedback are still poorly understood. One cell population in the pineal gland that has been implicated as mediators of these immune effects on pinealocyte functions are the microglia/macrophages. These cells regulate pinealocyte neurite length and serotonin content in an invitro system and they upregulate cytokine expression, MHC class II and other surface antigens in response to cytokines and bacterial wall components^ref1,
ref2 (Tsai SY, McNulty JA: Interleukin-1b expression in the pineal gland of the rat; J Pineal Res 1999, 1:42-48). Feedback of the immune system on the pineal gland is further indicated by reports of accumulations of lymphocytes in the pineal of both avian and mammalian species^{ref1,
ref2, ref3,
ref4, ref5,
ref6, ref7}. In some species such as the chicken, these accumulations of lymphocytes account for up to 30% of the total volume of the gland^ref. The large size of this pineal-associated lymphoid tissue (PALT) and the extent of lymphocyte infiltration suggest novel mechanisms of neuro-immune interactions in this part of the brain. The presence of PALT raises several important questions regarding the mechanisms of interactions between lymphocytes and the pineal gland, including effects on circadian rhythms in both the immune system and the pineal gland. To date, there are no studies on possible changes in the composition and distribution of lymphocytes in the pineal over a light: dark cycle. The phenotypes and distribution of lymphocytes in the chicken pineal gland have been characterized, and it has been shown that lymphocyte subsets vary over the 24-h light: dark cycle^ref.
interesting experimental evidences :

noradrenergic sympathetic nerve fibers run from the CNS to primary and secondary lymphoid organs, such as the thymus, spleen, and lymph nodes. These nerve terminals make synaptic like connections with neighboring immune cells releasing noradrenalin. The most important receptor receptor in terms of the immune system is the b₂-AR . Expression of a- and b-ARs on T and B lymphocytes, neutrophils, mononuclear cells, and NK cells has been described.
HPA axis

short bursts of stress (such as public speaking, which induce the 'flight or fight’ response, enhanced natural immunity) boost the immune system, and only chronic stress (such as becoming permanently disabled) is associated with global immunosuppression. These stress-related changes in immune function are more likely to affect the elderly and sick.
acute (2h) stress experienced before primary or secondary antigen exposure induces a significant mobilization of leukocytes from the blood to the skin, significantly enhancing skin DTH. Just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges which may be imposed by a stressor. Adrenalectomy eliminates the stress-induced enhancement of DTH.
chronic stimulation of the hormonal stress response (e.g. caregivers of Alzheimer's patients, students taking exams, couples during marital conflict, Army Rangers undergoing extreme exercise and stress) is associated with

significant suppression of leukocyte mobilization, suppressing skin DTH.
enhanced susceptibility to viral infection
prolonged wound healing
decreased antibody production after vaccination
angry men are 70% more likely to develop gum disease than chilled-out ones. Anger prompts the release of stress hormones, which dampen the immune system and can encourage gum inflammation. Guys with one or more close friends are less stressed and lower their risk of the disease^ref.

many animal models exist in which a blunted HPA axis response has been associated with susceptibility to autoimmune/inflammatory disease

obese strain (OS) chicken as a model for autoimmune thyroiditis
certain mouse SLE models
the inbred rat strains

Lewis (LEW/N), with a hypoactive HPA axis
Fischer (F344/N), with a hyperactive HPA axis

