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Psychoneuroimmunology and the Skin

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Psychoneuroimmunology and the Skin Acta Derm Venereol 2016; Suppl 217: 38–46 REVIEW ARTICLE Psychoneuroimmunology and the Skin Juan F. HONEYMAN Department of Dermatology, University of Chile, Catholic University of Chile, Santiago, Chile The nervous, immune, endocrine and integumentary influenced by cytokine actions. Several psychiatric systems are closely related and interact in a number of conditions (depression, schizophrenia, psychosomatic normal and pathological conditions. Nervous system me- disorders) can cause immunological alteration whilst diators may bring about direct changes to the skin or behavioural disturbances such as aggression and mood may induce the release of immunological or hormonal swings are associated with immunological changes. mediators that cause pathological changes to the skin. Furthermore, they may play a significant role in aller- This article reviews the psychological mechanisms in- gies and autoimmune collagen ailments, for example, volved in the development of skin diseases. Key words: systemic lupus erythematous, systemic sclerosis, melanocyte-stimulating hormones (MSH). rheumatoid arthritis, Sjögren’s syndrome and mixed connective tissue disease. Feelings of helplessness or Accepted Feb 16, 2016; Epub ahead of print Jun 9, 2016 the suppression of negative emotions can stimulate the Acta Derm Venereol 2016; Suppl 217: 38–46. growth or spread of cancer. It is worth noting that hypnosis, psychological re- Juan F. Honeyman, MD, Department of Dermatology, laxation, and classical conditioning treatments have University of Chile, Catholic University of Chile, 8320000 had positive results with immune system disorders; Santiago, Chile. E-mail: [email protected] relaxation techniques and the placebo effect have been found to stimulate Th-1 lymphocytes (1, 2). The nervous and immune systems reciprocally regulate each other through different cross-reaction mechanisms. ACTION MECHANISMS OF THE SMALL The link between the central nervous system (CNS) and PROTEIN-LIKE MOLECULES EXPRESSED AND the immune system is represented by the hypothalamic- PRODUCED BY NEURONS hypophyseal-adrenal (HPA) axis, which secretes the corticotrophin releasing hormone (CRH) and the autono- Neuropeptides, neurotrophins, neurotransmitters and mous nervous system. The CNS and the immune system catecholamines play a significant role in modulating intercommunicate via neurotransmitters, cytokines and the immune response (2, 3). endocrine neurotransmitter hormones (adrenalin and corticoids). The interconnection between the two sys- Neropeptides tems is complex and the interactions between them are bidirectional. The human genome contains about 90 genes that Neurons use many different chemical signals to encode precursors of neuropeptides. About 100 dif- communicate information. They release neuropeptides, ferent peptides are known to be released by different neurotransmitters, cannabinoids and even some gases populations of neurons in the mammalian brain (1–4). like nitric oxide. Neurons often produce a conventio- There are 3 groups of hormones that act as neuro- nal neurotransmitter (glutamate, glutamate gamma- peptides: (i) Hypothalamic hormones (somatostatin, aminobutyric acid (GABA) or dopamine) and one or corticotropin-releasing hormone, gonadotropin-relea- more neuropeptides. sing hormone, GHRH, orexins, thyrotropin-releasing The small protein-like molecules generated by neu- hormone, and proopiomelanocortin [ACTH, MSH, rons function in different ways; they modulate neuronal lipotropin]). (ii) Gastrointestinal hormones (cholecys- communication by acting on the cell-surface specific tokinin, gastric inhibitory polypeptide, gastrin, motilin, receptors of other neurons and this can have a number secretin and vasoactive intestinal peptide. Other hor- of effects on human behaviour. They can also have a mones acting as neuropeptides are calcitonin, oxytocin biological impact on gene expression, local blood flow, and vasopressin and (iii) protein-like compounds with synaptogenesis and glial cell morphology. neuropeptide activity [angiotensin, neuropeptide Y, Most immune cells have surface membrane receptors neuropeptide S, neurotensin, calcitonin gene-related for neurotransmitters, neuropeptides and hormones and peptide, and kinins (bradykinin, tachykinins]). they can be directly influenced by these receptors or, Neuropeptides induce the release of hormones (cor- in the event of CNS activation, they can be indirectly ticotropin, ACTH and glucocorticosteroids), monoa- Acta Derm Venereol Suppl 217 © 2016 The Authors. doi: 10.2340/00015555-2376 Journal Compilation © 2016 Acta Dermato-Venereologica. ISSN 0001-5555 Psychoneuroimmunology and the skin 39 mine neurotransmitters (epinephrine, norepinephrine, Antimicrobial