생명과학회지 (Journal of Life Science)

  • 제26권11호
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  • Pages.1345-1354
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  • 2016
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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원형탈모증(alopecia areata)의 최신 이해와 치료

Advance Understanding and New Treatment of Alopecia Areata

  • Kang, Kyung-Hwa (Department of Physiology, College of Korean Medicine, Dong-Eui University)
  • 투고 : 2016.11.03
  • 심사 : 2016.11.25
  • 발행 : 2016.11.30
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⟨ 이전 논문 다음 논문 ⟩

초록

원형탈모증은 흔하게 발병하고 두피와 전신에 모발의 탈락을 일으키는 모낭조직 특이 자가면역질환이다. 모낭은 자체적으로 면역체계와 내분비 환경을 가지고 각 모발주기 단계에 따라 다른 면역 상태를 나타내는 특이한 기관이다. 성장기 모낭의 면역특권의 파괴는 모낭상피 MHC class I 발현과 자가반응성 CD8+T세포에 대한 자가항원 발현을 유도하는 자가면역의 공격을 일으키고 원형탈모증을 유발한다. 임상적 실험적 연구에 의하면, 심리적 스트레스도 모낭 면역/호르몬 체계에 영향을 미쳐 원형탈모증의 유도에 관여할 수 있다고 지적한다. 원형탈모증의 핵심적인 병리기전은 면역특권 수호자(ACTH, ${\alpha}-MSH$와 $TGF-{\beta}$ 등), 자연살해세포그룹 2D-양성(NKG2D+) 세포(NK 세포와 CD8+T 세포 등)와 스트레스 호르몬(CRH와 substance P)과 관련되어 있다. 효과적인 치료법은 여전히 요구되고 있다. 앞으로 치료목표 중의 하나는 스트레스를 포함한 모낭 면역특권을 개선하는 것일 것이다. 최근 연구는 건선, 아토피피부염, 류마티스 관절염 같은 다른 자가면역질환에서 사용되는 JAK억제제와 면역조절제, Tregs, 혈소판풍부혈장요법, 스타틴과 프로스타글란딘 유사제가 원형탈모증에 효과적이라고 보고하였다. 본 논문은 모낭주위 내분비/면역과 관련된 발병기전에 대한 새로운 이해와 원형탈모증의 새로운 치료법에 대해 고찰하였다.

Alopecia areata (AA) is a common and tissue-specific autoimmune disease of hair follicle resulting in the loss of hair on the scalp and elsewhere on the body. Hair follicles is a unique organ because it has its own immune system and hormonal milieu and has a different immune state at each hair cycle stage. The collapses of anagen-dependent hair follicle immune privilege arise autoimmune attack, inducing ectopic MHC class I expression in the hair follicle epithelium and autoantigen presentation to autoreactive CD8+T cells, which results in AA. Clinical and experimental studies have pointed that psychological stress may also influence the hair follicle immune/hormone systems and contribute to the induction of AA. The key pathogenesis of AA is associated with immune privilege guardians (including ACTH, ${\alpha}-MSH$, and $TGF-{\beta}$), natural killer group 2D-positive (NKG2D+) cells (including NK and CD8+T cells), and stress hormones (including CRH and substance P). Effective treatments for AA are still demanded. One of the future targets of treatment will be the modification of hair follicle immune privilege including stress. Recent studies have reported that JAK inhibitors and immunomodulators used in other autoimmune disease, such as psoriasis, atopic dermatitis, and rheumatoid arthritis, Tregs, platelet-rich plasma therapy, statins, and prostaglandin anaolgues are effective for AA. Here the article reviews the recent understanding in the pathogenesis associated with perifollicular endocrine/immunology and new treatments of AA.

