The Basics of Neuroimmunology: Comparison
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Neuroimmunology is an interdisciplinary field that brings together knowledge from biology, immunology, chemistry, neurology, pathology, psychiatry, and virology to examine the intricate interrelations between the central nervous system (CNS) and immune system (IS), its interactions during various developmental stages, as well as maintaining homeostasis or responding to injuries. 

  • neuroimmunology
  • immune system
  • CNS

1. Definition and Overview

Neuroimmunology is an interdisciplinary field devoted to understanding the complex relationships and interactions between the nervous system (including the brain and spinal cord) and immune system (including antibodies and their targets) in maintaining equilibrium in our bodies and responding to infections, injuries, or diseases that affect these vital systems. Neuroimmunology offers an examination of this topic that spans numerous fields [4][1].
Multiple sclerosis (MS) is one of the most prevalent disabling neurological afflictions among young adults, typically appearing between 20 and 40 years of age.
MS is an autoimmune condition in which immune system cells, normally responsible for protecting against viruses, bacteria, and abnormal cells in the body, attack myelin in the central nervous system (brain, optic nerves, and spinal cord). Myelin acts as a protective substance by creating sheaths (myelin sheaths) around nerve fibers (axons).
MS is a chronic condition that varies considerably among its victims, from mild cases with limited disability to progressive decline leading to greater disability over time. Most commonly seen are intermittent symptoms surfacing followed by periods of relative quiescence or dormancy and then either partial or full recovery—MS is rarely fatal. Individuals diagnosed tend to have life expectancies comparable to the general population [5][2].

2. Key Players in Neuroimmunology: Cells and Molecules

As part of their shared response to environmental challenges, the nervous and immune systems have formed an interdependent communication mechanism between themselves in response to environmental challenges. Neurons exhibit various receptors found on immune cells, such as Toll-like receptors (TLRs) and inflammatory cytokine receptors found on immune cells; this allows immune cells to influence and regulate neuronal activity—for instance, using IL-1β to sensitize sensory neurons during inflammation while managing pain levels [6][3].
Immune cells are capable of sensing signals from neurons by expressing receptors for neurotransmitters and neuropeptides produced by neurons; for example, innate lymphoid cells express such receptors for neuropeptides as Calcitonin Gene-Related Peptide (CGRP) and Neuromedin U (NMU). This mutual sensing between immune cells and neurons has proved highly advantageous, decreasing costs related to dealing with certain insults and helping coordinate complex host responses more efficiently.
Furthermore, the microbiome—or collection of microorganisms that live inside your body—plays a key role in both neuronal activation and immune development. Immune cells and neurons both interact directly or indirectly with microbes present in the environment, making their composition key for shaping neuronal programming and maturation. In turn, this affects various aspects of intestinal physiology, including visceral pain management, gut motility regulation, and related functions. This interaction between the nervous system, immune system, and microbiome plays an intricate, evolutionary, beneficial process that plays its part in controlling host responses overall [7,8,9][4][5][6].

3. Neuroimmune Communication Pathways

Recent research has demonstrated that the peripheral immune system and nervous system can communicate effectively by using similar molecular signaling cues.
Veiga-Fernandes and Pachnis’ work presents the idea of an “enteric neuroimmune cell unit,” an internal sensory organ responsible for protecting and maintaining intestinal integrity and function. This enteric neuroimmune system plays an essential role in providing both innate defenses and memory responses against certain pathogens. During gestation, extracellular signals coordinate the development of enteric neuroprogenitor and hematopoietic cells, resulting in this complex network. Postnatal development of this system takes place through colonization with commensal microbes that colonize the gut, leading to mutual signals between neuronal–glial cells and tissue-resident immune cells that stimulate the maturation of an enteric neuroimmune system [10][7].
It is believed that gut microbiomes have an influence over peripheral immune cells and central nervous system (CNS)-residing cells, as well as having an influence over brain development and disease progression. They stress the role of commensal microbes in producing short-chain fatty acids and aryl hydrocarbon ligands that may alter glial cell development and function within the CNS. Neuroendocrine mediators produced through the hypothalamic–pituitary–adrenal axis can influence intestinal permeability, immune-cell activation, and the composition of gut microbiomes. Dysbiosis of microbiota has been observed in neurological and psychiatric conditions, suggesting it could contribute to their causes; however, more research needs to be conducted in order to uncover its exact nature and causal role.
Prinz and Priller examine how peripheral immune cells may enter the CNS under pathological circumstances. A healthy CNS does not normally contain blood-borne immune cells, as immune surveillance is provided by tissue-resident microglia, meningeal macrophages, and perivascular macrophages, which produce their own immunological mediators. In conditions like autoimmune diseases, infections, or injuries, where blood–brain barrier permeability changes, activated adaptive immune cells are allowed into CNS via fenestrated capillaries, contributing towards disease progression [11][8].
Engelhardt and colleagues investigate the CNS’s immunological advantages towards peripheral immune cells under normal circumstances, distinguishing between lymphatic drainage of cerebrospinal fluid that bathes meninges and cerebral ventricles from its lack of drainage in interstitial fluid bathing CNS parenchymal tissues, such as interstitial drainage. They provide a detailed anatomical account of both human and rodent brain barriers limiting access to CNS parenchyma, which prevent lymphatic drainage of cerebrospinal fluid from meninges/ventricles, while discussing both trafficking of cells/solutes through these barrier sites via their perivascular areas allowing lymphatic drainage or non-drainage channels [12][9].
Further research explores neurological impairments caused by acute infections caused by neurotropic pathogens. Acute infections trigger the release of pro-inflammatory cytokines by astrocytes, microglia, and leukocytes into the CNS from cells like astrocytes and microglia, which release these inflammatory agents into circulation, leading to potential effects on blood–brain barrier integrity as well as symptoms like fatigue, hypersomnia, cognitive difficulties, or chronic inflammation that persists beyond antimicrobial treatments such as treating pathogens like memory deficits, depression or mood disorders—raising questions regarding the involvement of immunological factors in different neurological diseases [13][10].

