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Strong direct and indirect evidence supports an autoimmune etiology for alopecia areata. T lymphocytes that have been shown to be oligoclonal and autoreactive are predominantly present in the peribulbar inflammatory infiltrate. Alopecia areata frequently occurs in association with other autoimmune diseases, such as thyroiditis and vitiligo, and autoantibodies to follicular components have been detected. Finally, the use of immune modulating drugs, including corticosteroids and contact sensitizers such as dyphencyprone, can be beneficial in the management of this disease. Recent studies have demonstrated that alopecia areata scalp skin grafted onto nude mice with severe combined immunodeficiency grow hair and that infiltrating lymphocytes in the graft are lost. It is now also possible to induce alopecia areata in human scalp explants on these mice by injecting T lymphocytes with scalp homogenate. Neuropeptides produced by cutaneous nerves are known to modify immune reactivity and, in all likelihood, affect the alopecia areata process. Future studies may show that modulation of neuropeptide expression is associated with hair regrowth. Likewise, testing the efficacy of the newly developed immunomodulatory agents in patients with alopecia areata may lead to the introduction of novel therapies for this immune-mediated disease of the hair follicle.
Autoimmune Polyglandular Syndrome
Calcitonin Gene-Related Peptide
Dundee Experimental Bald Rat
Eulex europeaus agglutinin I
Human Lymphocyte Antigen
Intracellular Adhesion Molecule
Major Histocompatibility Complex
Protein Gene Product
Severe Combined Immunodeficiency
Tumor Necrosis Factor α
ALOPECIA AREATA–CLINICAL PRESENTATIONS
Alopecia areata (AA) is postulated to be an organ-specific autoimmune disease. The incidence of AA in the United States (Minnesota) is 20.2/100,000 person-years (
), and the lifetime risk is estimated to be approximately 1.7%. AA is characterized by nonscarring hair loss that may be patchy (areata) or extensive. Loss of all scalp hair is described as alopecia totalis (AT); the term alopecia universalis (AU) is frequently used when all body hair is lost (Figure 1). Guidelines have been established to assess disease extent and take into consideration that extent of hair loss may vary from one region of the body to another (
AA has been described as occurring in association with many diseases, several of which are considered autoimmune. The two main associations are with thyroid disease and vitiligo. Muller and Winkelman examined 736 patients with AA; 8% reported thyroid disorder, whereas the controls had an incidence of 2% (
). A very strong disease association with autosomal recessive disease autoimmune polyglandular syndrome (APS-1, chronic hypoparathyroidism-mucocutaneous candidiasis-autoimmune adrenal insufficiency) was recently reported. Also, AA commonly occurs in patients with Down's syndrome or Turner's syndrome and, in some studies, atopies (allergic rhinitis, asthma, and atopic dermatitis) have been found in more than 40% of AA patients whereas their prevalence in the general population is estimated to be around 20%.
One of the interesting observations made about disease associations of AA is the decreased incidence of Type I (insulin-dependent) diabetes in AA patients and an increased incidence in their relatives. This has suggested to some that AA may have a protective effect against Type I diabetes in predisposed individuals (
There are two rodent models for AA: a subpopulation of the C3H/HeJ mouse strain and the Dundee experimental bald rat (DEBR). In both models, the affected surface provides a test site for studying the pathophysiology of AA and for testing the mechanism of action, safety, and efficacy of new therapies (
). C3H/HeJ mice produce a normal coat of agouti hair, but as early as four months after birth hair loss can develop on the ventral surface and, more focally, on the dorsal surface. The clinical and histopathologic features of this hair loss are similar to those in human AA (
). The DEBR rat is a hooded rat strain that also demonstrates hair loss similar to that observed in human AA. Rats develop a normal coat of hair from birth up until four months, but then up to 30% of males and 80% females experience hair loss on their heads, which can spread to the flanks (
Autoimmune diseases are commonly associated with an increase in certain HLA-region genes or haplotypes. Because the predisposition to autoimmunity has been associated with HLA-D alleles and AA is hypothesized to be a T cell–mediated autoimmune disease, several studies have looked for an association between HLA and AA (
HLA class I molecules are expressed on virtually all nucleated cells and platelets and present antigens to CD8+ T cells. HLA class II molecules have three main subclasses (DR, DQ, and DP); they are found on specific immune cells, including B cells, activated T cells, macrophages, keratinocytes, and dendritic cell and present peptides to CD4+ T cells. Because class II molecules are associated with antigen presentation, many studies have focused on this area of the HLA molecule.