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참고문헌

  1. Acikgoz, G., Ozmen, I., Cayirli, M., Yeniay, Y. and Kose, O. 2014. Pulse methylprednisolone therapy for the treatment of extensive alopecia areata. J. Dermatolog. Treat. 25, 164-166. https://doi.org/10.3109/09546634.2013.768759
  2. Alkhalifah, A., Alsantali, A., Wang, E., McElwee, K. J. and Shapiro, J. 2010. Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis. J. Am. Acad. Dermatol. 62, 177-188, quiz 189-190. https://doi.org/10.1016/j.jaad.2009.10.032
  3. Amano, W., Nakajima, S., Kunugi, H., Numata, Y., Kitoh, A., Egawa, G., Dainichi, T., Honda, T., Otsuka, A., Kimoto, Y., Yamamoto, Y., Tanimoto, A., Matsushita, M., Miyachi, Y. and Kabashima, K. 2015. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J. Allergy Clin. Immunol. 136, 667-677.e667. https://doi.org/10.1016/j.jaci.2015.03.051
  4. Amano, W., Nakajima, S., Yamamoto, Y., Tanimoto, A., Matsushita, M., Miyachi, Y. and Kabashima, K. 2016. JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation. J. Dermatol. Sci. In press.
  5. Anuset, D., Perceau, G., Bernard, P. and Reguiai, Z. 2016. Efficacy and safety of methotrexate combined with low- to moderate-dose corticosteroids for severe alopecia areata. Dermatology 232, 242-248. https://doi.org/10.1159/000441250
  6. Arakawa, Y., Nomiyama, T. and Katoh, N. 2016. Three hundred and eight nanometer excimer light therapy for alopecia universalis that is resistant to other treatments: A clinical study of 11 patients. J. Dermatol. In press.
  7. Arck, P. C., Handjiski, B., Peters, E. M., Peter, A. S., Hagen, E., Fischer, A., Klapp, B. F. and Paus, R. 2003. Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways. Am. J. Pathol. 162, 803-814. https://doi.org/10.1016/S0002-9440(10)63877-1
  8. Avidan, N., Le Panse, R., Berrih-Aknin, S. and Miller, A. 2014. Genetic basis of myasthenia gravis - a comprehensive review. J. Autoimmun. 52, 146-153. https://doi.org/10.1016/j.jaut.2013.12.001
  9. Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J. H., Lanier, L. L. and Spies, T. 1999. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727-729. https://doi.org/10.1126/science.285.5428.727
  10. Bertolini, M., Zilio, F., Rossi, A., Kleditzsch, P., Emelianov, V. E., Gilhar, A., Keren, A., Meyer, K. C., Wang, E., Funk, W., McElwee, K. and Paus, R. 2014. Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata. PLoS One 9, e94260. https://doi.org/10.1371/journal.pone.0094260
  11. Bertolini, M., Uchida, Y. and Paus, R. 2015. Toward the Clonotype Analysis of Alopecia Areata-Specific, Intralesional Human CD8+ T Lymphocytes. J. Investig. Dermatol. Symp. Proc. 17, 9-12.
  12. Betz, R. C., Petukhova, L., Ripke, S., Huang, H., Menelaou, A., Redler, S., Becker, T., Heilmann, S., Yamany, T., Duvic, M., Hordinsky, M., Norris, D., Price, V. H., Mackay-Wiggan, J., de Jong, A., DeStefano, G. M., Moebus, S., Bohm, M., Blume-Peytavi, U., Wolff, H., Lutz, G., Kruse, R., Bian, L., Amos, C. I., Lee, A., Gregersen, P. K., Blaumeiser, B., Altshuler, D., Clynes, R., de Bakker, P. I., Nothen, M. M., Daly, M. J. and Christiano, A. M. 2015. Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci. Nat. Commun. 6, 5966. https://doi.org/10.1038/ncomms6966
  13. Billingham, R. E. and Silvers, W. K. 1971. A biologist's reflections on dermatology. J. Invest Dermatol. 57, 227-240. https://doi.org/10.1111/1523-1747.ep12261543
  14. Bissonnette, R., Papp, K. A., Poulin, Y., Gooderham, M., Raman, M., Mallbris, L., Wang, C., Purohit, V., Mamolo, C., Papacharalambous, J. and Ports, W. C. 2016. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 175, 902-911. https://doi.org/10.1111/bjd.14871
  15. Boehm, T. 2006. Quality control in self/nonself discrimination. Cell 125, 845-858. https://doi.org/10.1016/j.cell.2006.05.017
