Dermatologic Therapy, Vol.

24, 2011, 337347 Printed in the United States All rights reserved

2011 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPY
ISSN 1396-0296

Etiopathogenesis of alopecia areata: Why do our patients get it?

dth_1416 337..347

Eddy Wang* & Kevin J. McElwee*

*Department of Dermatology and Skin Science, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada

ABSTRACT: Alopecia areata (AA) is a nonscarring, inammatory skin disease that results in patchy hair loss. AA is unpredictable in its onset, severity, and duration making it potentially very stressful for affected individuals. Currently, the treatment options for AA are limited and the efcacy of these treatments varies from patient to patient. The exact etiology of AA is unknown. This article provides some insights into the etiopathogenesis of AA and why some people develop it. The current knowledge on the pathogenesis of AA is summarized and some of the recent hypotheses and studies on AA are presented to allow for a fuller understanding of the possible biological mechanisms of AA. KEYWORDS: alopecia areata, autoimmune disease, disease pathogenesis

Introduction
Alopecia areata (AA) is a disease that most typically involves sudden loss of circular patches of scalp hair (1,2). The largest epidemiological study indicates a 1.7% lifetime risk of developing AA in the United States (3) and it is one of the more common forms of hair loss encountered in the dermatology clinic (4). A study of alopecia patients showed AA accounted for 25% of all alopecia cases and the majority of the patients belonged to the 30 to 59-year age group (5). The distribution of AA across both sexes and different races is generally equivalent; however, it appears that female, black patients have the highest frequencies of visits to clinics because of AA (5). AA can present anywhere on the body; however, in 90% of the cases seen in dermatology clinics,
Address correspondence and reprint requests to: Kevin J. McElwee, PhD, Department of Dermatology and Skin Science, The University of British Columbia, 835 West Tenth Avenue, Vancouver, BC, Canada, V5Z 4E8, or email: kmcelwee@interchange.ubc.ca.

the hair loss is predominantly on the scalp (6). It is characterized by the sudden loss of hair in ovalshaped patches with spontaneous remission, reoccurrence, and exacerbation (1,7). AA can develop into more severe forms; alopecia totalis (AT) involves the loss of all scalp hair and alopecia universalis (AU) is the complete loss of all body hair. Approximately 5% of AA patients will progress into AT/AU. Unlike other forms of hair loss, such as cicatricial alopecia, the AA lesion is nonscarring by nature. The areas of skin with hair loss are smooth, have a natural color or slightly pink/peach tone, and the hair bers at the border of these patches may have an exclamation mark appearance: short, broken hair bers with a broader distal end compared to the proximal end (1,7). Nail abnormalities such as pitting and longitudinal ridging can also be observed in 17% of AA patients (8). AA is usually a reversible disease but it can be recurrent and abrupt, making it very unpredictable and emotionally disturbing despite it being nonlifethreatening (9). The presentation of AA and its treatment are discussed in more detail elsewhere in this publication.

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Alopecia areata pathology There are three key phases in the normal hair cycle: the anagen (growth) phase, the catagen (regression) phase, and telogen (resting) phase (10). During the controlled shedding phase (exogen) in healthy follicles, old hair ber is typically shed from the hair follicle after a new growth cycle begins. Consequently, overall hair coverage is maintained. During the development of alopecias, exogen often occurs before anagen is renewed or when anagen is dystrophic and this results in a state called kenogen where no visible hair ber is left in the hair follicle (11). Essentially, AA-affected skin can be said to be in a state of kenogen (1). The severity and duration of AA can result in several different abnormal hair cycle presentations. As observed in AA skin lesions, in general, there is a swarm of bees inltration of lymphocytes into the peribulbar space of anagen stage hair follicles and some penetration of lymphocytes to intrafollicular locations (1,7,12). In all stages of AA, there can also be a diffuse inltration of eosinophils and mast cells into the AA-affected skin, the signicance of which is unknown (1315). However, the histological presentation of AA can be very different as it progresses from acute to chronic (1). In the acute phase, when both CD8+ and CD4+ T lymphocytes inltrate into the peribulbar area, the cell density is an indication of active disease progression (16). The net effect of the initial inammatory cell inltrate may not modify the hair cycle, but rather it adversely affects hair follicle activity and results in a dystrophic anagen state. Though anagen is maintained, the inltration of inammatory cells apparently disrupts the ability of the hair follicles to produce hair bers of sufcient size or integrity (17). The exogen event may occur normally as part of the overall hair cycle, but due to the anagen dystrophy, the expelled hair ber is not replaced by ber that can provide equivalent scalp coverage. As the number of inammatory cells in and around the hair follicles increases, miniaturization of the hair follicles can occur and the hair cycle can become truncated with rapid cycling of anagen and telogen phases (so-called nanogen hair follicles). As the process continues, progressively up to 50% of total hair follicles can be observed in nanogen in tissue biopsies (1,18). The number of catagen/telogen stage hair follicles increases with time. Notably, the amount of inammation in the skin decreases as more hair follicles move into a telogen phase (18).

