Alopecia areata (AA) is a hair loss disease marked by a focal inflammatory infiltrate of dystrophic anagen stage hair follicles by CD4+ and CD8+ lymphocytes. Although AA is thought to be an autoimmune disorder, definitive proof is lacking. Moreover, characterization of the primary pathogenic mechanisms by which hair loss is induced in AA is limited. In this context, animal models may provide a vital contribution to understanding AA. Recent research using animal models of AA has focused on providing evidence in support of a lymphocyte-mediated pathogenic mechanism consistent with AA as an autoimmune disease. In the future, research with both humans and animal models shall likely concentrate on identifying the primary antigenic epitopes involved in AA and the genetics of AA susceptibility. With a comprehensive understanding of the key elements in AA pathogenesis, new avenues for therapeutic research and intervention will be defined.

1.
Safavi KH, Muller SA, Suman VJ, Moshell AN, Melton LJ 3rd: Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc 1995;70:628–633.
2.
Muller SA, Winkelmann RK: Alopecia areata: An evaluation of 736 patients. Arch Dermatol 1963;88:290–297.
3.
Robinson T: Baldness and Greyness, Their Etiology, Pathology and Treatment, ed 2. London, Kimpton, 1883.
4.
McElwee KJ, Tobin DJ, Bystryn JC, King LE Jr, Sundberg JP: Alopecia areata: An autoimmune disease? Exp Dermatol 1999;8:371–379.
5.
Duckworth D: Case of area Celsi (porrigo decalvans), in which the parts were examined after death. Trans Pathol Soc 1882;33:386–392.
6.
Giovannini S: Recherches sur l’histologie pathologique de la pelade. Ann Dermatol Syphiligr 1891;3:921–957.
7.
Van Scott EJ: Morphologic changes in pilosebaceous units and anagen hairs in alopecia areata. J Invest Dermatol 1958;31:35–43.
8.
Randall VA: Is alopecia areata an autoimmune disease? Lancet 2001;358:1922–1924.
9.
McDonagh AJ, Messenger AG: Alopecia areata. Clin Dermatol 2001;19:141–147.
10.
McElwee KJ, Hoffmann R: Alopecia areata – Animal models. Clin Exp Dermatol 2002;27:410–417.
11.
Paus R, Slominski A, Czarnetzki BM: Is alopecia areata an autoimmune response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb? Yale J Biol Med 1993;66:541–554.
12.
Rose NR, Bona C: Defining criteria for autoimmune diseases (Witebsky’s postulates revisited). Immunol Today 1993;14:426–430.
13.
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;64:26–30.
14.
Ranki A, Kianto U, Kanerva L, Tolvanen E, Johansson E: Immunohistochemical and electron microscopic characterization of the cellular infiltrate in alopecia (areata, totalis, and universalis). J Invest Dermatol 1984;83:7–11.
15.
Wiesner-Menzel L, Happle R: Intrabulbar and peribulbar accumulation of dendritic OKT 6-positive cells in alopecia areata. Arch Dermatol Res 1984;276:333–334.
16.
Hoffmann R, Wenzel E, Huth A, van der Steen P, Schaufele M, Henninger HP, Happle R: Cytokine mRNA levels in alopecia areata before and after treatment with the contact allergen diphenylcyclopropenone. J Invest Dermatol 1994;103:530–533.
17.
Tang L, Cao L, Bernardo O, Chen Y, Sundberg JP, Lui H, Chung S, Shapiro J: Topical mechlorethamine restores autoimmune-arrested follicular activity in mice with an alopecia areata-like disease by targeting infiltrated lymphocytes. J Invest Dermatol 2003;120:400–406.
18.
Tang L, Cao L, Sundberg JP, Lui H, Shapiro J: Restoration of hair growth in mice with an alopecia areata-like disease using topical anthralin. Exp Dermatol 2004;13:5–10.
19.
Freyschmidt-Paul P, Hoffmann R, Levine E, Sundberg JP, Happle R, McElwee KJ: Current and potential agents for the treatment of alopecia areata. Curr Pharm Des 2001;7:213–230.
20.
