Immunity, Stress, and Nail Psoriasis Richard D. Granstein, M.D.

F020 American Academy of Dermatology  Summer Meeting 2016 Boston, Massachusetts

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DISCLOSURES Galderma: Advisory Board - Honoraria Castle Biosciences: Advisory Board - Honoraria Vellius: Advisory Board - Stock Options Elysium Health: Scientific Advisory Board - Stock Options National Rosacea Society: Grant Support NIH: Grant Support

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Stress is a medical term for a wide range of strong external stimuli, both physiological and psychological, which can cause a physiological response called the general adaptation syndrome, first described in 1936 by Hans Selye in the journal Nature.

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Processive stressors are elements in the environment perceived as potential dangers. These do not cause damage directly, but are processed in the cerebral cortex. The processed information is then sent via the limbic system in the hypothalamus, where they activate the autonomic nervous system, resulting in a fight-or-flight (or sympathetico-adrenal) response.

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Systemic stressors cause a disturbance in the organism's homeostasis, such as through physical perturbations (injury, illness, etc.). Often both types of stressors occur simultaneously. They are usually accompanied by pain and/or intensive emotions.

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“Stress can cause psoriasis to appear suddenly (flare) or can make symptoms worse.” Source: http://www.wakehealth.edu/Health-Encyclopedia/HealthTopics/Psoriasis.htm

Wake Forest Baptist Medical Center Website

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Kabat‐Zinn J, Wheeler E, Light T, Skillings A, Scharf MJ, Cropley TG,  Hosmer D, Bernhard JD.  Influence of a mindfulness meditation‐ based stress reduction intervention on rates of skin clearing in  patients with moderate to severe psoriasis undergoing  phototherapy (UVB) and photochemotherapy (PUVA).   Psychosom Med 60:625‐632, 1998.

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Reportedly, Psoriasis, Atopic Dermatitis, Acne and  Rosacea are Exacerbated by Stress  Dika E, Bardazzi F, Balestri R, Maibach HI.  Enviornmental factors and psoriasis.  Curr Probl Dermatol 2007;  35:118‐35. Yosipovitch G, Tang M, Dawn AG, Chen M, Goh CL, Huak Y, Seng LF.  Study of psychological stress, sebum  production and acne vulgaris in adolescents.  Acta Derm Venereol 2007; 87:135‐9. Sowińska‐Glugiewicz I, Ratajczak‐Stefańska V, Maleszka R.  Role of psychological factors in course of the rosacea.   Rocz Akad Med Bialymst 2005; 50 Suppl 1:49‐53.

Alleviation of Stress Reportedly Improves  Atopic Dermatitis and Psoriasis  Ersser SJ, Latter S, Sibley A, Satherley PA, Welbourne S.  Psychological and educational interventions  for atopic eczema in children.  Cochrane Database Syst Rev 2007; 18:CD004054.  Zachariae R, Oster H, Bjerring P, Kragballe K.  Effects of psychologic intervention on psoriasis: a  preliminary report.  J Am Acad Dermatol 1996; 34:1008‐15.  9

Psoriatic Arthritis Has Also Been Reported  to Worsen With Stress Harvima RJ, Viinamäki H, Harvima IT, Naukkarinen A, Savolainen L, Aalto ML,  Horsmanheimo M. Association of psychic stress with clinical severity and symptoms of  psoriatic patients. Acta Derm Venereol. 1996; 76:467‐71. Piazzini M, Fioravanti A, Sabadini L, Vassalli D, Bellisai F, Marcolongo R. Laboratory  and instrumental clinical study of 150 patients with psoriatic arthritis]. Recenti Prog Med. 1995; 86:183‐8. 

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Reprinted by permission from Macmillan Publishers Ltd:  Nat Clin Pract Neurol, Lauria G and  Devigili G: Skin biopsy as a diagnostic tool in peripheral neuropathy 3: 546–557, copyright 2007

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From John Wiley & Sons, Inc with permission:  Farber EM, Lanigan SW, Boer J. The role of cutaneous  Sensory nerves in the maintenance of psoriasis. Int J Dermatol. 1990; 29:418‐20, copyright 1990. 13

Arch Dermatol 105: 128‐129, 1972

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Reproduced from Protective [Effect of Sensory Denervation in Inflammatory Arthritis (Evidence of Regulatory Neuroimmune Pathways in  the Arthritic Joint). D Kane, J C Lockhart, P V Balint, C Mann, W R Ferrell, I B McInnes, 64, 325‐327, copyright notice 2005 with permission  from BMJ Publishing Group Ltd.

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Reprinted from Am J Pathol, 174, Wolfram JA, Diaconu D, Hatala DA, Rastegar J,  Knutsen DA, Lowther A, Askew D, Gilliam AC, McCormick TS, Ward NL,  Keratinocyte but Not Endothelial Cell‐Specific Overexpression of Tie2 Leads to  the Development of Psoriasis, 1443‐58,  copyright 2009, with permission from Elsevier.

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Reprinted from J Invest Dermatol, 132, Ostrowski SM, Belkadi A,  Loyd CM, Diaconu D, Ward NL, Cutaneous Denervation of  Psoriasiform Mouse Skin Improves Acanthosis and Inflammation in  a Sensory Neuropeptide‐Dependent Manner, 153‐38,  copyright  2011, with permission from Elsevier.

