421
Views
52
CrossRef citations to date
0
Altmetric
Review

The role of lymphocytes in the development and treatment of alopecia areata

, , &

References

  • Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol 2010;62(2):177-88
  • Gilhar A, Kalish RS. Alopecia areata: a tissue specific autoimmune disease of the hair follicle. Autoimmun Rev 2006;5(1):64-9
  • Thomas EA, Kadyan RS. Alopecia areata and autoimmunity: a clinical study. Indian J Dermatol 2008;53(2):70-4
  • Mirzoyev SA, Schrum AG, Davis MD, Torgerson RR. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009. J Invest Dermatol 2014;134(4):1141-2
  • Kos L, Conlon J. An update on alopecia areata. Curr Opin Pediatr 2009;21(4):475-80
  • McMichael AJ, Pearce DJ, Wasserman D, et al. Alopecia in the United States: outpatient utilization and common prescribing patterns. J Am Acad Dermatol 2007;57(2 Suppl):S49-51
  • Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata update: part II. Treatment. J Am Acad Dermatol 2010;62(2):191-202
  • Wang E, McElwee KJ. Etiopathogenesis of alopecia areata: Why do our patients get it? Dermatol Ther 2011;24(3):337-47
  • Xiao FL, Yang S, Liu JB, et al. The epidemiology of childhood alopecia areata in China: a study of 226 patients. Pediatr Dermatol 2006;23(1):13-18
  • Barahmani N, Schabath MB, Duvic M. History of atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol 2009;61(4):581-91
  • Lomas M, Hanon E, Tanaka Y, et al. Presentation of a new H-2D(k)-restricted epitope in the Tax protein of human T-lymphotropic virus type I is enhanced by the proteasome inhibitor lactacystin. J Gen Virol 2002;83(Pt 3):641-650
  • Nanda A, Al-Fouzan AS, Al-Hasawi F. Alopecia areata in children: a clinical profile. Pediatr Dermatol 2002;19(6):482-5
  • Ma XJ, Cao SL, Lin L, et al. Hydrothermal pretreatment of bamboo and cellulose degradation. Bioresour Technol 2013;148:408-13
  • Chu SY, Chen YJ, Tseng WC, et al. Comorbidity profiles among patients with alopecia areata: the importance of onset age, a nationwide population-based study. J Am Acad Dermatol 2011;65(5):949-56
  • McElwee KJ, Gilhar A, Tobin DJ, et al. What causes alopecia areata? Exp Dermatol 2013;22(9):609-26
  • Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 2014;20(9):1043-9
  • Kurashima Y, Amiya T, Fujisawa K, et al. The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis. Immunity 2014;40(4):530-41
  • Bertolini M, Zilio F, Rossi A, et al. Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata. PLoS One 2014;9(5):e94260
  • Abou Rahal J, Kurban M, Kibbi AG, Abbas O. Plasmacytoid dendritic cells in alopecia areata: missing link? J Eur Acad Dermatol Venereol 2014. [Epub ahead of print]
  • Heffler LC, Kastman AL, Jacobsson Ekman G, et al. Langerhans cells that express matrix metalloproteinase 9 increase in human dermis during sensitization to diphenylcyclopropenone in patients with alopecia areata. Br J Dermatol 2002;147(2):222-9
  • Gupta P, Freyschmidt-Paul P, Vitacolonna M, et al. A chronic contact eczema impedes migration of antigen-presenting cells in alopecia areata. J Invest Dermatol 2006;126(7):1559-73
  • Veldhoen M, Ferreira C. Influence of nutrient-derived metabolites on lymphocyte immunity. Nat Med 2015;21(7):709-18
  • Watanabe R, Gehad A, Yang C, et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Transl Med 2015;7(279):279ra239
  • Biran R, Zlotogorski A, Ramot Y. The genetics of alopecia areata: new approaches, new findings, new treatments. J Dermatol Sci 2015;78(1):11-20
  • Petukhova L, Duvic M, Hordinsky M, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 2010;466(7302):113-17
  • Perret C, Wiesner-Menzel L, Happle R. Immunohistochemical analysis of T-cell subsets in the peribulbar and intrabulbar infiltrates of alopecia areata. Acta Derm Venereol 1984;64(1):26-30
  • Wiesner-Menzel L, Happle R. Intrabulbar and peribulbar accumulation of dendritic OKT 6-positive cells in alopecia areata. Arch Dermatol Res 1984;276(5):333-4