4. The Role of the Immune System in Maintaining Neuronal Health

The immune system plays a pivotal role in protecting and maintaining neuronal health in multiple ways. One mechanism by which it affects neuronal activity is through signaling molecules known as cytokines that control immune responses and may have an effect on neuronal activity—proinflammatory cytokines such as IL-1, IL-6, and TNFα are believed to trigger fever responses during infections by increasing body temperature to counter infection symptoms [14][11].
Immune cells become activated upon contact with infectious agents, producing proinflammatory cytokines, which then induce the production and release of prostaglandins in the brain—specifically PGE2. PGE2 plays an essential role here, acting on thermosensitive neurons in the hypothalamus to induce fever; specifically, its effect is known to activate thermosensitive neurons within this area and induce fever by inducing thermosensitivity responses from thermosensitive neurons. This then triggers further heat production via thermosensitive neurons within the liver, followed by a sustained phase by brain astrocyte production of IL-6, which further stimulates PGE2 production; all this action provides a sustained phase fever response [15][12].
Cytokines play a pivotal role in activating the hypothalamic–pituitary–adrenal (HPA) axis. When immune cells release cytokines in response to pathogens, PGE2 is produced within brain vasculature and interacts with catecholaminergic neurons before projecting onto corticotropin-releasing hormone-containing neurons of the hypothalamus; these send projections onto corticotropin-releasing hormone (CRH), leading to elevated levels of ACTH and corticosterone. Additionally, cytokines directly influence the pituitary gland to increase the release of ACTH. This complex process demonstrates just how powerfully these proteins exert diverse effects upon this part of our immune response as well as stress regulation mechanisms [16][13].
Longer exposure to cytokines may result in glucocorticoid resistance, making the body less responsive to their effects and diminishing their effects on homeostasis and stress responses. Resistance predominantly manifests itself at the level of the hippocampus and impairs regulation of the HPA axis, consequently compromising one’s ability to effectively respond to stressors and maintain homeostasis [17][14].
Communication between the immune and nervous systems, enabled by cytokines, plays an integral part in protecting neuronal health and orchestrating physiological responses during infections or inflammation events. A thorough understanding of these complex pathways is vital to unlocking their underlying mechanisms as well as their profound implications for overall health and disease development; such knowledge could pave the way for novel therapeutic interventions aimed at maintaining harmony between these vital systems for increased human wellbeing [14][11].

References

  1. Caldwell, L.J.; Subramaniam, S.; MacKenzie, G.; Shah, D.K. Maximising the potential of neuroimmunology. Brain Behav. Immun. 2020, 87, 189–192.
  2. Multiple Sclerosis. National Institute of Neurological Disorders and Stroke. Available online: https://www.ninds.nih.gov/health-information/disorders/multiple-sclerosis (accessed on 24 July 2023).
  3. Kraus, A.; Buckley, K.M.; Salinas, I. Sensing the world and its dangers: An evolutionary perspective in neuroimmunology. eLife 2021, 10, e66706.
  4. Aguilera-Lizarraga, J.; Florens, M.V.; Viola, M.F.; Jain, P.; Decraecker, L.; Appeltans, I.; Cuende-Estevez, M.; Fabre, N.; Van Beek, K.; Perna, E.; et al. Local immune response to food antigens drives meal-induced abdominal pain. Nature 2021, 590, 151–156.
  5. Binshtok, A.M.; Wang, H.; Zimmermann, K.; Amaya, F.; Vardeh, D.; Shi, L.; Brenner, G.J.; Ji, R.-R.; Bean, B.P.; Woolf, C.J.; et al. Nociceptors Are Interleukin-1β Sensors. J. Neurosci. 2008, 28, 14062–14073.
  6. Nagashima, H.; Mahlakõiv, T.; Shih, H.Y.; Davis, F.P.; Meylan, F.; Huang, Y.; Harrison, O.J.; Yao, C.; Mikami, Y.; Urban, J.F., Jr.; et al. Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation. Immunity 2019, 51, 682–695.e6.
  7. Veiga-Fernandes, H.; Pachnis, V. Neuroimmune regulation during intestinal development and homeostasis. Nat. Immunol. 2017, 18, 116–122.
  8. Prinz, M.; Priller, J. The role of peripheral immune cells in the CNS in steady state and disease. Nat. Neurosci. 2017, 20, 136–144.
  9. Engelhardt, B.; Vajkoczy, P.; Weller, R.O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 2017, 18, 123–131.
  10. Neuroimmune communication. Nat. Immunol. 2017, 18, 115.
  11. Dantzer, R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol. Rev. 2018, 98, 477–504.
  12. Besedovsky, H.; Sorkin, E.; Keller, M.; Müller, J. Changes in blood hormone levels during the immune response. Proc. Soc. Exp. Biol. Med. 1975, 150, 466–470.
  13. Besedovsky, H.; del Rey, A.; Sorkin, E.; Dinarello, C.A. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986, 233, 652–654.
  14. Pace, T.W.W.; Hu, F.; Miller, A.H. Cytokine-Effects on Glucocorticoid Receptor Function: Relevance to Glucocorticoid Resistance and the Pathophysiology and Treatment of Major Depression. Brain Behav. Immun. 2007, 21, 9–19.
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