  16. Byun, J. W., Moon, J. H., Bang, C. Y., Shin, J. and Choi, G. S. 2015. Effectiveness of 308-nm excimer laser therapy in treating alopecia areata, determined by examining the treated sides of selected alopecic patches. Dermatology 231, 70-76. https://doi.org/10.1159/000381912
  17. Castela, E., Le Duff, F., Butori, C., Ticchioni, M., Hofman, P., Bahadoran, P., Lacour, J. P. and Passeron, T. 2014. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 150, 748-751. https://doi.org/10.1001/jamadermatol.2014.504
  18. Cerwenka, A. and Swain, S. L. 1999. TGF-beta1: immunosuppressant and viability factor for T lymphocytes. Microbes Infect. 1, 1291-1296. https://doi.org/10.1016/S1286-4579(99)00255-5
  19. Chiang, K. S., Mesinkovska, N. A., Piliang, M. P. and Bergfeld, W. F. 2015. Clinical efficacy of diphenylcyclopropenone in alopecia areata: retrospective data analysis of 50 patients. J. Investig. Dermatol. Symp. Proc. 17, 50-55. https://doi.org/10.1038/jidsymp.2015.28
  20. Christoph, T., Muller-Rover, S., Audring, H., Tobin, D. J., Hermes, B., Cotsarelis, G., Ruckert, R. and Paus, R. 2000. The human hair follicle immune system: cellular composition and immune privilege. Br. J. Dermatol. 142, 862-873. https://doi.org/10.1046/j.1365-2133.2000.03464.x
  21. Chu, T. W., AlJasser, M., Alharbi, A., Abahussein, O., Mc-Elwee, K. and Shapiro, J. 2015. Benefit of different concentrations of intralesional triamcinolone acetonide in alopecia areata: An intrasubject pilot study. J. Am. Acad. Dermatol. 73, 338-340. https://doi.org/10.1016/j.jaad.2015.04.049
  22. Coronel-Perez, I. M., Rodriguez-Rey, E. M. and Camacho-Martinez, F. M. 2010. Latanoprost in the treatment of eyelash alopecia in alopecia areata universalis. J. Eur. Acad. Dermatol. Venereol. 24, 481-485. https://doi.org/10.1111/j.1468-3083.2009.03543.x
  23. Foitzik, K., Lindner, G., Mueller-Roever, S., Maurer, M., Botchkareva, N., Botchkarev, V., Handjiski, B., Metz, M., Hibino, T., Soma, T., Dotto, G. P. and Paus, R. 2000. Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo. Faseb J. 14, 752-760. https://doi.org/10.1096/fasebj.14.5.752
  24. Garcia-Hernandez, M. J., Ruiz-Doblado, S., Rodriguez- Pichardo, A. and Camacho, F. 1999. Alopecia areata, stress and psychiatric disorders: a review. J. Dermatol. 26, 625-632. https://doi.org/10.1111/j.1346-8138.1999.tb02063.x
  25. Gasser, S. and Raulet, D. H. 2006. Activation and self-tolerance of natural killer cells. Immunol. Rev. 214, 130-142. https://doi.org/10.1111/j.1600-065X.2006.00460.x
  26. Gilhar, A., Landau, M., Assy, B., Shalaginov, R., Serafimovich, S. and Kalish, R. S. 2001. Melanocyte-associated T cell epitopes can function as autoantigens for transfer of alopecia areata to human scalp explants on Prkdc (scid) mice. J. Invest Dermatol. 117, 1357-1362. https://doi.org/10.1046/j.0022-202x.2001.01583.x
  27. Gilhar, A. and Kalish, R. S. 2006. Alopecia areata: a tissue specific autoimmune disease of the hair follicle. Autoimmun Rev. 5, 64-69. https://doi.org/10.1016/j.autrev.2005.07.001
  28. Gilhar, A., Paus, R. and Kalish, R. S. 2007. Lymphocytes, neuropeptides, and genes involved in alopecia areata. J. Clin. Invest. 117, 2019-2027. https://doi.org/10.1172/JCI31942
  29. Gilhar, A., Etzioni, A. and Paus, R. 2012. Alopecia areata. N Engl. J. Med. 366, 1515-1525. https://doi.org/10.1056/NEJMra1103442
  30. Goh, C., Finkel, M., Christos, P. J. and Sinha, A. A. 2006. Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history. J. Eur. Acad. Dermatol. Venereol. 20, 1055-1060. https://doi.org/10.1111/j.1468-3083.2006.01676.x
  31. Gregoriou, S., Papafragkaki, D., Kontochristopoulos, G., Rallis, E., Kalogeromitros, D. and Rigopoulos, D. 2010. Cytokines and other mediators in alopecia areata. Mediators Inflamm. 2010, 928030.
