STM Journals Peer-reviewed research from Consortium e-Learning Network

International Journal of Vaccines Review Article

Alopecia Areata: Complex Roots and Potential Cures

  1. Vidit Deshpande
  2. Kedar P. Navsariwala Department of Biotechnology, Dr D. Y. Patil Biotechnology and Bioinformatics Institute, Tathawade, Pune
  3. Atharva Shinde1 Department of Biotechnology, Dr D. Y. Patil Biotechnology and Bioinformatics Institute, Tathawade, Pune
  4. Adri Raj Saha Department of Biotechnology, Dr D. Y. Patil Biotechnology and Bioinformatics Institute, Tathawade, Pune
  5. Navyansh Asthana Department of Biotechnology, Dr D. Y. Patil Biotechnology and Bioinformatics Institute, Tathawade, Pune

Abstract

Autoimmunity is when the healthy organs of an individual’s body are attacked by its own immune system, leading to illness or functional abnormalities. The hair follicles (HFs) are wrongly destroyed by the immune system in a condition known as Alopecia Areata and results in chronic non-cicatricial hair loss discernible by spherical patches. It’s a severely worsening or relapsing malady that can be permanent during severe falling out of hair. In 'Alopecia areata', the phenomenon of lymphocytic penetration is also detected during the 'anagen phase' of proliferating HFs. The ‘JAK-STAT’ pathway is a critical factor that carries out the coordination of the self-inflammatory system ('Immune system'), helps in polarizing ‘T-helper cells’, and carries out multiple functions via several transmembrane receptor families. A major participant in alopecia areata is the infiltrating interferons 'IFN-γ' and the 'TNF-α' in the HF. This compensates HF’s immunity and upregulates the expression of MHC-I. Importantly, the SOCS-3 protein exercises a major part in preventing CD8+ T cell maturation and IFNγ signaling. Immunoglobulin-G (IgG) also appears prevalent in AA victims. The objective covered in the review article is to converse about the diverse immunological, molecular, therapeutic elements in addition to the clinical assessments and their findings that result in loss of hair in AA subjects.

Keywords

References (92)