  • Ranki A, Kianto U, Kanerva L, et al. Immunohistochemical and electron microscopic characterization of the cellular infiltrate in alopecia (areata, totalis, and universalis). J Invest Dermatol 1984;83(1):7-11
  • McElwee KJ, Silva K, Boggess D, et al. Alopecia areata in C3H/HeJ mice involves leukocyte-mediated root sheath disruption in advance of overt hair loss. Vet Pathol 2003;40(6):643-50
  • Ono S, Otsuka A, Yamamoto Y, et al. Serum granulysin as a possible key marker of the activity of alopecia areata. J Dermatol Sci 2014;73(1):74-9
  • Bodemer C, Peuchmaur M, Fraitaig S, et al. Role of cytotoxic T cells in chronic alopecia areata. J Invest Dermatol 2000;114(1):112-16
  • Carroll JM, McElwee KJ, Byrne MC, Sundberg JP. Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans. J Invest Dermatol 2002;119(2):392-402
  • Freyschmidt-Paul P, McElwee KJ, Botchkarev V, et al. Fas-deficient C3.MRL-Tnfrsf6(lpr) mice and Fas ligand-deficient C3H/HeJ-Tnfsf6(gld) mice are relatively resistant to the induction of alopecia areata by grafting of alopecia areata-affected skin from C3H/HeJ mice. J Investig Dermatol Symp Proc 2003;8(1):104-8
  • Zoller M, McElwee KJ, Vitacolonna M, Hoffmann R. The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells. Exp Dermatol 2004;13(7):435-44
  • Zoller M, McElwee KJ, Vitacolonna M, Hoffmann R. Apoptosis resistance in peripheral blood lymphocytes of alopecia areata patients. J Autoimmun 2004;23(3):241-56
  • Divito SJ, Kupper TS. Inhibiting Janus kinases to treat alopecia areata. Nat Med 2014;20(9):989-90
  • Geyfman M, Plikus MV, Treffeisen E, et al. Resting no more: re-defining telogen, the maintenance stage of the hair growth cycle. Biol Rev Camb Philos Soc 2014; Epub ahead of print
  • Breitkopf T, Leung G, Yu M, et al. The basic science of hair biology: what are the causal mechanisms for the disordered hair follicle? Dermatol Clin 2013;31(1):1-19
  • Paus R, Bertolini M. The role of hair follicle immune privilege collapse in alopecia areata: status and perspectives. J Investig Dermatol Symp Proc 2013;16(1):S25-7
  • Westgate GE, Craggs RI, Gibson WT. Immune privilege in hair growth. J Invest Dermatol 1991;97(3):417-20
  • Becker JC, Varki N, Brocker EB, Reisfeld RA. Lymphocyte-mediated alopecia in C57BL/6 mice following successful immunotherapy for melanoma. J Invest Dermatol 1996;107(4):627-32
  • McElwee KJ, Hoffmann R. Alopecia areata - animal models. Clin Exp Dermatol 2002;27(5):410-17
  • Boffa MJ, Wood P, Griffiths CE. Iron status of patients with alopecia areata. Br J Dermatol 1995;132(4):662-4
  • Ferguson TA, Griffith TS. A vision of cell death: Fas ligand and immune privilege 10 years later. Immunol Rev 2006;213:228-38
  • Wang X, Marr AK, Breitkopf T, et al. Hair follicle mesenchyme-associated PD-L1 regulates T-cell activation induced apoptosis: a potential mechanism of immune privilege. J Invest Dermatol 2014;134(3):736-45
  • Guleria I, Khosroshahi A, Ansari MJ, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 2005;202(2):231-7
  • Habicht A, Dada S, Jurewicz M, et al. A link between PDL1 and T regulatory cells in fetomaternal tolerance. J Immunol 2007;179(8):5211-19
  • Ritprajak P, Hashiguchi M, Tsushima F, et al. Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses. J Immunol 2010;184(9):4918-25
  • Azuma T, Yao S, Zhu G, et al.7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 2008;111(7):3635-43
  • Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007;27(1):111-22
  • Ito T, Ito N, Bettermann A, et al. Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model. Am J Pathol 2004;164(2):623-34
  • Breitkopf T, Lo BK, Leung G, et al. Somatostatin expression in human hair follicles and its potential role in immune privilege. J Invest Dermatol 2013;133(7):1722-30
  • Mahi-Brown CA, Yule TD, Tung KS. Adoptive transfer of murine autoimmune orchitis to naive recipients with immune lymphocytes. Cell Immunol 1987;106(2):408-19