  32. Gulec, A. T., Tanriverdi, N., Duru, C., Saray, Y. and Akcali, C. 2004. The role of psychological factors in alopecia areata and the impact of the disease on the quality of life. Int. J. Dermatol. 43, 352-356. https://doi.org/10.1111/j.1365-4632.2004.02028.x
  33. Guttman-Yassky, E., Ungar, B., Noda, S., Suprun, M., Shroff, A., Dutt, R., Khattri, S., Min, M., Mansouri, Y., Zheng, X., Estrada, Y. D., Singer, G. K., Suarez-Farinas, M., Krueger, J. G. and Lebwohl, M. G. 2016. Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. J. Allergy Clin. Immunol. 137, 301-304. https://doi.org/10.1016/j.jaci.2015.11.001
  34. Han, Y. M., Sheng, Y. Y., Xu, F., Qi, S. S., Liu, X. J., Hu, R. M., Miao, Y., Huang, G. Q. and Yang, Q. P. 2015. Imbalance of T-helper 17 and regulatory T cells in patients with alopecia areata. J. Dermatol. 42, 981-988. https://doi.org/10.1111/1346-8138.12978
  35. Harbuz, M. S., Richards, L. J., Chover-Gonzalez, A. J., Marti-Sistac, O. and Jessop, D. S. 2006. Stress in autoimmune disease models. Ann. NY Acad. Sci. 1069, 51-61. https://doi.org/10.1196/annals.1351.005
  36. Higgins, E., Al Shehri, T., McAleer, M. A., Conlon, N., Feighery, C., Lilic, D. and Irvine, A. D. 2015. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation. J. Allergy Clin. Immunol. 135, 551-553. https://doi.org/10.1016/j.jaci.2014.12.1867
  37. Holsboer, F. and Ising, M. 2008. Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. Eur. J. Pharmacol. 583, 350-357. https://doi.org/10.1016/j.ejphar.2007.12.032
  38. Inui, S., Nakajima, T., Toda, N. and Itami, S. 2009. Fexofenadine hydrochloride enhances the efficacy of contact immunotherapy for extensive alopecia areata: Retrospective analysis of 121 cases. J. Dermatol. 36, 323-327. https://doi.org/10.1111/j.1346-8138.2009.00647.x
  39. Inui, S. and Itami, S. 2015. Contact immunotherapy-resistant alopecia areata totalis/universalis reactive to topical corticosteroid. J. Dermatol. 42, 937-939. https://doi.org/10.1111/1346-8138.12938
  40. Ito, N., Ito, T., Betterman, A. and Paus, R. 2004. The human hair bulb is a source and target of CRH. J. Invest Dermatol. 122, 235-237. https://doi.org/10.1046/j.1523-1747.2003.22145.x
  41. Ito, N., Ito, T., Kromminga, A., Bettermann, A., Takigawa, M., Kees, F., Straub, R. H. and Paus, R. 2005. Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol. Faseb J. 19, 1332-1334. https://doi.org/10.1096/fj.04-1968fje
  42. Ito, N., Sugawara, K., Bodo, E., Takigawa, M., van Beek, N., Ito, T. and Paus, R. 2010. Corticotropin-releasing hormone stimulates the in situ generation of mast cells from precursors in the human hair follicle mesenchyme. J. Invest Dermatol. 130, 995-1004. https://doi.org/10.1038/jid.2009.387
  43. Ito, T., Ito, N., Bettermann, A., Tokura, Y., Takigawa, M. and Paus, R. 2004. Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model. Am. J. Pathol. 164, 623-634. https://doi.org/10.1016/S0002-9440(10)63151-3
  44. Ito, T., Ito, N., Saathoff, M., Bettermann, A., Takigawa, M. and Paus, R. 2005. Interferon-gamma is a potent inducer of catagen-like changes in cultured human anagen hair follicles. Br. J. Dermatol. 152, 623-631. https://doi.org/10.1111/j.1365-2133.2005.06453.x
  45. Ito, T., Ito, N., Saatoff, M., Hashizume, H., Fukamizu, H., Nickoloff, B. J., Takigawa, M. and Paus, R. 2008. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J. Invest Dermatol. 128, 1196-1206. https://doi.org/10.1038/sj.jid.5701183