in situations where there is an excess of glucocorticoid production, e.g. animals models with a hyperactive HPA axis or in women in the third trimester of pregnancy, there is a relative resistence to T_h1-associated autoimmune diseases .
sleep is often considered a state of the brain that improves immune function, although overall evidence for this notion is presently weak^ref1,
ref2 (Born J. Sleep and immune functions. In: Schedlowski M, Tewes U, eds. Psychoneuroimmunology. New York: Kluwer, Plenum Publishers, 1999: 417–42). Indirect evidence for this view derives from findings suggesting that sleep facilitates the extravasation of (certain types of) WBC, and increases the production of T-cell-derived cytokines such as IL-2, which are central for the development of an adaptive immune response^ref1,
ref2. However, those data do not directly prove a positive influence of sleep on host defense as launched by acute infection. The antibody response to vaccination represents a straightforward model for testing in vivo immune responses under experimental conditions in humans. Previous studies have indicated reduced antibody titers in response to hepatitis A vaccine and an influenza vaccine in subjects exposed to acute or chronic stressors^ref1,
ref2. However, effects of sleep on specific antibody formation after immunization so far have not been examined in humans. Also, only a few animal studies have addressed this issue using an influenza challenge^{ref1,
ref2,
ref3}. However, none of these studies focused on an examination of the primary response to antigen challenge, determining the generation of immunological long-term memories^ref1,
ref2. The present study aimed at showing in humans for the first time that in comparison with a night of sleep deprivation, regular nocturnal sleep after primary vaccination (with hepatitis A antigen) enhances antibody titers measured 4 weeks later^ref. Brown et al.^ref observed in vaccinated mice a decreased antibody titer and virus clearance to a secondary influenza challenge, when this was followed by sleep deprivation. However, two further trials attempting to demonstrate similar effects of sleep deprivation on secondary antibody responses to influenza infection in mice failed^ref1,
ref2. Although these discrepancies highlight the complexity of sleep/immune interactions in which factors such as timing of sleep, the route of vaccine administration, and inherent features of the antigen may eventually determine the response amplitude, it should be noted that all those previous animal studies focused on influences of sleep on aspects of the secondary immune response. In contrast, the present data in humans revealing a sleep-induced increase in anti-HAV titers provide first evidence that sleep supports the emergence of a primary adaptive immune response. Sleep might in particular ease the induction of immunological memories, rather than the recall of maintained memories^ref1,
ref2 (Born J. Sleep and immune functions. In: Schedlowski M, Tewes U, eds. Psychoneuroimmunology. New York: Kluwer, Plenum Publishers, 1999: 417–42) . Mounting of a specific antibody response is a multistep, cascade-like process. At an initial stage, cells processing and presenting the antigen like macrophages/monocytes, dendritic cells, and neutrophils interact with T and B cells in a specific environment of cytokines to stimulate lymphocytic differentiation and eventually antibody secretion by plasma cells^ref1,
ref2. These processes take place to a great extent in secondary lymphoid tissues and are relatively slow, taking several days. Because the wake period in the sleep deprivation condition only covered the first 36 hours after vaccination, it presumably influenced the development of the specific antibody response at a rather early stage. Indicators reflecting these early steps of antibody response were not measured here. Notably, however, previous experiments in humans not challenged by vaccination showed that sleep as compared with sleep deprivation enhances the T-cell production of IL-2, a most powerful activator of T- and B-cell differentiation^ref. Also, the reduced counts for WBC subsets in circulating blood observed during sleep in other studies^ref1,
ref2 as well as here (for neutrophils and activated T cells expressing HLA–DR) could point to an increased extravasation of these cells that may eventually support acute immune processes in the tissue^ref. That sleep affects the specific host defense via an influence on cell migration has been recently proposed based on animal data^ref. However, the effects of sleep on circulating immune cells after vaccination were mild in comparison with the profound sleep-induced alterations of endocrine activity. These included an increased release of GH, prolactin, and dopamine, and a diminished release of TSH, norepinephrine, and epinephrine. Although blood sampling frequency was kept low because of the long study period of 48 hours, which weakens reliability of the measurements, the major effects of sleep deprivation versus sleep on hormonal secretion shown in previous studies appeared to be reproduced. Although the hormonal regulation of specific immune defense is extremely complex^ref1,
ref2, it is likely that some of these endocrine changes contributed relevantly to the mechanisms mediating the immediate effects of sleep on anti-HAV titers. Although they are not obligate immunoregulators, both GH and prolactin have been proven to exert profound stimulating influences on various aspects of adaptive immune processes including the in vivo production of antibodies^{ref1,
ref2,
ref3,
ref4,
ref5}. Both GH and prolactin also share distinct augmenting effects on specific T-cell function, especially on the T-helper subsets^{ref1,
ref2,
ref3}. Additive facilitating influences on cell trafficking and viral defense might originate from the increase in dopamine concentration developing after regular sleep^ref1,
ref2. The relevance of the sleep-induced decreases in the concentration of TSH, norepinephrine, and epinephrine is less clear. Depending on the dose and experimental model used, for all of these hormones increasing as well as suppressing influences on aspects of adaptive immunity and antibody formation have been reported, and extrapolations to the conditions in healthy humans are presently not justified^{ref1,
ref2,
ref3}. The pattern of hormonal changes argues against the view that acute stress during the wake condition reduced antibody formation. Foregoing studies in humans indicated that acute as well as chronic stressors can reduce the antibody titer response to hepatitis A vaccine or an influenza vaccine, and this was ascribed to increased release of glucocorticoids and catecholamines^ref1,
ref2. However, in the present study, the increase in cortisol concentration during the nocturnal vigil was negligible and remained nonsignificant. Concentrations of norepinephrine and epinephrine, although enhanced during nighttime wakefulness, were still distinctly lower than during daytime wakefulness, and were by far lower than those typically associated with an acute stress response during the wake phase. Moreover, except for increased tiredness, assessment of self-reported mood (in the morning after experimental nights) did not provide evidence of increased feelings of strain in the wake condition, making a significant contribution of stress unlikely. Overall, our data show that sleep orchestrates a coordinate pattern of neuroendocrine changes that could provide the decisive signal enhancing adaptive immune processes in secondary lymphoid tissue. Which of the humoral factors is most critical and whether sleep at a later stage of an emerging immune response acts differently, remain to be examined. The present data of reduced antibody formation after sleep deprivation also point to a link between poor sleep and clinically relevant decreases in immunoresponsiveness to vaccines^ref. Results suggest that sleep should be considered an essential factor contributing to the success of vaccination^ref.

psychoneuroimmunology (PNI) emerged in the neurosciences in the late 1970s to early 1980s and has extended to influence the fields of psychology, psychiatry, endocrinology, physiology, and the biomedical research community.

individuals with high comparative levels of activation of the right-hand side of the prefrontal cortex of the brain (at baseline and in response to a negative-emotion-inducing task) experience more intense negative emotions and are more likely to suffer from depression . These individuals produce lower antibody titres in response to an influenza vaccination. Antibody titres are also correlated with the eye-blink response to a task that induces negative emotions. Individuals with a larger eye-blink response (which indicates stronger negative emotion) produce lower antibody titres in response to vaccination.

Web resources

Neuroimmune network at COPE
Psychoneuroimmunology by Chen Hao
Psychoneuroimmunology Research
Pyschoneuroimmunology Research at the Institute of Psychology, Aurhus University.
Simonton Cancer Center : mind-body cancer treatment.
Wellness Support Programme : cancer support
Associations

PsychoNeuroImmunology Research Society (PNIRS)
Neuro Immuno Therapeutics Research Foundation (NITRF)

Bibliography

NeuroImmune Biology by E.Berczi and R.M.Gorozynski [free introduction]

Journals

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