  • Tung KS, Yule TD, Mahi-Brown CA, Listrom MB. Distribution of histopathology and Ia positive cells in actively induced and passively transferred experimental autoimmune orchitis. J Immunol 1987;138(3):752-9
  • Kaplan HJ, Streilein JW. Immune response to immunization via the anterior chamber of the eye. II. An analysis of F1 lymphocyte-induced immune deviation. J Immunol 1978;120(3):689-93
  • Tafuri A, Alferink J, Moller P, et al. T cell awareness of paternal alloantigens during pregnancy. Science 1995;270(5236):630-3
  • Kang H, Wu WY, Lo BK, et al. Hair follicles from alopecia areata patients exhibit alterations in immune privilege-associated gene expression in advance of hair loss. J Invest Dermatol 2011;130(11):2677-80
  • Saxena A, Martin-Blondel G, Mars LT, Liblau RS. Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis. FEBS Lett 2011;585(23):3758-63
  • Ganguly D, Haak S, Sisirak V, Reizis B. The role of dendritic cells in autoimmunity. Nat Rev Immunol 2013;13(8):566-77
  • Turley S, Poirot L, Hattori M, et al. Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med 2003;198(10):1527-37
  • McElwee KJ, Boggess D, Olivry T, et al. Comparison of alopecia areata in human and nonhuman mammalian species. Pathobiology 1998;66(2):90-107
  • Ito T, Ito N, Saatoff M, et al. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J Invest Dermatol 2008;128(5):1196-206
  • Gregoriou S, Papafragkaki D, Kontochristopoulos G, et al. Cytokines and other mediators in alopecia areata. Mediators Inflamm 2010;928030
  • Kim HS, Cho DH, Kim HJ, et al. Immunoreactivity of corticotropin-releasing hormone, adrenocorticotropic hormone and alpha-melanocyte-stimulating hormone in alopecia areata. Exp Dermatol 2006;15(7):515-22
  • Megiorni F, Pizzuti A, Mora B, et al. Genetic association of HLA-DQB1 and HLA-DRB1 polymorphisms with alopecia areata in the Italian population. Br J Dermatol 2011;165(4):823-7
  • Xiao FL, Zhou FS, Liu JB, et al. Association of HLA-DQA1 and DQB1 alleles with alolpecia areata in Chinese Hans. Arch Dermatol Res 2005;297(5):201-9
  • Akar A, Orkunoglu E, Sengul A, et al. HLA class II alleles in patients with alopecia areata. Eur J Dermatol 2002;12(3):236-9
  • Gilhar A, Kam Y, Assy B, Kalish RS. Alopecia areata induced in C3H/HeJ mice by interferon-gamma: evidence for loss of immune privilege. J Invest Dermatol 2005;124(1):288-9
  • Sundberg JP, Silva KA, Edwards K, et al. C3H/HeJ mice with exogenous interferon gamma. J Exp Animal Sci 2007;43(4):265-70
  • Freyschmidt-Paul P, McElwee KJ, Hoffmann R, et al. Interferon-gamma-deficient mice are resistant to the development of alopecia areata. Br J Dermatol 2006;155(3):515-21
  • Paus R, Ito N, Takigawa M, Ito T. The hair follicle and immune privilege. J Investig Dermatol Symp Proc 2003;8(2):188-94
  • Kaka AS, Shaffer DR, Hartmaier R, et al. Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes. J Immunother 2009;32(7):726-36
  • Romagnani S. Immunological tolerance and autoimmunity. Intern Emerg Med 2006;1(3):187-96
  • Andersen MH, Schrama D, Thor Straten P, Becker JC. Cytotoxic T cells. J Invest Dermatol 2006;126(1):32-41
  • Gravano DM, Hoyer KK. Promotion and prevention of autoimmune disease by CD8+ T cells. J Autoimmun 2013;45:68-79
  • McElwee KJ, Freyschmidt-Paul P, Zoller M, Hoffmann R. Alopecia areata susceptibility in rodent models. J Investig Dermatol Symp Proc 2003;8(2):182-7
  • Alli R, Nguyen P, Boyd K, et al. A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis. J Immunol 2012;188(1):477-86
  • Paus R, Eichmuller S, Hofmann U, et al. Expression of classical and non-classical MHC class I antigens in murine hair follicles. Br J Dermatol 1994;131(2):177-83
  • McElwee KJ, Hoffmann R, Freyschmidt-Paul P, et al. Resistance to alopecia areata in C3H/HeJ mice is associated with increased expression of regulatory cytokines and a failure to recruit CD4+ and CD8+ cells. J Invest Dermatol 2002;119(6):1426-33