  46. Ito, T., Meyer, K. C., Ito, N. and Paus, R. 2008. Immune privilege and the skin. Curr. Dir. Autoimmun. 10, 27-52.
  47. Ito, T. and Tokura, Y. 2014. The role of cytokines and chemokines in the T-cell-mediated autoimmune process in alopecia areata. Exp. Dermatol. 23, 787-791. https://doi.org/10.1111/exd.12489
  48. Jabbari, A., Dai, Z., Xing, L., Cerise, J. E., Ramot, Y., Berkun, Y., Sanchez, G. A., Goldbach-Mansky, R., Christiano, A. M., Clynes, R. and Zlotogorski, A. 2015. Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib. EBioMedicine 2, 351-355. https://doi.org/10.1016/j.ebiom.2015.02.015
  49. Johansson, M. H. and Hoglund, P. 2006. The dynamics of natural killer cell tolerance. Semin Cancer Biol. 16, 393-403.
  50. Kakourou, T., Karachristou, K. and Chrousos, G. 2007. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity. J. Eur. Acad. Dermatol. Venereol. 21, 356-359. https://doi.org/10.1111/j.1468-3083.2006.01931.x
  51. Kang, H., Wu, W. Y., Lo, B. K., Yu, M., Leung, G., Shapiro, J. and McElwee, K. J. 2010. Hair follicles from alopecia areata patients exhibit alterations in immune privilege-associated gene expression in advance of hair loss. J. Invest Dermatol. 130, 2677-2680. https://doi.org/10.1038/jid.2010.180
  52. Katsarou-Katsari, A., Singh, L. K. and Theoharides, T. C. 2001. Alopecia areata and affected skin CRH receptor upregulation induced by acute emotional stress. Dermatology 203, 157-161. https://doi.org/10.1159/000051732
  53. Kaufman, G., d'Ovidio, R., Kaldawy, A., Assy, B., Ullmann, Y., Etzioni, A., Paus, R. and Gilhar, A. 2010. An unexpected twist in alopecia areata pathogenesis: are NK cells protective and CD49b+ T cells pathogenic? Exp. Dermatol. 19, e347-349. https://doi.org/10.1111/j.1600-0625.2010.01065.x
  54. Keren, A., Shemer, A., Ullmann, Y., Paus, R. and Gilhar, A. 2015. The PDE4 inhibitor, apremilast, suppresses experimentally induced alopecia areata in human skin in vivo. J Dermatol. Sci. 77, 74-76. https://doi.org/10.1016/j.jdermsci.2014.11.009
  55. Kim, H. S., Cho, D. H., Kim, H. J., Lee, J. Y., Cho, B. K. and Park, H. J. 2006. Immunoreactivity of corticotropinreleasing hormone, adrenocorticotropic hormone and alphamelanocyte- stimulating hormone in alopecia areata. Exp. Dermatol. 15, 515-522. https://doi.org/10.1111/j.1600-0625.2006.00003.x
  56. Kumamoto, T., Shalhevet, D., Matsue, H., Mummert, M. E., Ward, B. R., Jester, J. V. and Takashima, A. 2003. Hair follicles serve as local reservoirs of skin mast cell precursors. Blood 102, 1654-1660. https://doi.org/10.1182/blood-2003-02-0449
  57. Lattouf, C., Jimenez, J. J., Tosti, A., Miteva, M., Wikramanayake, T. C., Kittles, C., Herskovitz, I., Handler, M. Z., Fabbrocini, G. and Schachner, L. A. 2015. Treatment of alopecia areata with simvastatin/ezetimibe. J. Am. Acad. Dermatol. 72, 359-361. https://doi.org/10.1016/j.jaad.2014.11.006