  1. Pratt CH, King LE, Messenger AG, Christiano AM, Sundberg JP. Alopecia areata. Nature Reviews Disease Primers. 2017;3(1). doi:10.1038/nrdp.2017.11
  2. Qi J, Garza LA. An Overview of Alopecias. Cold Spring Harbor Perspectives in Medicine. 2014;4(3):a013615-a013615. doi:10.1101/cshperspect.a013615
  3. Buckley, J., & Rapini, R. P. (2022). Totalis Alopecia. In StatPearls. StatPearls Publishing.
  4. Price VH, Gummer CL. Loose anagen syndrome. Journal of the American Academy of Dermatology. 1989;20(2):249-256. doi:10.1016/s0190-9622(89)70030-x
  5. Duvic, M., Christiano, A. M., Hordinsky, M. K., Norris, D. A., Price, V. H., & Amos, C. I. (2013). The national alopecia areata registry-update. The journal of investigative dermatology. Symposium
  6. proceedings, 16(1), S53. https://doi.org/10.1038/jidsymp.2013.20
  7. Amy J. McMichael, The genetic epidemiology and autoimmune pathogenesis of alopecia areata, Journal of the European Academy of Dermatology and Venereology, Volume 9, Issue 1, 1997,
  8. Pages 36-43, ISSN 0926-9959, https://doi.org/10.1016/S0926-9959(97)00062-7.
  9. McDonagh, A. J., & Tazi-Ahnini, R. (2002). Epidemiology and genetics of alopecia areata. Clinical and experimental dermatology, 27(5), 405–409. https://doi.org/10.1046/j.1365-
  10. 2230.2002.01077.x
  11. Tau G, Rothman P. Biologic functions of the IFN‐γ receptors. Allergy. 1999;54(12):1233-1251. doi:10.1034/j.1398-9995.1999.00099.x
  12. Harmon, C. S., & Nevins, T. D. (1993). IL-1 alpha inhibits human hair follicle growth and hair fiber production in whole-organ cultures. Lymphokine and cytokine research, 12(4), 197–203.
  13. Tomaszewska, K., Kozłowska, M., Kaszuba, A., Lesiak, A., Narbutt, J., & Zalewska-Janowska, A. (2020). Increased Serum Levels of IFN-γ, IL-1β, and IL-6 in Patients with Alopecia Areata and
  14. Nonsegmental Vitiligo. Oxidative medicine and cellular longevity, 2020, 5693572. https://doi.org/10.1155/2020/5693572
  15. McDonagh AJG, Tazi-Ahnini R. Epidemiology and genetics of alopecia areata. Clinical and Experimental Dermatology. 2002;27(5):405-409. doi:10.1046/j.1365-2230.2002.01077.x
  16. Colombe, B. W., Lou, C. D., & Price, V. H. (1999). The genetic basis of alopecia areata: HLA associations with patchy alopecia areata versus alopecia totalis and alopecia universalis. The journal
  17. of investigative dermatology. Symposium proceedings, 4(3), 216–219. https://doi.org/10.1038/sj.jidsp.5640214
  18. Barahmani, N., de Andrade, M., Slusser, J. P., Zhang, Q., & Duvic, M. (2006). Major histocompatibility complex class I chain-related gene A polymorphisms and extended haplotypes
  19. are associated with familial alopecia areata. The Journal of investigative dermatology, 126(1), 74–
  20. https://doi.org/10.1038/sj.jid.5700009
  21. Tazi-Ahnini, R., Cork, M. J., Gawkrodger, D. J., Birch, M. P., Wengraf, D., McDonagh, A. J., & Messenger, A. G. (2002). Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong
  22. association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue antigens, 60(6), 489–495. https://doi.org/10.1034/j.1399-0039.2002.600604.x
  23. Kemp, E. H., McDonagh, A. J., Wengraf, D. A., Messenger, A. G., Gawkrodger, D. J., Cork, M. J., & Tazi-Ahnini, R. (2006). The non-synonymous C1858T substitution in the PTPN22 gene is
  24. associated with susceptibility to the severe forms of alopecia areata. Human immunology, 67(7), 535–539. https://doi.org/10.1016/j.humimm.2006.04.006
  25. Tazi-Ahnini, R., Cox, A., McDonagh, A. J., Nicklin, M. J., di Giovine, F. S., Timms, J. M., Messenger, A. G., Dimitropoulou, P., Duff, G. W., & Cork, M. J. (2002). Genetic analysis of the
  26. interleukin-1 receptor antagonist and its homologue IL-1L1 in alopecia areata: strong severity association and possible gene interaction. European journal of immunogenetics : official journal of
  27. the British Society for Histocompatibility and Immunogenetics, 29(1), 25–30. https://doi.org/10.1046/j.1365-2370.2002.00271.x
  28. Shimizu, T., Hizawa, N., Honda, A., Zhao, Y., Abe, R., Watanabe, H., Nishihira, J., Nishimura, M., & Shimizu, H. (2005). Promoter region polymorphism of macrophage migration inhibitory factor
  29. is strong risk factor for young onset of extensive alopecia areata. Genes and immunity, 6(4), 285–289. https://doi.org/10.1038/sj.gene.6364191