  • Zoller M, McElwee KJ, Engel P, Hoffmann R. Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata. J Invest Dermatol 2002;118(6):983-92
  • Zhang B, Zhao Y, Cai Z, et al. Early stage alopecia areata is associated with inflammation in the upper dermis and damage to the hair follicle infundibulum. Australas J Dermatol 2013;54(3):184-91
  • McElwee KJ, Freyschmidt-Paul P, Sundberg JP, Hoffmann R. The pathogenesis of alopecia areata in rodent models. J Investig Dermatol Symp Proc 2003;8(1):6-11
  • McElwee KJ, Spiers EM, Oliver RF. In vivo depletion of CD8+ T cells restores hair growth in the DEBR model for alopecia areata. Br J Dermatol 1996;135(2):211-17
  • McElwee KJ, Spiers EM, Oliver RF. Partial restoration of hair growth in the DEBR model for Alopecia areata after in vivo depletion of CD4+ T cells. Br J Dermatol 1999;140(3):432-7
  • McElwee KJ, Tobin DJ, Bystryn JC, et al. Alopecia areata: an autoimmune disease? Exp Dermatol 1999;8(5):371-9
  • McElwee KJ, Freyschmidt-Paul P, Hoffmann R, et al. Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model. J Invest Dermatol 2005;124(5):947-57
  • Gilhar A, Ullmann Y, Berkutzki T, et al. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest 1998;101(1):62-7
  • Gilhar A, Landau M, Assy B, et al. Mediation of alopecia areata by cooperation between CD4+ and CD8+ T lymphocytes: transfer to human scalp explants on Prkdc(scid) mice. Arch Dermatol 2002;138(7):916-22
  • Gebhardt T, Whitney PG, Zaid A, et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 2011;477(7363):216-19
  • Yu M, Kissling S, Freyschmidt-Paul P, et al. Interleukin-6 cytokine family member oncostatin M is a hair-follicle-expressed factor with hair growth inhibitory properties. Exp Dermatol 2008;17(1):12-19
  • Tobin DJ. Morphological analysis of hair follicles in alopecia areata. Microsc Res Tech 1997;38(4):443-51
  • Lu W, Shapiro J, Yu M, et al. Alopecia areata: pathogenesis and potential for therapy. Expert Rev Mol Med 2006;8(14):1-19
  • Veldhoen M, Seddon B. Empowering T helper 17 cells in autoimmunity. Nat Med 2010;16(2):166-8
  • Isailovic N, Daigo K, Mantovani A, Selmi C. Interleukin-17 and innate immunity in infections and chronic inflammation. J Autoimmun 2015;60:1-11
  • Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441(7090):235-8
  • Tato CM, O’Shea JJ. Immunology: what does it mean to be just 17? Nature 2006;441(7090):166-8
  • Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 2014;14(9):585-600
  • Lew BL, Cho HR, Haw S, et al. Association between IL17A/IL17RA Gene Polymorphisms and Susceptibility to Alopecia Areata in the Korean Population. Annals of dermatology 2012;24(1):61-5
  • Tembhre MK, Sharma VK. T-helper and regulatory T-cell cytokines in the peripheral blood of patients with active alopecia areata. Br J Dermatol 2013;169(3):543-8
  • Tanemura A, Oiso N, Nakano M, et al. Alopecia areata: infiltration of Th17 cells in the dermis, particularly around hair follicles. Dermatology 2013;226(4):333-6
  • Tojo G, Fujimura T, Kawano M, et al. Comparison of interleukin-17- producing cells in different clinical types of alopecia areata. Dermatology 2013;227(1):78-82
  • Avitabile S, Sordi D, Garcovich S, et al. Effective squaric acid dibutylester immunotherapy is associated with a reduction of skin infiltrating T-helper (Th)1 and Th17 cells in alopecia areata patients. J Dermatol 2015;42(1):98-9
  • Sakaguchi S, Ono M, Setoguchi R, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006;212:8-27
  • Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299(5609):1057-61
  • Corthay A. How do regulatory T cells work? Scand J Immunol 2009;70(4):326-36
  • Rubtsov YP, Rasmussen JP, Chi EY, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008;28(4):546-58
  • Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450(7169):566-9