Finally, in the chronic stages of AA, most affected hair follicles are forced into prolonged telogen and no attempt at reentering anagen or new growth of hair is observed (17). The number of terminal scalp hair follicles will decrease to about the same number of vellus hair follicles (18). At this point, any inammation present will typically be localized in the papillary dermis around miniaturized hair follicles. From these observations, AA is circumstantially an inammation driven disease where changes to the hair follicle are closely correlated with changes in the peri- and intrafollicular inammatory inltrate. Alopecia areata role of the immune system Although the AA phenotype is restricted to the skin and its appendages, there is evidence that much of the disease mechanism and the decision on disease activation occurs away from the skin in the immune system and its organs. To fully explain AA, one must consider events that can occur both in and beyond the skin. Inammatory cells that comprise the skin immune system (SIS) are transitory. On antigenic challenge, SIS antigen-presenting cells typically migrate to lymphoid organs to educate and to be educated (1921). Lymphocytes are not normally resident in healthy skin in large numbers. The intense inammatory inltrate observed in association with AA suggests in-migration of activated cells from the central immune system. Studies with mice conrm that blocking lymphocyte skin-homing receptors or impeding antigen-presenting cell migration to skin-draining lymph nodes can prevent AA development and modulate its progression (2225). In short, we are dealing with the whole of the immune system and not just the SIS when we investigate and elucidate AA disease mechanisms. Alopecia areata autoimmunity It is generally accepted that AA is an autoimmune disease. However, the research data produced thus far is best described as consistent with an autoimmune mechanism in AA. Incontrovertible evidence of autoimmunity would require the identity of the primary antigen target(s) in the inammatory cell attack to be characterized as selfantigen(s) derived from the hair follicle unit, but this remains to be proven (26). Nevertheless, an autoimmune scenario is currently the best explanation for the clinical research data we have for the majority of AA patients. Using animal models, functional evidence has been produced that dem-

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onstrates the dominance of the immune system in the AA disease mechanism (2732). Essentially, if there is no functional immune system and/or focal hair follicle inammation, then AA does not occur in these disease models. Alopecia areata autoantibody activity The presence of hair follicle specic autoantibodies in AA patients suggests that AA is an autoimmune disease (10). Hair follicle specic IgG antibody concentration is increased in the peripheral blood of AA patients and it can be found localized around the periphery of hair follicles, especially near the border of the active lesions (10,33). In a recent study, it was found that the antigens bound by some of these serum antibodies are keratin 16 and hair follicle specic trichohyalin (3436). However, the specicity of hair follicle autoantibody targets can be very variable between AA-affected individuals (3740). Further, studies involving the injection of autoantibodies in different models have not shown the autoantibodies to have a signicant pathogenic effect (41). This suggests the AA disease mechanism is more likely cell mediated rather than antibody mediated. However, the presence of hair follicle specic autoantibodies does suggest an autoimmune mechanism is active and such autoantibodies may provide clues as to the antigenic targets for T cells. Alopecia areata immune cell activity In both animal models of AA and in humans, follicular inammation is mainly comprised of CD4+ and CD8+ T cells. However, a clear difference in the location of these cells is observed. From immunohistological analysis, it is observed that activated CD8+ T cells can be found inltrated into hair follicles, whereas CD4+ T cells are almost exclusively located in the perifollicular area (16,4244). Due to the cytotoxic nature of most CD8+ T cells, their presence inside hair follicles could easily disrupt the growth of hair. Various molecules are produced by activated cytotoxic T lymphocytes in AA such as tumor necrosis factors, granzymes and Fas ligand (32,42,4548). Potentially, these molecules may trigger apoptosis in AA-affected hair follicle cells and generally disrupt normal functioning (49,50). In both rodent AA models, the depletion of CD8+ T cells can inhibit the development of AA (28,29). In the rat model, depletion of CD8+ T cells yields a better hair growth response compared to depletion of CD4+ T cells, and AA quickly redevelops when the cell depletion protocol is stopped (28,29). The

