Alopecia areata: Current state of knowledge

David Norris, MD

Denver, Colorado

At the recent National Institute of Arthritis andMusculoskeletal and Skin Diseases (NIAMS)-sponsored fourth research workshop on alo-

pecia areata (AA), the state of current understandingof the mechanisms of alopecia areata was presentedin the context of current understanding of hair bi-ology and differentiation of the skin. Three majorareas of research were presented: (1) genetics; (2)immunology; and (3) targets, triggers, and controls.Summaries of current and future treatment ap-proaches were presented. It is clear that the researchenterprise related to hair biology, and AA in partic-ular, is now firmly established and expanding intoimportant areas of fundamental biology, includingstem cell research and sophisticated studies of epi-dermal differentiation and morphogenesis. It is evi-dent that the mechanism of hair follicle dysfunctionin AA is immunological, controlled by activated Tcells. Whether this response is truly autoimmuneremains to be firmly established, but there are strongindications that self-antigens, including melanocyteantigens, are the key targets. Susceptibility to AA islikely to be genetically determined. Linkage to genescontrolling the immune response is strongest inpatients with severe AT and AU, and it is likely thatAA is a polygenic complex trait, with distinct geneticlinkages determining specific gene subsets. Themechanisms through which the cycling hair follicleis damaged and dysfunctional in AAwere thoroughlyreviewed. In spite of impressive progress, we havea long way to go to completely understand themechanisms of disease and to identify AA-specifictargets for treatment. On the other hand, we may bevery close to providing better treatment approachesfor AA. Treatments proven to be effective in otherautoimmune skin diseases can be used in AA in‘‘proof of concept’’ trials, which will both verify

From the University of Colorado Health Sciences Center.

Funding sources: None.

Conflicts of interest: None identified.

Reprint requests: David A. Norris, MD, Professor and Chairman,

B-153, 4200 E. Ninth Avenue, Denver, CO 80262. E-mail:

david.norris@uchsc.edu.

0190-9622/$30.00

ª 2004 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2004.01.013

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mechanisms of disease and provide practicalapproaches for treatment of this important disease.

GENETICSAA is likely a complex polygenic trait. Complex

traits don’t follow Mendel’s laws, the correlations areoften not linear, and there are complex networks ofinteraction that can be mathematically modeled.Multiple immune-response related loci have beenimplicated in determining susceptibility or severity ofAA: HLAClass II loci, tumor necrosis factor (TNF) andTNF receptor, and AIRES. Initial efforts at wholegenome screens have shown significant linkages atfour sites: chromosomes 10, 6, 16, and 18. Poly-morphisms in TNF interleukin (IL)-1 and other majorhistocompatibility complex-associated moleculeswill be important in studies of AA biology andgenetics.

In the robust C3H/HEJ mouse model of AA,genetic linkage studies identify multiple immuneresponse genes. The genetic associations in thisanimal model show strong linkage to chromosome17:DQB1, DRB1, TNF and LT, and to chromosome9:CD3 neural cell adhesion molecule.

IMMUNOLOGYIn more than 10 years of experiments using

a severe combined immunodeficiency (SCID)mousemodel of human AA, Kalish and Gilhar1 have clearlydemonstrated that AA is an autoimmune diseasemediated by T lymphocytes in which autoantigensare necessary to activate T cells that produce thedisease. Leukocytes from AA patients are stimulatedin vitro with hair follicle antigens and injected intothese engrafted mice, producing immunologic hairloss similar to that seen in AA. Similar SCID mousemodels have been effectively used to study autoim-mune skin disease in psoriasis and photosensitivelupus, but the Kalish/Gilhar model is particularlyuseful and robust. Using this model, they haveshown that cells from AA patients, activated by hairfollicle antigens, can transfer AA. In this adoptivetransfer model, both CD4 and CD8 T cells arenecessary for maximal effect, even though CD8 cellsare sufficient to induce hair loss. They have morerecently shown that the requirement for hair follicleantigens to stimulate T cells in this transfer model can

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be replaced by follicular melanocytes. This providesevidence that follicular melanocytes may be thetargets for activated T cells in AA, as originallyproposed by Tobin and Bystryn.2 It is interesting thatcontrol of certain melanocytic peptides are linked toimmune response (MHC) loci, providing anotherpossible point of control of AA by the MHC.

In the C3H/HEJ mouse model of AA, McElwee3

has shown complex immunologic changes: inflam-matory infiltrates consisting of CD4 > CD8 lympho-cytes; macrophage and B cells; local increases incytokines IL-12, IL-6 > IL10, IL-4; all T-cell subsetsincluding T regulatory cells, and hair follicle changesrequiring Fas and FasL.