Mcdonagh AJ, Snowden JA, Stierle C, Elliott K, Messenger AG: HLA and ICAM-1 expression in alopecia areata in vivo and in vitro: The role of cytokines. Br J Dermatol 1993;129:250–256.
21.
de Andrade M, Jackow CM, Dahm N, Hordinsky M, Reveille JD, Duvic M: Alopecia areata in families: Association with the HLA locus. J Invest Dermatol Symp Proc 1999;4:220–223.
22.
Colombe BW, Lou CD, Price VH: The genetic basis of alopecia areata: HLA associations with patchy alopecia areata versus alopecia totalis and alopecia universalis. J Invest Dermatol Symp Proc 1999;4:216–219.
23.
Barahmani N, Whaley K, Duvic M: Alopecia areata after allogeneic bone marrow transplantation from an affected, human leukocyte antigen-matched sibling. J Am Acad Dermatol 2003;49:1192.
24.
Sanli H, Kusak F, Arat M, Ekmekci P, Ilhan O: Simultaneous onset of chronic graft versus host disease and alopecia areata following allogeneic haematopoietic cell transplantation. Acta Derm Venereol 2004;84:86–87.
25.
Morel L: Mouse models of human autoimmune diseases: Essential tools that require the proper controls. Plos Biol 2004;2:E241.
26.
Gilhar A, Krueger GG: Hair growth in scalp grafts from patients with alopecia areata and alopecia universalis grafted onto nude mice. Arch Dermatol 1987;123:44–50.
27.
Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS: Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest 1998;101:62–67.
28.
Tobin DJ, Gardner SH, Luther PB, Dunston SM, Lindsey NJ, Olivry T: A natural canine homologue of alopecia areata in humans. Br J Dermatol 2003;149:938–950.
29.
Tobin DJ, Alhaidari Z, Olivry T: Equine alopecia areata autoantibodies target multiple hair follicle antigens and may alter hair growth: A preliminary study. Exp Dermatol 1998;7:289–297.
30.
McElwee KJ, Boggess D, Olivry T, Oliver RF, Whiting D, Tobin DJ, Bystryn JC, King LE Jr, Sundberg JP: Comparison of alopecia areata in human and nonhuman mammalian species. Pathobiology 1998;66:90–107.
31.
McElwee KJ, Boggess D, Miller J, King LE Jr, Sundberg JP: Spontaneous alopecia areata-like hair loss in one congenic and seven inbred laboratory mouse strains. J Invest Dermatol Symp Proc 1999;4:202–206.
32.
Smyth JR Jr, McNeil M: Alopecia areata and universalis in the Smyth chicken model for spontaneous autoimmune vitiligo. J Invest Dermatol Symp Proc 1999;4:211–215.
33.
Michie HJ, Jahoda CA, Oliver RF, Johnson BE: The DEBR rat: An animal model of human alopecia areata. Br J Dermatol 1991;125:94–100.
34.
Michie HJ, Jahoda CA, Oliver RF, Poulton TA: Immunobiological studies on the alopecic (DEBR) rat. Br J Dermatol 1990;123:557–567.
35.
Zhang JG, Oliver RF: Immunohistological study of the development of the cellular infiltrate in the pelage follicles of the DEBR model for alopecia areata. Br J Dermatol 1994;130:405–414.
36.
McElwee KJ, Pickett P, Oliver RF: The DEBR rat, alopecia areata and autoantibodies to the hair follicle. Br J Dermatol 1996;134:55–63.
37.
Sundberg JP, Cordy WR, King LE Jr: Alopecia areata in aging C3H/HeJ mice. J Invest Dermatol 1994;102:847–856.
38.
McElwee KJ, Silva K, Boggess D, Bechtold L, King LE Jr, Sundberg JP: Alopecia areata in C3H/HeJ mice involves leukocyte-mediated root sheath disruption in advance of overt hair loss. Vet Pathol 2003;40:643–650.
39.
McElwee KJ, Boggess D, King LE Jr, Sundberg JP: Experimental induction of alopecia areata-like hair loss in C3H/HeJ mice using full-thickness skin grafts. J Invest Dermatol 1998;111:797–803.
40.
Carroll JM, McElwee KJ, King LE, 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;119:392–402.