The nomenclature of HLA molecules has changed over the years. The World Health Organization HLA Nomenclature committee now specifies a four-digit code to define each allele of each HLA locus at the DNA level (e.g., DRB1*1101), and two-digit codes to define the previous, lower-resolution serological equivalents (e.g., DRw11).
The association of AA with HLA-DR and HLA-DQ antigens suggests a role for CD4+ T cells in this disease, as MHC class II molecules present peptides to CD4+ cells. Recent transplantation studies indicate that CD8+ cells are also involved in AA, implicating MHC class I HLA-A,B,C molecules, which are associated with the presentation of peptides to CD8+ T cells, in addition to MHC class II molecules.
A genetic difference between patients who have extensive AA (AT or AU) and those who patchy AA has been identified. Both patient groups have been found to have a positive association with DQB1*03. The HLA alleles DRB1*0401 and HLA-DQB1*0303 are now also viewed as markers for more severe, long-standing disease (
). Presently, other genes in addition to the HLA region are under investigation for possible genetic associations.
AA may occur concurrently or sequentially in both monozygotic and fraternal twins. A concordance rate of 55% has been reported in monozygotic twins and 0% in fraternal twins. This leaves much room for the role of the environment in AA pathophysiology (
The histology of AA is characterized by the presence of peribulbar and intrabulbar mononuclear infiltrates, degenerative changes in the hair matrix, decreased numbers of terminal anagen follicles, increased numbers of terminal catagen and telogen follicles, increased numbers of follicular stelae, increased numbers of miniaturized vellus hair follicles, and pigment incontinence of hair bulbs (
). In AA, in contrast, HLA-A,B,C as well as HLA-DR antigens are expressed by follicular epithelium, suggesting that the expression of these antigens may result in the presentation of follicular autoantigens and loss of immune privilege. Paus and colleagues have hypothesized that the induction of MHC class I (HLA-A,B,C) antigens in AA permits a response by melanocyte reactive CD8+ T cells (
). The hypothesis is that CD8+ cells induce HLA-DR expression on affected hair follicles by the production of interferon-γ with the subsequent recruitment of CD4+ cells. Supporting this hypothesis is the work of Kalish and colleagues describing the presence of CD4+ autoreactive T cells in the infiltrate of AA (
). Adhesion molecules, such as intracellular adhesion molecule 1 (ICAM-1), E-selectin, and others, which are important in the homing of lymphocytes to sites of inflammation, have also been identified in microvascular endothelial cells in the perifollicular region of affected hair follicles.
B CELL FUNCTION
Circulating antibodies to follicular structures have been found in both humans and animal models of AA, but they have not been found to be pathogenic in either (
). Circulating antibodies to follicular structures have also been reported in normal controls.