Tobin has continued and persisted in his quest toidentify antibodies in different alopecia areatamodels—human, mouse, horse, chicken, and others.In human AA, there are high titer antibodies to hairfollicle antigen, sometimes as high as 1 to 10,000. Inthe rat model they precede hair loss. Effective treat-ment of AA decreases the antibody titers. Theseantibodies can also be used as tools to determineimmunologic specificity in AA: the antibodies can beeasily sampled and one can measure antibody spec-ificitiesmore easily thanwith Tcells. This promises tobe a useful way to look at epitope spreading andmaturation of the immune response in AA.

Paus4 has proposed an ‘‘immune privilege col-lapse model’’ to explain the development of autoim-munity in AA. In this model, infections, bacterialsuper antigens, or follicular damage trigger the re-lease of gamma interferon, which induces expres-sion of Class I MHC on follicular cells, leading to theinduction of both CD8 positive cytotoxic cells andClass II MHC molecules, leading to induction of CD4help, and then to downstream autoimmune phe-nomenon with generation of auto-reactive T-cells.Eventually there is a spread of the immune responsewith antibody, macrophages, expression of Fas li-gand, apoptosis, and damage to follicular cells.

TARGETS TRIGGERS AND CONTROLSWe are developing a fundamental understanding

of control of the development and cycling of hairfollicles involving multiple signaling elements andgrowth factors: WNT and hedgehog pathway,keratinocyte growth factor, fibroblast growth factorV, and NOGGIN. It is likely that these signalingpathways are distributed by the immune response inAA, causing follicle arrest.

Microarray analysis has been effectively used tostudy gene regulation in human AA; in animalmodels of AA as it is induced and as it responds totherapy. In human AA, Sinha5 has confirmed pre-dictable changes in keratin genes and cytokines. In

the C3H/HEJ mouse, Sundberg6 has found similarchanges; as hair follicles are involuting, there areincreases in gamma interferon and in antigen pre-senting cells, and later on induction of antibodies ofmultiple specificities. The changes in antigen-pre-senting cells may be an important determinant of thedevelopment of autoimmunity. In the Dundee ratmodel, Tang7 has shown by microarray and pro-teomics that interferon gamma is down-regulated inanimals that responded to topical therapy for AA.Modern gene expression studies have confirmeddata derived from more traditional immunologicstudies, placing gamma interferon in the center ofthe immune response inducing hair loss in AA.

TREATMENTThere are effective treatments for patchy AA, but

treatment for widespread disease is unsatisfactory.Local therapy with topical steroids or calcineurin in-hibitors, topical minoxidil, or intralesional steroids areeffective in restoring local hair growth. For extensivedisease, oral or pulse intravenous steroids are effectivein returning hair growth in a majority of patients, butmany experience renewed hair loss when steroids arediscontinued, and the side effects of systemic steroidsare a major barrier to widespread use of this modality.Topical therapy with anthralin, topical induction ofcontact sensitivity with DNCP or squaric acid, andtopical nitrogen mustard treatment are successful ina subset of patients (about 25%). These treatmentsmust be used for many months, are messy and in-convenient, and have a low response rate.

There is great interest in using modern biologicaltherapies to selectively inhibit the immune response inAA. There are currently 4 trials in development inanimal or human models using modern biologicalimmunomodulators. These trials will serve as ‘‘proofof concept’’ experiments to determine whether selec-tive immunomodulation can induce hair regrowth inAA, and whether remissions are retained when treat-ment is discontinued, and will surely lead to moreeffective treatments for patients with extensive AA.

REFERENCES

1. Kalish RS, Gilhar A. Alopecia areata: Autoimmunity—the

evidence is compelling. J Investig Dermatol Symp Proc 2003;

8:164-7.

2. Tobin and Bystryn.

3. McElwee.

4. Paus R, Ito N, Takigawa M, Ito T. The hair follicle and immune

privilege. J Investig Dermatol Symp Proc 2003;8:188-94.

5. Sinha.

6. Sundberg JP, King LE Jr. Mouse alopecia areata models: An

array of data on mechanisms and genetics. J Investig Derma-

tol Symp Proc 2003;8:173-5.

7. Tang L, Sundberg JP, Lui H, Shapiro J. Old wine in new bottles:

Reviving old therapies for alopecia areata using rodent

models. J Investig Dermatol Symp Proc 2003;8:212-6.