  58. Li, S. F., Zhang, X. T., Qi, S. L., Ye, Y. T., Cao, H., Yang, Y. Q., McElwee, K. J. and Zhang, X. 2015. Allergy to dust mites may contribute to early onset and severity of alopecia areata. Clin. Exp. Dermatol. 40, 171-176. https://doi.org/10.1111/ced.12471
  59. Li, Y., Yan, B., Wang, H., Li, H., Li, Q., Zhao, D., Chen, Y., Zhang, Y., Li, W., Zhang, J., Wang, S., Shen, J., Li, Y., Guindi, E. and Zhao, Y. 2015. Hair regrowth in alopecia areata patients following Stem Cell Educator therapy. BMC Med. 13, 87. https://doi.org/10.1186/s12916-015-0331-6
  60. Long, E. O. 1999. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875-904. https://doi.org/10.1146/annurev.immunol.17.1.875
  61. Lucas, P., Bodemer, C., Barbarot, S., Vabres, P., Royer, M. and Mazereeuw-Hautier, J. 2016. Methotrexate in Severe Childhood Alopecia Areata: Long-term Follow-up. Acta. Derm. Venereol. 96, 102-103. https://doi.org/10.2340/00015555-2173
  62. Mackay-Wiggan, J., Jabbari, A., Nguyen, N., Cerise, J. E., Clark, C., Ulerio, G., Furniss, M., Vaughan, R., Christiano, A. M. and Clynes, R. 2016. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight. 1, 1-5.
  63. Madani, S. and Shapiro, J. 2000. Alopecia areata update. J. Am. Acad. Dermatol. 42, 549-566. https://doi.org/10.1067/mjd.2000.103909
  64. Maurer, M., Fischer, E., Handjiski, B., von Stebut, E., Algermissen, B., Bavandi, A. and Paus, R. 1997. Activated skin mast cells are involved in murine hair follicle regression (catagen). Lab Invest. 77, 319-332.
  65. Messenger, A. G., McKillop, J., Farrant, P., McDonagh, A. J. and Sladden, M. 2012. British Association of Dermatologists' guidelines for the management of alopecia areata 2012. Br. J. Dermatol. 166, 916-926. https://doi.org/10.1111/j.1365-2133.2012.10955.x
  66. Noso, S., Park, C., Babaya, N., Hiromine, Y., Harada, T., Ito, H., Taketomo, Y., Kanto, K., Oiso, N., Kawada, A., Suzuki, T., Kawabata, Y. and Ikegami, H. 2015. Organ specificity in autoimmune diseases: thyroid and islet autoimmunity in alopecia areata. J. Clin. Endocrinol. Metab. 100, 1976-1983. https://doi.org/10.1210/jc.2014-3985
  67. Ohyama, M., Shimizu, A., Tanaka, K. and Amagai, M. 2010. Experimental evaluation of ebastine, a second-generation anti-histamine, as a supportive medication for alopecia areata. J. Dermatol. Sci. 58, 154-157. https://doi.org/10.1016/j.jdermsci.2010.03.009
  68. Pandhi, D., Singal, A., Gupta, R. and Das, G. 2009. Ocular alterations in patients of alopecia areata. J. Dermatol. 36, 262-268. https://doi.org/10.1111/j.1346-8138.2009.00636.x
  69. Papp, K. A., Krueger, J. G., Feldman, S. R., Langley, R. G., Thaci, D., Torii, H., Tyring, S., Wolk, R., Gardner, A., Mebus, C., Tan, H., Luo, Y., Gupta, P., Mallbris, L. and Tatulych, S. 2016. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study. J. Am. Acad. Dermatol. 74, 841-850. https://doi.org/10.1016/j.jaad.2016.01.013
  70. Paus, R., Slominski, A. and Czarnetzki, B. M. 1993. Is alopecia areata an autoimmune-response against melanogenesisrelated proteins, exposed by abnormal MHC class I expression in the anagen hair bulb? Yale J. Biol. Med. 66, 541-554.
