Background: Recent evidence indicates that acute stress can precipitate a number of dermatological conditions, including alopecia areata. This effect may be mediated by corticotropin-releasing hormone (CRH) released locally in the skin from dorsal root ganglia or immune cells. CRH typically acts through activation of specific receptors that are either type 1 or types 2α and 2β. CRH, or related peptides such as urocortin, could have proinflammatory effects directly or through activation of mast cells leading to destruction of the hair root. Objectives: To investigate the expression of CRH receptors on the affected skin of patients who developed alopecia areata following acute emotional stress. Methods: Scalp skin biopsies were obtained from 1 normal volunteer and 3 patients after ring infiltration of the relevant site with lidocaine. The biopsies were frozen and were later processed for in situ hybridization for CRH receptors type 1 or types 2α and 2β. Sections showing positive results were photographed. Results: The skin from the normal volunteer showed weak background expression of all three receptor types. However, skin from the affected sites of all 3 patients studied showed intense expression only on the type 2β receptor around the hair follicles. Conclusion: Acute emotional stress may precipitate alopecia areata by activation of overexpressed type 2β CRH receptors around the hair follicles leading to intense local inflammation.

1.
Rabkin JG, Struening EL: Life events, stress and illness. Science 1976;194:1013–1020.
2.
Sternberg EM, Chrousos GP, Wilder RL, Gold PW: The stress response and the regulation of inflammatory disease. Ann Intern Med 1992;117:854–866.
3.
Wallengren J, Ekman R, Moller H: Substance P and vasoactive intestinal peptide in bullous and inflammatory skin disease. Acta Derm Venereol (Stockh) 1986;66:23–28.
4.
Rabier MJ, Farber EM, Wilkinson DI: Neuropeptides modulate leukotriene R4 mitogenicity toward cultured human keratinocytes. J Invest Dermatol 1993;100:132–136.
5.
Williams K, Bienenstock J, Perdue MH: The role of psychological and neurological factors in allergic reactions. ACI News 1992;4/3:77–85.
6.
Orfan NA, Kolski GB: Physical urticarias. Ann Allergy 1993;71:205–216.
7.
Van Moffaert M: Psychodermatology: An overview: Psychother Psychosom 1992;58:125–136.
8.
Reichlin S: Neuroendocrine-immune interactions. N Engl J Med 1993;329:1246–1253.
9.
Champion RH, Parish WE: Atopic dermatitis; in Rook A, Wilkinson DS, Ebling FJG (ed): Textbook of Dermatology ed 3. Philadelphia, Blackwell, 1979, pp 349–361.
10.
De Waard-Vanderspek FB, Orange AP, De Raeymaecker DM, Peereboom-Wynia JD: Juvenile versus maturity-onset alopecia areata – A comparative retrospective clinical study. Clin Exp Dermatol 1989;14:429–433.
11.
Chrousos GP: The hypothalamic-pituitary- adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332:1351–1362.
12.
Lovenberg TW, Chalmers DT, Liu C, DeSouza EB: CRF and CRF receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 1995;136:4139–4142.
13.
Karalis K, Sano H, Redwine J, Listwak S, Wilder RL, Chrousos GP: Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science 1991;254:421–423.
14.
Karalis K, Louis JM, Bae D, Hilderbrand H, Majzoub JA: CRH and the immune system. J Neuroimmunol 1997;72:131–136.
15.
Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E, Chrousos G: Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology 1998;139:403–413.
16.
Singh LK, Pang X, Alexacos N, Letourneau R, Theoharides TC: Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin and substance P: A link to neurogenic skin disorders. Brain Behav Immun 1999;13:225–239.
17.
Jaworsky C, Kligman AM, Murphy GF: Characterization of inflammatory infiltrates in male pattern alopecia: Implications for pathogenesis: Br J Dermatol 1992;127:239–246.
18.
Friedman PS: Alopecia areata and autoimmunity. Br J Dermatol 1981;105:153–157.
19.
Muller SA, Winkelmann RK: Alopecia areata. Arch Dermatol 1963;88:290–297.
20.
Bertolino AP: Alopecia areata: A clinical overview. Postgrad Med 2000;107:81–90.
21.
Lattanand A, Johnson WC: Male pattern alopecia: A histopathologic and histochemical study. J Cutan Pathol 1975;2:58–70.
22.
Okun MR, Donnellan B: Ultrastructural relationship of melanocytes to mast cells and ‘melanophages’ in a lesion of alopecia mucinosa. J Invest Dermatol 1972;59:211–224.
23.