EVIDENCE THAT AA IS MEDIATED BY T LYMPHOCYTES: REVIEW OF THE HUMAN SCALP EXPLANT EXPERIMENTS
A series of experiments have demonstrated the transfer of AA to human scalp explants on SCID mice. In the first published experiments, Gilhar and colleagues transferred AA scalp explants from patients to mice. Once transplanted, hairs grew in the grafts and at day 40 the grafts were injected with (1) autologous peripheral blood mononuclear cells, (2) autologous T cells isolated from the AA scalp biopsy specimens, or (3) scalp T cells cultured with hair follicle homogenate. T lymphocytes that had been cultured with hair follicle homogenate were capable of inducing changes of histologic AA in the grafts. Clinically, hair loss was documented, and perifollicular infiltrates of T cells, as well as HLA-DR and ICAM-1 expression on the follicular epithelium, were observed (
To determine the role of CD4+ and CD8+ T lymphocytes in the pathogenesis of AA, Gilhar and colleagues separated CD4+ and CD8+ T cells using magnetic beads, and injected not only unseparated T cells but also mixed CD4+ and CD8+ T cells, CD4+ cells alone, and CD8+ T cells alone. Injection of unseparated T cells and mixed CD4+ and CD8+ T cells resulted in significant hair loss, whereas injection of purified CD4+ or CD8+ T cells alone did not result in reproducible hair loss. The current hypothesis is that both CD4+ and CD8+ T cells have a role in the pathogenesis of AA, the CD8+ cells acting as the effector cells with help from the CD4+ T cells (
The autoantigen(s) in AA remains to be identified, but results of current studies suggest that it may be melanocyte derived. Support for this hypothesis comes from clinical observations that pigmented hair fibers are preferentially lost and that vitiligo is commonly associated with AA. In addition, hair bulb melanocytes in AA demonstrate both histologic and ultrastructural abnormalties (
To test the hypothesis that melanocyte-associated antigens can function as autoantigens and induce hair loss in AA, HLA-A2–positive patients with AA were selected for studies of HLA-A2-restricted melanocyte peptide epitopes. Scalp T cells were cultured with autologous antigen- presenting cells and either hair follicle homogenate as the positive control or melanocyte T cell epitopes. Cells were then transferred to autologous scalp explants on SCID mice. Histologic changes and hair regrowth were monitored. Melanocyte peptide–activated T cells significantly reduced the number of regrowing hair fibers, and injected scalp grafts demonstrated histologic and immunocytochemical features of AA. The most consistent peptide autoantigens were the Gp100-derived G9-209 and G9-280 peptides, as well as MART-1 (
). Recently completed studies of CD69 expression suggest that T cells in scalp biopsies taken from patients with extensive AA are specific for and activated by an antigen in the skin, and that T cell responses in such skin are tightly, albeit aberrantly, regulated via mechanisms of peripheral T cell tolerance).
). CGRP released from cutaneous nerves can induce mast cell degranulation and subsequent release of immunosuppressive tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10). CGRP can also interact with keratinocyte factors to promote melanization (
Results of immunocytochemical studies combined with laser scanning confocal microscopy have demonstrated that perifollicular innervation is arranged in a basket-weave network around the miniaturized AA anagen follicles in patients with long-standing (>2 years' duration) extensive AA. A prominent hair follicle nerve plexus, which appears as a stockade of nerves around the bulge region of small miniaturized follicles, has also been described in some patients with long-standing AA.
Modulating the peripheral nervous system in the management of AA has been explored. Capsaicin, derived from chile peppers, is known to excite subsets of sensory neurons associated with pain and thermoreception, and it is also known to release the neuropeptides SP and CGRP. In a cream formulation, capsaicin is frequently used as a topical medication to treat painful syndromes. When applied to normal skin, it elicits a sensation of burning pain by selectively activating sensory neurons that send information about noxious stimuli to the central nervous system. Capsaicin releases SP from sensory nerve fibers and, after repeated application, depletes neurons of SP and results in nonpermanent injury to epidermal nerves (
In a small pilot study, we wanted to ascertain how perifollicular nerves in scalp biopsy specimens taken from patients with long-standing extensive AA respond to the topical application of capsaicin cream 0.075% (Zostrix-HP). Two adult female patients participated in this study after signing an informed consent approved by the University of Minnesota Institutional Review Board, Human Subjects Committee. Each subject applied 0.075% capsaicin cream to her entire bald scalp for three weeks. Both treated patients experienced a burning pain sensation, which improved over the 21-day treatment period but never completely disappeared. Both patients also experienced vellus hair regrowth by day 21.