  71. Paus, R., Botchkarev, V. A., Botchkareva, N. V., Mecklenburg, L., Luger, T. and Slominski, A. 1999. The skin POMC system (SPS). Leads and lessons from the hair follicle. Ann. NY Acad. Sci. 885, 350-363.
  72. Paus, R., Nickoloff, B. J. and Ito, T. 2005. A 'hairy' privilege. Trends Immunol. 26, 32-40. https://doi.org/10.1016/j.it.2004.09.014
  73. Peters, E. M., Liotiri, S., Bodo, E., Hagen, E., Biro, T., Arck, P. C. and Paus, R. 2007. Probing the effects of stress mediators on the human hair follicle: substance P holds central position. Am. J. Pathol. 171, 1872-1886. https://doi.org/10.2353/ajpath.2007.061206
  74. Petukhova, L., Duvic, M., Hordinsky, M., Norris, D., Price, V., Shimomura, Y., Kim, H., Singh, P., Lee, A., Chen, W. V., Meyer, K. C., Paus, R., Jahoda, C. A., Amos, C. I., Gregersen, P. K. and Christiano, A. M. 2010. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 466, 113-117. https://doi.org/10.1038/nature09114
  75. Roloff, B., Fechner, K., Slominski, A., Furkert, J., Botchkarev, V. A., Bulfone-Paus, S., Zipper, J., Krause, E. and Paus, R. 1998. Hair cycle-dependent expression of corticotropin-releasing factor (CRF) and CRF receptors in murine skin. Faseb J. 12, 287-297. https://doi.org/10.1096/fasebj.12.3.287
  76. Seetharam, K. A. 2013. Alopecia areata: an update. Indian J. Dermatol. Venereol. Leprol. 79, 563-575. https://doi.org/10.4103/0378-6323.116725
  77. Senila, S. C., Danescu, S. A., Ungureanu, L., Candrea, E. and Cosgarea, R. M. 2015. Intravenous methylprednisolone pulse therapy in severe alopecia areata. Indian J. Dermatol. Venereol. Leprol. 81, 95.
  78. Shellow, W. V., Edwards, J. E. and Koo, J. Y. 1992. Profile of alopecia areata: a questionnaire analysis of patient and family. Int. J. Dermatol. 31, 186-189. https://doi.org/10.1111/j.1365-4362.1992.tb03932.x
  79. Shin, B. S., Furuhashi, T., Nakamura, M., Torii, K. and Morita, A. 2013. Impaired inhibitory function of circulating CD4+ CD25+ regulatory T cells in alopecia areata. J. Dermatol. Sci. 70, 141-143. https://doi.org/10.1016/j.jdermsci.2013.01.006
  80. Siebenhaar, F., Sharov, A. A., Peters, E. M., Sharova, T. Y., Syska, W., Mardaryev, A. N., Freyschmidt-Paul, P., Sundberg, J. P., Maurer, M. and Botchkarev, V. A. 2007. Substance P as an immunomodulatory neuropeptide in a mouse model for autoimmune hair loss (alopecia areata). J. Invest Dermatol. 127, 1489-1497. https://doi.org/10.1038/sj.jid.5700704
  81. Slominski, A., Paus, R. and Mazurkiewicz, J. 1992. Proopiomelanocortin expression in the skin during induced hair growth in mice. Experientia 48, 50-54. https://doi.org/10.1007/BF01923606
  82. Slominski, A., Wortsman, J., Mazurkiewicz, J. E., Matsuoka, L., Dietrich, J., Lawrence, K., Gorbani, A. and Paus, R. 1993. Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin. J. Lab Clin. Med. 122, 658-666.