41.
McElwee KJ, Hoffmann R, Freyschmidt-Paul P, Wenzel E, Kissling S, Sundberg JP, Zöller M: 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;119:1426–1433.
42.
Zöller 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;118:983–992.
43.
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;135:211–217.
44.
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;140:432–437.
45.
Freyschmidt-Paul P, Seiter S, Zoller M, Konig A, Ziegler A, Sundberg JP, Happle R, Hoffmann R: Treatment with an anti-CD44v10-specific antibody inhibits the onset of alopecia areata in C3H/HeJ mice. J Invest Dermatol 2000;115:653–657.
46.
McElwee KJ, Freyschmidt-Paul P, Hoffmann R, Kissling S, Hummel S, Vitacolonna M, Zöller M: 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: 947–957.
47.
Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR, Morris PJ, Powrie F, Wood KJ: IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 2001;166:3789–3796.
48.
Kumanogoh A, Wang X, Lee I, Watanabe C, Kamanaka M, Shi W, Yoshida K, Sato T, Habu S, Itoh M, Sakaguchi N, Sakaguchi S, Kikutani H: Increased T cell autoreactivity in the absence of CD40-CD40 ligand interactions: A role of CD40 in regulatory T cell development. J Immunol 2001;166:353–360.
49.
Zöller M, McElwee KJ, Vitacolonna M, Hoffmann R: Apoptosis resistance in peripheral blood lymphocytes of alopecia areata patients. J Autoimmun 2004;23:241–256.
50.
Zöller 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;13:435–444.
51.
Huber S, Schramm C, Lehr HA, Mann A, Schmitt S, Becker C, Protschka M, Galle PR, Neurath MF, Blessing M: Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 2004;173:6526–6531.
52.
Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA: In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004;199:1455–1465.
53.
Walker MR, Carson BD, Nepom GT, Ziegler SF, Buckner JH: De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25– cells. Proc Natl Acad Sci USA 2005;102:4103–4108.
54.
Freyschmidt-Paul P, McElwee KJ, Botchkarev V, Kissling S, Wenzel E, Sundberg JP, Happle R, Hoffmann R: 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 Invest Dermatol Symp Proc 2003;8:104–108.
55.
McElwee KJ, Freyschmidt-Paul P, Zoller M, Hoffmann R: Alopecia areata susceptibility in rodent models. J Invest Dermatol Symp Proc 2003;8:182–187.
56.
Sundberg JP, Boggess D, Silva KA, McElwee KJ, King LE, Li R, Churchill G, Cox GA: 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;120:771–775.
57.
McElwee KJ, Niiyama S, Freyschmidt-Paul P, Wenzel E, Kissling S, Sundberg JP, Hoffmann R: Dietary soy oil content and soy-derived phytoestrogen genistein increase resistance to alopecia areata onset in C3H/HeJ mice. Exp Dermatol 2003;12:30–36.
58.
McElwee K, Freyschmidt-Paul P, Ziegler A, Happle R, Hoffmann R: Genetic susceptibility and severity of alopecia areata in human and animal models. Eur J Dermatol 2001;11:11–16.
59.
Burnet FM: The Clonal Selection Theory of Acquired Immunity. London, Cambridge University Press, 1959.
60.
Matzinger P: Tolerance, danger and the extended family. Annu Rev Immunol 1994;12:991–1045.
61.
Theofilopoulos AN: The basis of autoimmunity. I. Mechanisms of aberrant self-recognition. Immunol Today 1995;16:90–98.
62.
Theofilopoulos AN: The basis of autoimmunity. II. Genetic predisposition. Immunol Today 1995;16:150–159.
63.
Wucherpfennig KW: Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest 2001;108:1097–1104.
64.
Ohashi PS: T-cell signalling and autoimmunity: Molecular mechanisms of disease. Nat Rev Immunol 2002;2:427–438.
65.
Abbas AK, Lohr J, Knoechel B, Nagabhushanam V: T cell tolerance and autoimmunity. Autoimmun Rev 2004;3:471–475.
66.
Whiting DA: Histopathologic features of alopecia areata: A new look. Arch Dermatol 2003;139:1555–1559.
67.
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.
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