  • Csencsits K, Wood SC, Lu G, Bishop DK. Transforming growth factor-beta1 gene transfer is associated with the development of regulatory cells. Am J Transplant 2005;5(10):2378-84
  • Fu S, Zhang N, Yopp AC, et al. TGF-beta induces Foxp3 + T-regulatory cells from CD4 + CD25 - precursors. Am J Transplant 2004;4(10):1614-27
  • Andersson J, Tran DQ, Pesu M, et al. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med 2008;205(9):1975-81
  • Daley SR, Ma J, Adams E, et al. A key role for TGF-beta signaling to T cells in the long-term acceptance of allografts. J Immunol 2007;179(6):3648-54
  • Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007;8(9):942-9
  • Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006;126(6):1121-33
  • Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology 2006;117(3):289-300
  • Nagahama K, Nishimura E, Sakaguchi S. Induction of tolerance by adoptive transfer of Treg cells. Methods Mol Biol 2007;380:431-42
  • Bennett CL, Brunkow ME, Ramsdell F, et al. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA–>AAUGAA) leads to the IPEX syndrome. Immunogenetics 2001;53(6):435-9
  • Mahic M, Henjum K, Yaqub S, et al. Generation of highly suppressive adaptive CD8(+)CD25(+)FOXP3(+) regulatory T cells by continuous antigen stimulation. Eur J Immunol 2008;38(3):640-6
  • Shin BS, Furuhashi T, Nakamura M, et al. Impaired inhibitory function of circulating CD4+CD25+ regulatory T cells in alopecia areata. J Dermatol Sci 2013;70(2):141-3
  • Conteduca G, Rossi A, Megiorni F, et al. Single nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG genes are associated with Alopecia areata. Clin Exp Med 2014;14(1):91-7
  • Sanchez Rodriguez R, Pauli ML, Neuhaus IM, et al. Memory regulatory T cells reside in human skin. J Clin Invest 2014;124(3):1027-36
  • Boyman O, Letourneau S, Krieg C, Sprent J. Homeostatic proliferation and survival of naive and memory T cells. Eur J Immunol 2009;39(8):2088-94
  • Brownlie RJ, Zamoyska R. T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol 2013;13(4):257-69
  • Hogquist KA, Jameson SC. The self-obsession of T cells: how TCR signaling thresholds affect fate ’decisions’ and effector function. Nat Immunol 2014;15(9):815-23
  • Nolz JC, Starbeck-Miller GR, Harty JT. Naive, effector and memory CD8 T-cell trafficking: parallels and distinctions. Immunotherapy 2011;3(10):1223-33
  • Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity 2008;29(6):848-62
  • Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol 2000;1(5):426-32
  • McKinney EF, Lyons PA, Carr EJ, et al. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 2010;16(5):586-91
  • Sundberg JP, Boggess D, Silva KA, et al. Major locus on mouse chromosome 17 and minor locus on chromosome 9 are linked with alopecia areata in C3H/HeJ mice. J Invest Dermatol 2003;120(5):771-5
  • Tazi-Ahnini R, Cork MJ, Gawkrodger DJ, et al. Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue Antigens 2002;60(6):489-95
  • McDonagh AJ, Tazi-Ahnini R. Epidemiology and genetics of alopecia areata. Clin Exp Dermatol 2002;27(5):405-9
  • Laakso SM, Kekalainen E, Rossi LH, et al. IL-7 dysregulation and loss of CD8+ T cell homeostasis in the monogenic human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Immunol 2011;187(4):2023-30
  • Subramanya RD, Coda AB, Sinha AA. Transcriptional profiling in alopecia areata defines immune and cell cycle control related genes within disease-specific signatures. Genomics 2010;96(3):146-53
  • Berard M, Tough DF. Qualitative differences between naive and memory T cells. Immunology 2002;106(2):127-38
  • Seder RA, Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol 2003;4(9):835-42
  • Sallusto F, Baggiolini M. Chemokines and leukocyte traffic. Nat Immunol 2008;9(9):949-52
  • Shin H, Iwasaki A. Tissue-resident memory T cells. Immunol Rev 2013;255(1):165-81
  • Mueller SN, Zaid A, Carbone FR. Tissue-resident T cells: dynamic players in skin immunity. Front Immunol 2014;5:332