  83. Slominski, A., Botchkareva, N. V., Botchkarev, V. A., Chakraborty, A., Luger, T., Uenalan, M. and Paus, R. 1998. Hair cycle-dependent production of ACTH in mouse skin. Biochim. Biophys. Acta. 1448, 147-152. https://doi.org/10.1016/S0167-4889(98)00124-4
  84. Slominski, A., Wortsman, J., Luger, T., Paus, R. and Solomon, S. 2000. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol. Rev. 80, 979-1020. https://doi.org/10.1152/physrev.2000.80.3.979
  85. Stenn, K. S. and Paus, R. 2001. Controls of hair follicle cycling. Physiol. Rev. 81, 449-494. https://doi.org/10.1152/physrev.2001.81.1.449
  86. Tan, E., Tay, Y. K., Goh, C. L. and Chin Giam, Y. 2002. The pattern and profile of alopecia areata in Singapore--a study of 219 Asians. Int. J. Dermatol. 41, 748-753. https://doi.org/10.1046/j.1365-4362.2002.01357.x
  87. Todes-Taylor, N., Turner, R., Wood, G. S., Stratte, P. T. and Morhenn, V. B. 1984. T cell subpopulations in alopecia areata. J. Am. Acad. Dermatol. 11, 216-223. https://doi.org/10.1016/S0190-9622(84)70152-6
  88. Trink, A., Sorbellini, E., Bezzola, P., Rodella, L., Rezzani, R., Ramot, Y. and Rinaldi, F. 2013. A randomized, doubleblind, placebo- and active-controlled, half-head study to evaluate the effects of platelet-rich plasma on alopecia areata. Br. J. Dermatol. 169, 690-694. https://doi.org/10.1111/bjd.12397
  89. Wang, X., Marr, A. K., Breitkopf, T., Leung, G., Hao, J., Wang, E., Kwong, N., Akhoundsadegh, N., Chen, L., Mui, A., Carr, N., Warnock, G. L., Shapiro, J. and McElwee, K. J. 2014. Hair follicle mesenchyme-associated PD-L1 regulates T-cell activation induced apoptosis: a potential mechanism of immune privilege. J. Invest Dermatol. 134, 736-745. https://doi.org/10.1038/jid.2013.368
  90. Wasserman, D., Guzman-Sanchez, D. A., Scott, K. and McMichael, A. 2007. Alopecia areata. Int. J. Dermatol. 46, 121-131. https://doi.org/10.1111/j.1365-4632.2007.03193.x
  91. Wengraf, D. A., McDonagh, A. J., Lovewell, T. R., Vasilopoulos, Y., Macdonald-Hull, S. P., Cork, M. J., Messenger, A. G. and Tazi-Ahnini, R. 2008. Genetic analysis of autoimmune regulator haplotypes in alopecia areata. Tissue Antigens. 71, 206-212. https://doi.org/10.1111/j.1399-0039.2007.00992.x
  92. Wu, J., Song, Y., Bakker, A. B., Bauer, S., Spies, T., Lanier, L. L. and Phillips, J. H. 1999. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730-732. https://doi.org/10.1126/science.285.5428.730
  93. Xing, L., Dai, Z., Jabbari, A., Cerise, J. E., Higgins, C. A., Gong, W., de Jong, A., Harel, S., DeStefano, G. M., Rothman, L., Singh, P., Petukhova, L., Mackay-Wiggan, J., Christiano, A. M. and Clynes, R. 2014. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat. Med. 20, 1043-1049. https://doi.org/10.1038/nm.3645
  94. Yokoyama, W. M. and Kim, S. 2006. Licensing of natural killer cells by self-major histocompatibility complex class I. Immunol. Rev. 214, 143-154. https://doi.org/10.1111/j.1600-065X.2006.00458.x
  95. Zawar, V. P. and Karad, G. M. 2016. Liquid Nitrogen Cryotherapy in Recalcitrant Alopecia Areata: A Study of 11 Patients. Int. J. Trichology 8, 15-20. https://doi.org/10.4103/0974-7753.179403
  96. Zhang, X., Yu, M., Yu, W., Weinberg, J., Shapiro, J. and McElwee, K. J. 2009. Development of alopecia areata is associated with higher central and peripheral hypothalamic-pituitary- adrenal tone in the skin graft induced C3H/HeJ mouse model. J. Invest Dermatol. 129, 1527-1538. https://doi.org/10.1038/jid.2008.371