  30. Tazi-Ahnini, R., Cork, M. J., Wengraf, D., Wilson, A. G., Gawkrodger, D. J., Birch, M. P., Messenger, A. G., & McDonagh, A. J. (2003). Notch4, a non-HLA gene in the MHC is strongly
  31. associated with the most severe form of alopecia areata. Human genetics, 112(4), 400–403. https://doi.org/10.1007/s00439-002-0898-9
  32. Martinez-Mir, A., Zlotogorski, A., Gordon, D., Petukhova, L., Mo, J., Gilliam, T. C., Londono, D., Haynes, C., Ott, J., Hordinsky, M., Nanova, K., Norris, D., Price, V., Duvic, M., & Christiano, A.
  33. Martinez-Mir A, Zlotogorski A, Gordon D, Petukhova L, Mo J, Gilliam TC, et al. Genomewide Scan for Linkage Reveals Evidence of Several Susceptibility Loci for Alopecia Areata. The American Journal of Human Genetics. 2007;80(2):316-328. doi:10.1086/511442
  34. Thomas, S. J., Snowden, J. A., Zeidler, M. P., & Danson, S. J. (2015). The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. British journal of cancer,
  35. 113(3), 365–371. https://doi.org/10.1038/bjc.2015.233
  36. Pi, L. Q., Jin, X. H., Hwang, S. T., & Lee, W. S. (2013). Effects of calcitonin gene-related peptide on the immune privilege of human hair follicles. Neuropeptides, 47(1), 51–57.
  37. https://doi.org/10.1016/j.npep.2012.07.008
  38. Westgate, G. E., Craggs, R. I., & Gibson, W. T. (1991). Immune privilege in hair growth. The Journal of investigative dermatology, 97(3), 417–420. https://doi.org/10.1111/1523-
  39. 1747.ep12481002
  40. Gilhar A, Etzioni A, Paus R. Alopecia Areata. New England Journal of Medicine. 2012;366(16):1515-1525. doi:10.1056/nejmra1103442
  41. Gilhar, A., Kam, Y., Assy, B., & Kalish, R. S. (2005). Alopecia areata induced in C3H/HeJ mice by interferon-gamma: evidence for loss of immune privilege. The Journal of investigative
  42. dermatology, 124(1), 288–289. https://doi.org/10.1111/j.0022-202X.2004.23580.x
  43. Gilhar, A., Etzioni, A., Assy, B., & Eidelman, S. (1993). Response of grafts from patients with alopecia areata transplanted onto nude mice, to administration of interferon-gamma. Clinical
  44. immunology and immunopathology, 66(2), 120–126. https://doi.org/10.1006/clin.1993.1015
  45. Darwiche, R., Chong, M. M., Santamaria, P., Thomas, H. E., & Kay, T. W. (2003). Fas is detectable on beta cells in accelerated, but not spontaneous, diabetes in nonobese diabetic mice. Journal of
  46. immunology (Baltimore, Md. : 1950), 170(12), 6292–6297. https://doi.org/10.4049/jimmunol.170.12.6292
  47. Freyschmidt-Paul, P., McElwee, K. J., Botchkarev, V., Kissling, S., Wenzel, E., Sundberg, J. P.,
  48. Happle, R., & Hoffmann, R. (2003). Fas-deficient C3.MRL-Tnfrsf6(lpr) mice and Fas liganddeficient C3H/HeJ-Tnfsf6(gld) mice are relatively resistant to the induction of alopecia areata by
  49. grafting of alopecia areata-affected skin from C3H/HeJ mice. The journal of investigative
  50. dermatology. Symposium proceedings, 8(1), 104–108. https://doi.org/10.1046/j.1523-
  51. 1747.2003.12182.x
  52. Dai, Z., Xing, L., Cerise, J., Wang, E. H., Jabbari, A., de Jong, A., Petukhova, L., Christiano, A. M., & Clynes, R. (2016). CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents
  53. Development of Alopecia Areata. Journal of immunology (Baltimore, Md. : 1950), 197(4), 1089– 1099. https://doi.org/10.4049/jimmunol.1501798
  54. Ito T. Recent Advances in the Pathogenesis of Autoimmune Hair Loss Disease Alopecia Areata. Clinical and Developmental Immunology. 2013;2013:1-6. doi:10.1155/2013/348546
  55. Gao, Z., Jin, Y. Q., & Wu, W. (2017). SOCS-3 treatment prevents the development of alopecia
  56. areata by inhibiting CD8+ T cell-mediated autoimmune destruction. Oncotarget, 8(20), 33432– 33443. https://doi.org/10.18632/oncotarget.16504
  57. Paus, R., Slominski, A., & Czarnetzki, B. M. (1993). Is alopecia areata an autoimmune-responseagainst melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagenhair bulb?. The Yale journal of biology and medicine, 66(6), 541–554.
  58. Peereboom-Wynia, J. D., van Joost, T., Stolz, E., & Prins, M. E. (1986). Markers of immunologicinjury in progressive alopecia areata. Journal of cutaneous pathology, 13(5), 363–369.
  59. https://doi.org/10.1111/j.1600-0560.1986.tb00471.x/