  • Ariotti S, Beltman JB, Chodaczek G, et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc Natl Acad Sci U S A 2012;109(48):19739-44
  • Mackay LK, Rahimpour A, Ma JZ, et al. The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. Nat Immunol 2013;14(12):1294-301
  • Sowell RT, Marzo AL. Resident-Memory CD8 T Cells and mTOR: Generation, Protection, and Clinical Importance. Front Immunol 2015;6:38
  • Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 1997;389(6654):978-81
  • Clark RA, Chong B, Mirchandani N, et al. The vast majority of CLA+ T cells are resident in normal skin. J Immunol 2006;176(7):4431-9
  • Tufail S, Badrealam KF, Sherwani A, et al. Tissue specific heterogeneity in effector immune cell response. Front Immunol 2013;4:254
  • Clark RA, Huang SJ, Murphy GF, et al. Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med 2008;205(10):2221-34
  • Yano S, Nakamura K, Okochi H, Tamaki K. Analysis of the expression of cutaneous lymphocyte-associated antigen on the peripheral blood and cutaneous lymphocytes of alopecia areata patients. Acta Derm Venereol 2002;82(2):82-5
  • Lewis KL, Reizis B. Dendritic cells: arbiters of immunity and immunological tolerance. Cold Spring Harbor Perspect Biol 2012;4(8):a007401
  • Reizis B. Classical dendritic cells as a unique immune cell lineage. J Exp Med 2012;209(6):1053-6
  • Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol 2004;5(12):1219-26
  • Zaba LC, Krueger JG, Lowes MA. Resident and “inflammatory” dendritic cells in human skin. J Invest Dermatol 2009;129(2):302-8
  • Malissen B, Tamoutounour S, Henri S. The origins and functions of dendritic cells and macrophages in the skin. Nat Rev Immunol 2014;14(6):417-28
  • Forster R, Braun A, Worbs T. Lymph node homing of T cells and dendritic cells via afferent lymphatics. Trends Immunol 2012;33(6):271-80
  • Benoist C, Mathis D. Mast cells in autoimmune disease. Nature 2002;420(6917):875-8
  • Brown MA, Hatfield JK. Mast Cells are Important Modifiers of Autoimmune Disease: With so Much Evidence, Why is There Still Controversy? Front Immunol 2012;3:147
  • Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med 2015;373(2):163-72
  • Harvima IT, Nilsson G. Mast cells as regulators of skin inflammation and immunity. Acta Derm Venereol 2011;91(6):644-50
  • Theoharides TC, Alysandratos KD, Angelidou A, et al. Mast cells and inflammation. Biochim Biophys Acta 2012;1822(1):21-33
  • Xu Y, Chen G. Mast cell and autoimmune diseases. Mediators Inflamm 2015;246126
  • Christy AL, Brown MA. The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol 2007;179(5):2673-9
  • Sardesai VR, Prasad S, Agarwal TD. A study to evaluate the efficacy of various topical treatment modalities for alopecia areata. Int J Trichol 2012;4(4):265-70
  • Freyschmidt-Paul P, Happle R, McElwee KJ, Hoffmann R. Alopecia areata: treatment of today and tomorrow. J Investig Dermatol Symp Proc 2003;8(1):12-17
  • Freyschmidt-Paul P, Hoffmann R, Levine E, et al. Current and potential agents for the treatment of alopecia areata. Curr Pharm Des 2001;7(3):213-30
  • Chu T, Al Jasser M, Alharbi A, et al. Benefit of Different Concentrations of Intralesional Triamcinolone Acetonide in Alopecia Areata: An Intrasubject Pilot Study. J Am Acad Dermatol. 2015; Epub ahead of print
  • Happle R, Hausen BM, Wiesner-Menzel L. Diphencyprone in the treatment of alopecia areata. Acta Derm Venereol 1983;63(1):49-52
  • Happle R, Kalveram KJ, Buchner U, et al. Contact allergy as a therapeutic tool for alopecia areata: application of squaric acid dibutylester. Dermatologica 1980;161(5):289-97
  • Shapiro J. Topical immunotherapy in the treatment of chronic severe alopecia areata. Dermatol Clin 1993;11(3):611-17
  • Sun J, Silva KA, McElwee KJ, et al. The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results. Exp Dermatol 2008;17(10):793-805
  • Herbst V, Zoller M, Kissling S, et al. Diphenylcyclopropenone treatment of alopecia areata induces apoptosis of perifollicular lymphocytes. Eur J Dermatol 2006;16(5):537-42