Tonii T, Okada T, Fukai K, Nakagawa K, Hamada T: Increase of mast cells in the alopecia lesion of mice. Derm Venereol (Stockh) 1985;65:64–66.
24.
Christoph T, Muller-Rover S, Audring H, Tobin DJ, Hermes B, Cotsarelis G, Ruckert R, Paus R: The human hair follicle immune system: Cellular composition and immune privilege. Br J Dermatol 2000;142:862–873.
25.
Sueki H, Stoudemayer T, Kligman AM, Murphy GF: Quantitative and ultrastructural analysis of inflammatory infiltrates in male pattern alopecia. Acta Derm Venereol (Stockh) 1999;79:347–350.
26.
Walker SA, Rothman S: Alopecia areata: A statistical study and consideration of endocrine influences. J Invest Dermatol 1950;14:403–412.
27.
Klein U, Weinheimer B, Faun H: Simultaneous occurrence of alopecia areata and immunothyroiditis. Int J Dermatol 1974;13:116–118.
28.
Thompson DM: Alopecia areata, vitiligo, scleroderma and ulcerative colitis. Proc R Soc Med 1974;67:1010–1012.
29.
Schenk EAE: Autoantibodies in alopecia and vitiligo in hair; in Brown AC, Crounse RG (eds): Trace Elements and Human Illness. New York, Praeger, 1980, p 334.
30.
Gupta MA, Gupta AK, Watteel GN: Stress and alopecia areata: A psychodermatologic study. Acta Derm Venereol (Stockh) 1997;77:296–298.
31.
Katsarou-Katsari A, Filippou A, Theoharides TC: Effect of stress and other psychological factors on the pathophysiology and treatment of dermatoses. Int J Immunopathol Pharmacol 1999;12:7–11.
32.
Singh LK, Boucher W, Pang X, Letourneau R, Seretakis D, Green M, Theoharides TC: Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of CRH receptors. J Pharmacol Exp Ther 1999;288:1349–1356.
33.
Slominski A, Ermak G, Hwang J, Mazurkiewicz J, Corliss D, Eastman A: The expression of proopiomelanocortin (POMC) and of corticotropin releasing hormone receptor (CRH-R) genes in mouse skin. Biochim Biophys Acta 1996;1289:247–251.
34.
Slominski AJ, Ermak G, Mazurkiewicz JE, Baker J, Wortsman J: Characterization of corticotropin-releasing hormone (CRH) in human skin. J Clin Endocrinol Metab 1998;83:1020–1024.
35.
Slominski A, Wortsman J, Luger T, Paus R, Solomon S: Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev 2000;80:979–1020.
36.
Roloff B, Fechner K, Slominski A, Furkert J, Botchkarev VA, Bulfone-Paus S, Zipper J, Krause E, Paus R: Hair cycle-dependent expression of corticotropin-releasing factor (CRF) and CRF receptors in murine skin. FASEB J 1998;12:287–297.
37.
Toyoda M, Makino T, Kagoura M, Morohashi M: Expression of neuropeptide-degrading enzymes in alopecia areata: An immunohistochemical study. Br J Dermatol 2001;144:46–54.
38.
Conti P, Reale M, Barbacane RC, Letourneau R, Theoharides TC: Intramuscular injection of hrRANTES causes mast cell recruitment and increased transcription of histidine decarboxylase: Lack of effects in genetically mast cell-deficient W/Wv mice. FASEB J 1998;12:1693–1700.
39.
Theoharides TC: Mast cell: A neuroimmunoendocrine master player. Int J Tissue React 1996;18:1–21.
40.
Botchkarev VA, Eichmuller S, Peters EM, Pietsch P, Johansson O, Maurer M, Paus R: A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycledependent changes in mast cell-nerve fiber contacts in murine skin. Arch Dermatol Res 1997;289:292–302.
41.
Simoncini T, Apa R, Reis FM, Micelli F, Stomati M, Driul L, Lanzone A, Genazzani AR, Petraglia F: Human umbilical vein endothelial cells: A new source and potential target for corticotropin-releasing factor. J Clin Endocrinol Metab 1999;84:2802–2806.
42.
Clifton VL, Read MA, Leitch IM, Giles WB, Boura ALA, Robinson PJ, Smith R: Corticotropin-releasing hormone-induced vasodilatation in the human fetal-placental circulation: Involvement of the nitric oxide-cyclic guanosine 3′,5′-monophosphate-mediated pathway. J Clin Endocrinol Metab 1995;80:2888–2893.
43.
Fleisher-Berkovich S, Rimon G, Danon A: Modulation of endothelial prostaglandin synthesis by corticotropin releasing factor and antagonists. Eur J Pharmacol 1998;353:297–302.
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