Four-millimeter punch biopsies were taken at day 0, day 1, and day 21. Specimens were multilabeled with antibodies to panneuronal protein gene product 9.5 (PGP 9.5) and cyanine 3.18, substance p or CGRP, and Cyanine 5.18, as well as the vascular marker Ulex europeans agglutinin (UEA I) conjugated to fluorescein. In-focus images of well-defined optical sections (0.5–1.0 microns) were captured by laser scanning confocal microscopy. Computer reconstruction of captured images yielded three-dimensional views of the architecture, perifollicular nerves and blood vessels, and the expression of the neuropeptides SP and CGRP. Analysis of 21-day scalp biopsy samples compared to baseline revealed (1) a qualitative decrease in the number of nerves staining with PGP 9.5 and SP in the epidermis, (2) small extra-neuronal globules staining with antibody to SP, and (3) an abundance of SP expression in the stockade region of the miniaturized follicle (Figure 2,Figure 3,Figure 4).
The results indicate that cutaneous innervation is altered in AA. Though epidermal nerves have been reported to degenerate with intradermal injection and topical application of capsaicin, both patients experienced undiminished scalp sensation such as burning with drug application throughout the study. It is possible that the expression and targeting of the vanilloid receptor, VRI (the receptor for capsaicin and the transducer of noxious thermal stimuli), is different in patients with long-standing extensive AA. The SP staining within the vasculature (data not shown) may reflect lymphocytes, macrophages, or eosinophils, all of which have receptors for SP. The abundance of SP in the stockade region and the vellus hair regrowth support the need for additional studies to understand the role of the peripheral nervous system in the transmission of signals not only between nerve cells but also with cells of the immune system and the hair follicle in AA.
IMMUNOMODULATING AGENTS FOR THE TREATMENT OF AA
Because CD8+ cells have been implicated as effector cells in AA, testing of therapies that interfere with CD8+ activity appear reasonable (
). Agents that effect CD4+ T cells may also be beneficial in the management of AA, but the ideal agent will probably be specific for both CD4+ and CD8+ T cells. Antibodies that block antigen presentation or costimulation molecules such as CTLA-4Ig and anti-CD11a also have the potential to be successful therapeutic agents (
Steiner LP, Boeck CM, Ericson ME, Deeths MJ, Whiting DA, Hordinsky M: Effect of Aldara 5% Cream on Anagen:Telogen and Terminal:Vellus Ratios in Extensive Alopecia Areata. Poster Presentation, Fourth International Alopecia Areata Research Workshop, Washington DC, November, 2002.
THE ALOPECIA AREATA REGISTRY
The opportunity to establish a Registry for AA became a reality with grant support from the National Institutes of Health and the National Institute of Arthritis, Metabolism, and Skin Diseases. The goal of the protocol is to develop a registry from which subsequent analyses and selective patient sampling can be conducted. One goal is to search for associations between specific genetic markers, such as HLA-linked loci, and the development of AA. The overall goals are to understand the genetic control of autoimmunity in AA, to better understand the complex biology of the cycling hair follicle, and to use this knowledge to devise safe and effective treatments (Protocol Laboratory-0391). The operation of the registry is outlined in Figure 5.
The development of AA is most likely linked to many factors. One, genetic susceptibility, is related in part to HLA antigen–presenting molecules, alterations in neuropeptide expression, and an alteration in the immune privileged state of the hair follicle. AA appears to be a TH1 autoimmune condition mediated by both CD4+ and CD8+ T cells. Though the autoantigen is not known, it may well be melanocyte associated. Future therapeutic investigations should include testing immunomodulatory agents currently being developed and in clinical trials, particularly for the treatment of psoriasis, as well examining compounds that alter the peripheral nervous system. The establishment of the Alopecia Areata Registry will provide the patient material needed to conduct the many genetic studies that remain to be done in this disease.
We thank Christine Baker for her assistance with the preparation of this manuscript. This work was supported in part by grants from the National Alopecia Areata Foundation and 3M Pharmaceuticals.