peptides. Monocytes can release the anti- dopamine), free radicals, cytokins (IL-1, IL-6, TNF), microbial peptides proenkephalin and chromogranin opioids, peptides, endogenous opiates and endocan- B that are able to stimulate immune cells (1, 2). They nabinoid antimicrobial peptides (proenkephalin, chro- stimulate the chemotaxis and phagocytosis of the ma- mogranin B). crophages and provoke the release of pro-inflammatory Lymphocytes have receptors for neuropeptides cytokines (IL-1, IL-6, etc.). released by the peripheral nervous system; examples These peptides can also activate T lymphocytes that would be substance P, somatostatin, VIP and opioids. induce cytotoxic cell proliferation and the secretion of They also have catecholamine receptors. The activation immunoglobulins by the plasmacells. They are also able of α1, α2 and β2 catecholamine receptors are able to to activate NK cell cytotoxicity. induce humoral immunity stimulation and can increase Proenkephalin and chromogranin B can activate neu- specific IgM antibodies. trophils and release antimicrobial peptides, for example, Neuropeptides also activate cell-mediated immunity, defensine. They also cause central nervous pain. stimulating the release of T lymphocytes cytokines (e.g. Autonomous nervous system (ANS) mediators. The IL-2), macrophage proliferation, natural killer (NK) cell autonomous nervous system is composed of the activity and the endothelial adhesion of lymphocytes (4). sympathetic (noradrenergic) and the parasympathetic Along with the autonomous nervous system, opioid (cholinergic) systems. Chronic stress stimulates ACTH and antimicrobial peptides are important for regulating secretion that activates the secretion of corticoids, adre- immune responses. nalin and noradrenalin that suppress the production of Opioid peptides. Opioid peptides are neuropeptides of IL-12 by the antigen-presenting cells, the main Th1 cell short sequences of amino acids that mimic the effect response-inducing stimulus (1–3). Corticoids have a of opiates in the brain (1–3). Depending on the type direct impact on Th2 cells, increasing the production of of peptide, the concentration, the peptide receptor and IL-4, IL-10 and IL-13. This gives rise to a Th1/Th2 im- the contact time of the peptide with the immune cell, balance in favour of a Th2-cell-mediated response with they regulate immune responses. Brain opioid peptide the deregulation of the neuroimmunologic homeostatic systems are known to have a significant influence on mechanisms that are secondary to chronic stress. This motivation, emotions, attachment behaviour, the re- affects cytokine expression and favours an ‘allergic’ sponse to stress and pain and the control of food intake. inflammatory response. In addition to the stimulation Examples of opioid peptides are: dynorphin; endo- of immediate hypersensitivity reactions, chronic stress morphin; endorphin; enkephalin; nociceptin; VGF, depresses cell-mediated immunity. (non-acronymic genes generated in vivo by neurotro- phins – nerve growth factor (NGF), brain derived Neurotrophins growth factor and glial-derived growth factor). Opioid peptides that act as neuropeptides are: cocaine Neurotrophins are a family of proteins that act as NGFs and amphetamine-regulated transcript; bombesin, gast- that induce the survival, development and function of rin releasing peptide, carnosine, delta sleep-inducing neurons (5, 6). They may be considered as new cyto- peptide, FMRF amide, neurophysins, galanin, galanin- kines. Several cells have neurotrophin receptors and like peptide, neuromedin (B,N,S,U), pancreatic poly- may be activated by these proteins. peptide, opiorphin, and the pituitary adenylate cyclase One of the cell receptors is Pan-neurotrophine P75 activating peptide. that is of low affinity. Another receptor is Tyrosine Opioid peptides may be produced by the body or di- Kinase (trkA trkB trkC of high affinity) which may act gested in food. Some endogenous opioid peptides (with as receptor of the NGF, the brain-derived neurotrophic more than 8 amino acids) are: β-endorphin; enquefalins; factor (BDNF) and neurotrophins-3 and -4. Other neu- dinorfins (originally enkephalin B); and, probably, en- rotrophins have different receptors: GDNF; neurturin; domorfin. The human genome contains 3 homologous artemin; persephin (GDNF receptor); and Neuregulin genes that code the endogenous opioid peptides. (1–4), GMF, CNTF, PACAP (other receptors). The human gene for proopiomelanocortin codes for Neurotrophins with high affinity to tyrosine kinase endorphins such as β-endorphin and gamma-endorphin. cell receptors (trkA trkB trkC) are the BDNF, neurotro- Enkephalins have a specific gene. Opiorphin (human phins-3 and -4 and the NGF. saliva) is an enkephalinase inhibitor, i.e. it prevents the The BDNF and neurotrophins-3
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