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Classically, Langerhans cells were considered to be the principal antigen presenting cells of the epidermis. When activated or matured, they have been shown to be capable of presenting haptens, alloantigens, immunogenic proteins and tumor antigens for induction or elicitation of immune responses.

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Nature 363:159–63, 1993

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CALCITONIN GENE‐RELATED PEPTIDE (CGRP) CGRP IS A NEUROPEPTIDE AND POTENT VASODILATOR  PRESENT IN CENTRAL AND PERIPHERAL NERVES.   A NUMBER OF EFFECTS OF CGRP ON IMMUNE FUNCTIONS  HAVE BEEN REPORTED:  *Association with LC in esophageal mucosa *Inhibits T cell proliferation and IL‐2 production *Presence of specific receptors on macrophages *Inhibits several macrophage functions including  antigen presentation

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Immunization

Elicitation

DC

Lymph Node

T Cells

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Many epidermal LC are closely‐associated anatomically  with nerves that contain CGRP, a peptide that appears  to regulate LC function A small proportion of LC in normal skin appear to have  immunoreactive CGRP at their surfaces These results illustrate a possible locus of interaction between  the nervous system and cutaneous immune function

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T-bet STAT4

IFN-

Th1

DC

GATA-3 STAT6

IL-4

Th2

CD4+ T cell RORt STAT3

IL-17 IL-22

Th17

Foxp3

RORt STAT3

AHR

IL‐22 Th17

Treg

Th22

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IL-17

Reprinted by permission from Macmillan Publishers Ltd: Nat Med 510: 1748‐50, copyright 2012

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VPAC2

VPAC1

LC Expression of Neuropeptide Receptors

Antigen Presentation Assay 

+/‐ PACAP  or VIP

BALB/c

Wash 4X

Coculture LCs and DO11.10 T cells  +/‐ OVA323‐335

LC  2 h

48 h

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Measure  cytokine   production (ELISA)

PACAP and VIP Enhance Presentation for an IL‐17 Response

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VIP and CGRP concentrations are elevated  in the plasma of patients with psoriasis  Exp Dermatol. 2007;16:421‐8.   

CGRP is present on the surface of  endothelial cells in lesions of psoriasis Chin Med J (Engl). 2000;113:747‐51.

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Systemic  administration of  CGRP or substance  P significantly  inhibits loss of the  phenotype with  denervation. Reprinted from Am J Pathol, 174, Wolfram JA, Diaconu D, Hatala DA, Rastegar J,  Knutsen DA, Lowther A, Askew D, Gilliam AC, McCormick TS, Ward NL,  Keratinocyte but Not Endothelial Cell‐Specific Overexpression of Tie2 Leads to  the Development of Psoriasis, 1443‐58,  copyright 2009, with permission from Elsevier.

Reprinted from J Invest Dermatol, 132, Ostrowski SM, Belkadi A,  Loyd CM, Diaconu D, Ward NL, Cutaneous Denervation of  Psoriasiform Mouse Skin Improves Acanthosis and Inflammation in  a Sensory Neuropeptide‐Dependent Manner, 153‐38,  copyright  2011, with permission from Elsevier. 32

Co‐culture of Endothelial Cells in Antigen Presentation Assay 

+/‐CGRP or +/‐ NE

Wash 4x

Endothelial  cells

Co‐culture  endothelial cells,  LCs  and DO11.10  Tg CD4+ T cells +/‐ OVA 323‐339 48 h

3h

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Measure  cytokine   production (ELISA)

Exposure of bEnd.3 cells to CGRP or NE biases LC Ag  presentation towards an IL‐17A response while  decreasing IL‐4 and IFN responses

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The Effect of CGRP on Biasing LC Ag  Presentation Towards an IL‐17A Response  Does Not Depend Upon Cell‐Cell Contact

Transwell insert

Upper compartment LC + TC Microporous membrane  pDMEC

Lower compartment

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Reprinted by permission from Macmillan Publishers Ltd: Nature 510: 157‐161, copyright 2014

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Reprinted from Immunity, Kashem SW, Riedl MS, Yao C, Honda CN, Vulchanova L, Kaplan DH,  Nociceptive Sensory Fibers Drive Interleukin‐23 Production from CD301b+ Dermal Dendritic Cells  and Drive Protective Cutaneous Immunity, 515‐26,  copyright 2015, with permission from Elsevier. 37

PACAP, VIP, CGRP, (NE) and skin nociceptors have activities that may promote IL-17/Th17 activity. If stress induces release of these factors and/or the activity of skin nociceptors, such mechanism(s), may account for stress induced exacerbation of psoriasis, including nail psoriasis.

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Has the time come for stress  management techniques to be  part of the armamentarium for  treating skin disorders?  If so,  which one(s)? Autogenic training Biofeedback Deep breathing Meditation Mind‐body relaxation Zen Yoga Progressive Muscle Relaxation

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Pranayama Visualization Yoga Nidra Self‐hypnosis Qigong Zhineng Qigong Et cetera…….

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Inflammatory skin disorders almost certainly are influenced by stress and neurologic status. Inflammatory skin disorders induce stress and affect quality of life. Pathways by which the nervous system can influence cutaneous immunity and inflammation have been uncovered. In selected patients, it is reasonable to consider stress-alleviation strategies including counseling, support groups and psychotherapy.

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