  • Zoller M, Freyschmidt-Paul P, Vitacolonna M, et al. Chronic delayed-type hypersensitivity reaction as a means to treat alopecia areata. Clin Exp Immunol 2004;135(3):398-408
  • Marhaba R, Vitacolonna M, Hildebrand D, et al. The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema. J Immunol 2007;179(8):5071-81
  • Freyschmidt-Paul P, Ziegler A, McElwee KJ, et al. Treatment of alopecia areata in C3H/HeJ mice with the topical immunosuppressant FK506 (Tacrolimus). Eur J Dermatol 2001;11(5):405-9
  • Price VH, Willey A, Chen BK. Topical tacrolimus in alopecia areata. J Am Acad Dermatol 2005;52(1):138-9
  • Ucak H, Kandi B, Cicek D, et al. The comparison of treatment with clobetasol propionate 0.05% and topical pimecrolimus 1% treatment in the treatment of alopecia areata. J Dermatolog Treat 2012;23(6):410-20
  • Verma DD, Verma S, McElwee KJ, et al. Treatment of alopecia areata in the DEBR model using Cyclosporin A lipid vesicles. Eur J Dermatol 2004;14(5):332-8
  • Masihi KN. Fighting infection using immunomodulatory agents. Expert Opin Biol Ther 2001;1(4):641-53
  • Anderson RP, Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr Opin Immunol 2013;25(3):410-17
  • Marchingo JM, Kan A, Sutherland RM, et al. T cell signaling. Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion. Science 2014;346(6213):1123-7
  • Feldmann M, Steinman L. Design of effective immunotherapy for human autoimmunity. Nature 2005;435(7042):612-19
  • Fong KY. Immunotherapy in autoimmune diseases. Ann Acad Med Singapore 2002;31(6):702-6
  • Liblau RS, Wong FS, Mars LT, Santamaria P. Autoreactive CD8 T cells in organ-specific autoimmunity: emerging targets for therapeutic intervention. Immunity 2002;17(1):1-6
  • Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008;117(2):244-79
  • Hoffmann R, Eicheler W, Huth A, et al. Cytokines and growth factors influence hair growth in vitro. Possible implications for the pathogenesis and treatment of alopecia areata. Arch Dermatol Res 1996;288(3):153-6
  • Kasumagic-Halilovic E, Prohic A, Cavaljuga S. Tumor necrosis factor-alpha in patients with alopecia areata. Indian J Dermatol 2011;56(5):494-6
  • Pan Y, Rao NA. Alopecia areata during etanercept therapy. Ocul Immunol Inflamm 2009;17(2):127-9
  • Ettefagh L, Nedorost S, Mirmirani P. Alopecia areata in a patient using infliximab: new insights into the role of tumor necrosis factor on human hair follicles. Arch Dermatol 2004;140(8):1012
  • Skurkovich S, Korotky NG, Sharova NM, Skurkovich B. Treatment of alopecia areata with anti-interferon-gamma antibodies. J Investig Dermatol Symp Proc 2005;10(3):283-4
  • Sundberg JP, McElwee KJ, Carroll JM, King LEJr. Hypothesis testing: CTLA4 co-stimulatory pathways critical in the pathogenesis of human and mouse alopecia areata. J Invest Dermatol 2011;131(11):2323-4
  • Frauwirth KA, Thompson CB. Activation and inhibition of lymphocytes by costimulation. J Clin Invest 2002;109(3):295-9
  • Leung MC, Sutton CW, Fenton DA, Tobin DJ. Trichohyalin is a potential major autoantigen in human alopecia areata. J Proteome Res 2010;9(10):5153-63
  • Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349(20):1907-15
  • Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013;13(4):227-42
  • Walter U, Santamaria P. CD8+ T cells in autoimmunity. Curr Opin Immunol 2005;17(6):624-31
  • Traidl C, Sebastiani S, Albanesi C, et al. Disparate cytotoxic activity of nickel-specific CD8+ and CD4+ T cell subsets against keratinocytes. J Immunol 2000;165(6):3058-64
  • Chun-yan G, Bo H, Hong C, et al. Anti-perforin neutralizing antibody reduces myocardial injury in viral myocarditis. Cardiol Young 2009;19(6):601-7
  • Ko GJ, Jang HR, Huang Y, et al. Blocking Fas ligand on leukocytes attenuates kidney ischemia-reperfusion injury. J Am Soc Nephrol 2011;22(4):732-42