  60. Nakamura, M., Jo, J., Tabata, Y., & Ishikawa, O. (2008). Controlled delivery of T-box21 smallinterfering RNA ameliorates autoimmune alopecia (Alopecia Areata) in a C3H/HeJ mouse model.
  61. The American journal of pathology, 172(3), 650–658. https://doi.org/10.2353/ajpath.2008.061249 Alopecia Areata: Complex Roots and Potential Cures Shinde et al.
  62. Freyschmidt-Paul, P., McElwee, K. J., Hoffmann, R., Sundberg, J. P., Vitacolonna, M., Kissling, S., & Zöller, M. (2006). Interferon-gamma-deficient mice are resistant to the development of
  63. alopecia areata. The British journal of dermatology, 155(3), 515–521. https://doi.org/10.1111/j.1365-2133.2006.07377.x
  64. Eisman, S., & Sinclair, R. (2021). Ritlecitinib: an investigational drug for the treatment of moderate to severe alopecia areata. Expert opinion on investigational drugs, 30(12), 1169–1174.
  65. https://doi.org/10.1080/13543784.2021.2012149
  66. Muñoz-Bellido, F. J., Moreno, E., & Dávila, I. (2022). Dupilumab: A Review of Present Indications and Off-Label Uses. Journal of investigational allergology & clinical immunology, 32(2), 97–115.
  67. https://doi.org/10.18176/jiaci.0682
  68. Fahr A. Cyclosporin Clinical Pharmacokinetics. Clinical Pharmacokinetics. 1993;24(6):472-495. doi:10.2165/00003088-199324060-00004
  69. Wu, S. Z., Wang, S., Ratnaparkhi, R., & Bergfeld, W. F. (2018). Treatment of pediatric alopecia areata with anthralin: A retrospective study of 37 patients. Pediatric dermatology, 35(6), 817–820.
  70. https://doi.org/10.1111/pde.13703
  71. King, B., Ohyama, M., Kwon, O., Zlotogorski, A., Ko, J., Mesinkovska, N. A., Hordinsky, M., Dutronc, Y., Wu, W. S., McCollam, J., Chiasserini, C., Yu, G., Stanley, S., Holzwarth, K., DeLozier, A. M., Sinclair, R., & BRAVE-AA Investigators (2022). Two Phase 3 Trials of
  72. Baricitinib for Alopecia Areata. The New England journal of medicine, 386(18), 1687–1699.
  73. https://doi.org/10.1056/NEJMoa2110343
  74. King, B., Guttman-Yassky, E., Peeva, E., Banerjee, A., Sinclair, R., Pavel, A. B., Zhu, L., Cox, L.
  75. A., Craiglow, B., Chen, L., Banfield, C., Page, K., Zhang, W., & Vincent, M. S. (2021). A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase
  76. inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results. Journal of the American Academy of Dermatology, 85(2), 379–387. https://doi.org/10.1016/j.jaad.2021.03.050
  77. Guttman-Yassky, E., Renert-Yuval, Y., Bares, J., Chima, M., Hawkes, J. E., Gilleaudeau, P.,
  78. Sullivan-Whalen, M., Singer, G. K., Garcet, S., Pavel, A. B., Lebwohl, M. G., & Krueger, J. G. (2022). Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients.
  79. Allergy, 77(3), 897–906. https://doi.org/10.1111/all.15071
  80. Guttman-Yassky, E., Pavel, A. B., Diaz, A., Zhang, N., Del Duca, E., Estrada, Y., King, B., Banerjee, A., Banfield, C., Cox, L. A., Dowty, M. E., Page, K., Vincent, M. S., Zhang, W., Zhu, L.,
  81. & Peeva, E. (2022). Ritlecitinib and brepocitinib demonstrate significant improvement in scalp alopecia areata biomarkers. The Journal of allergy and clinical immunology, 149(4), 1318–1328.
  82. https://doi.org/10.1016/j.jaci.2021.10.036
  83. Lai, V., Chen, G., & Sinclair, R. (2021). Impact of cyclosporin treatment on health-related quality of life of patients with alopecia areata. The Journal of dermatological treatment, 32(2), 250–257.
  84. https://doi.org/10.1080/09546634.2019.1654068
  85. Xing, L., Dai, Z., Jabbari, A. et al. Alopecia areata is driven by cytotoxic T lymphocytes and is
  86. reversed by JAK inhibition. Nat Med 20, 1043–1049 (2014). https://doi.org/10.1038/nm.3645
  87. Poole R, Ballantyne A (2014) Apremilast: first global approval. Drugs 74(7):825–837. https://doi.org/10.1007/ s40265-014-0218-4
  88. Keren A, Shemer A, Ullmann Y, Paus R, Gilhar A (2015) The PDE4 inhibitor, apremilast, suppresses experimentally induced alopecia areata in human skin in vivo. J Dermatol Sci 77(1):74–
  89. https://doi.org/10.1016/j.jdermsci.2014.11.009
  90. NIH US (2020) National Library of Medicine. http://www.clini caltrials.gov/
  91. Mackay-Wiggan J, Sallee BN, Chun Wang EH, Sansaricq F, Nguyen N, Kim C, Chen JC, Christiano AM, Clynes R (2020) An open-label study evaluating the efficacy of abatacept in
  92. alopecia areata. J Am Acad Dermatol. https://doi.org/10.1016/j.jaad.2020. 09.091