  • Cao Y, Xu W, Xiong S. Adoptive transfer of regulatory T cells protects against Coxsackievirus B3-induced cardiac fibrosis. PLoS One 2013;8(9):e74955
  • Heuer JG, Zhang T, Zhao J, et al. Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol 2005;174(11):7141-6
  • Yi S, Ji M, Wu J, et al. Adoptive transfer with in vitro expanded human regulatory T cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice. Diabetes 2012;61(5):1180-91
  • Xu W, Lan Q, Chen M, et al. Adoptive transfer of induced-Treg cells effectively attenuates murine airway allergic inflammation. PLoS One 2012;7(7):e40314
  • Castela E, Le Duff F, Butori C, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol 2014;150(7):748-51
  • Wong M. What has happened in the last 50 years in immunology. J Paediatr Child Health 2015;51(2):135-9
  • Aranow C. Vitamin D and the immune system. J Investig Med 2011;59(6):881-6
  • Peelen E, Knippenberg S, Muris AH, et al. Effects of vitamin D on the peripheral adaptive immune system: a review. Autoimmun Rev 2011;10(12):733-43
  • Bennett L, Palucka AK, Arce E, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 2003;197(6):711-23
  • Aksu Cerman A, Sarikaya Solak S, Kivanc Altunay I. Vitamin D deficiency in alopecia areata. Br J Dermatol 2014;170(6):1299-304
  • Kim DH, Lee JW, Kim IS, et al. Successful treatment of alopecia areata with topical calcipotriol. Annals of dermatology 2012;24(3):341-4
  • Teoh D, Johnson LA, Hanke T, et al. Blocking development of a CD8+ T cell response by targeting lymphatic recruitment of APC. J Immunol 2009;182(4):2425-31
  • Leuschner F, Dutta P, Gorbatov R, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 2011;29(11):1005-10
  • Freyschmidt-Paul P, Seiter S, Zoller M, et al. Treatment with an anti-CD44v10-specific antibody inhibits the onset of alopecia areata in C3H/HeJ mice. J Invest Dermatol 2000;115(4):653-7
  • Fiorino G, Correale C, Fries W, et al. Leukocyte traffic control: a novel therapeutic strategy for inflammatory bowel disease. Expert Rev Clin Immunol 2010;6(4):567-72
  • Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 2011(10):CD007621
  • Peakman M, Dayan CM. Antigen-specific immunotherapy for autoimmune disease: fighting fire with fire? Immunology 2001;104(4):361-6
  • Miller SD, Turley DM, Podojil JR. Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol 2007;7(9):665-77
  • Correale J, Farez M, Gilmore W. Vaccines for multiple sclerosis: progress to date. CNS Drugs 2008;22(3):175-98
  • Fontoura P, Garren H, Steinman L. Antigen-specific therapies in multiple sclerosis: going beyond proteins and peptides. Int Rev Immunol 2005;24(5-6):415-46
  • Wang EH, Breitkopf T, Akhoundsadegh N, et al. Screening for autoantigen epitopes involved in the development of alopecia areata. J Invest Dermatol 2014;134:S43
  • Erb U, Freyschmidt-Paul P, Zoller M. Tolerance induction by hair-specific keratins in murine alopecia areata. J Leukoc Biol 2013;94(4):845-57
  • Ito T. Recent advances in the pathogenesis of autoimmune hair loss disease alopecia areata. Clin Dev Immunol 2013;348546
  • Wang X, Hao J, Leung G, et al. Hair follicle dermal sheath derived cells improve islet allograft survival without systemic immunosuppression. J Immunol Res 2015;607328
  • Li Y, Yan B, Wang H, et al. Hair regrowth in alopecia areata patients following Stem Cell Educator therapy. BMC Med 2015;13:87
  • Jalili RB, Forouzandeh F, Rezakhanlou AM, et al. Local expression of indoleamine 2,3 dioxygenase in syngeneic fibroblasts significantly prolongs survival of an engineered three-dimensional islet allograft. Diabetes 2010;59(9):2219-27
  • Ruckert R, Hofmann U, van der Veen C, et al. MHC class I expression in murine skin: developmentally controlled and strikingly restricted intraepithelial expression during hair follicle morphogenesis and cycling, and response to cytokine treatment in vivo. J Invest Dermatol 1998;111(1):25-30

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.