subcutaneous injection of activated CD8+ T cells will quickly induce localized hair loss exclusively at the site of injection while the injection of CD4+ T cells does not induce local hair loss but will eventually promote a systemic hair loss (multiple alopecia patches) beyond the immediate site of injection (31). These studies suggest that CD8+ cells are the primary instigators of hair follicle disruption and alopecia while CD4+ cells are likely to promote AA through their classic helper role. Alopecia areata hair follicle immune privilege It is suggested that the hair follicle is an immune privileged site where there is an absence of immune cells (1,10,5154). In a healthy hair follicle, the epithelium does not express major histocompatibility complex (MHC) class I and II molecules. There is also a high expression level of various immunosuppressive molecules such as TGF-b, IGF-1, and a-MSH (5557). In contrast, the epithelium of hair follicles in both AA patients and C3H/HeJ mice with AA shows an increased expression of MHC-I and II and a decrease in immunosuppressive molecules; a sign of possible change in immune modulation in the AA-affected skin (7,53). It has also been shown that there is a higher expression of adhesion molecules (ICAM-2 and ELAM-1) in the perivascular and peribulbar zone of AA-affected skin in a progressive disease stage. Adhesion molecules bind leukocytes to the endothelial cells and mediate the trafcking of leukocytes into the dermis (58). This evidence has led to the hypothesis of immune privilege collapse in the hair follicle leading to targeting of the hair follicle by inammatory cells and the onset of AA (51,53,55). A recent brief study has suggested there is downregulated expression of several immunoregulatory genes in association with AA of which at least one (Red/IK) is signicantly downregulated in advance of overt hair loss (57). This has been taken as evidence in support of the immune privilege collapse hypothesis (59). However, the putative immune privilege deciencies were present when the same hair follicles were not under inammatory attack suggesting that immune privilege deciencies of themselves are not enough to elicit AA. Further, where AA is transferred from affected to unaffected mice by skin grafting (27), injury to follicles through the sham grafting of normal skin in comparative control mice, and the associated induction of follicle damage and MHC I and II expression, does not induce AA (42,47). Logically, any putative hair follicle immune privilege must be

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lost or overridden for AA to develop, but other events must also occur to launch the disease mechanism. Alopecia areata disordered antigen presentation The immune privilege hypothesis of AA development is attractive, but it disregards many generally accepted immune system conventions. Typically, lymphocyte-mediated inammation is only induced after active antigen epitope presentation in association with multiple costimulatory ligands on antigen-presenting cells (23,42,48). The inltration of immune cells in AA might be due to inappropriately presented antigenic peptides derived from within the hair follicles. Catagen regression of hair follicles involves signicant apoptosis and tissue remodeling (60) during which immune cells normally inltrate around the hair follicles (6164). This process may constantly expose the immune system to hair follicle-derived antigens. Autoimmunity is not an all or nothing event. It is a progressive scale of response with a threshold level above which overt autoimmune disease is observed (65). Evidence of this may be the low level of hair folliclespecic autoantibodies found in some people and rodents in the absence of overt AA (3739,66). Langerhans cells and dendritic cells are capable of presenting cell apoptosis-derived antigens to lymphocytes and have been shown to promote autoimmunity (1921). Potentially, a disorderly regression of catagen may involve hair follicle antigen uptake and presentation to lymphocytes, along with inappropriate expression of costimulatory factors, to induce the onset of overt AA (10,67 69). Studies with mice reveal pro-inammatory events occur in skin draining lymph nodes several weeks in advance of alopecia onset or even inltration of the skin by lymphocytes (42,47,70). As such, the fate decision for AA onset likely occurs not in the skin but in the draining lymph nodes (67,68). Alopecia areata atopy and other autoimmune diseases Studies have reported the association of AA with the development of other diseases. AA is found to be associated with an increased frequency, and possibly an increased severity, of allergies (atopy) compared to the general population (10). Hay fever, asthma, and/or atopic dermatitis, are found in 1060% of AA patients (7173). Association of AA with other autoimmune diseases including thyroid disorders (18%), anemia (0.9%), and psoriasis

(0.4%) has been observed (71,72,74,75). It can also be associated with autoimmune diseases like ulcerative colitis and multiple sclerosis according to individual case reports (1,76). Notably, the development of AA seems to decrease the incidence of Type I diabetes while being associated with an increase in the incidence of diabetes in healthy relatives (77). A recent retrospective study has revealed that a subject with a history of atopy or other autoimmune disease has an increased risk of subsequent AA development (71). These apparent associations between AA and atopy and other autoimmune diseases could be the result of a nonspecic increase in immune system sensitivity coupled to genetic predispositions. For example, gene alleles coding for higher general levels of immunosurveillance, or increased levels of costimulation in association with antigen presentation to lymphocytes, could make an individual more susceptible to the development of aberrant immune responses. It is also possible the link is more direct. Atopy or presence of other autoimmune diseases could be causal events that lead to the destabilization of the immune system which then enable the onset of AA. The role of atopy and non-AA autoimmunity in AA is still to be elucidated (10). Alopecia areata environmental input The onset and progression of AA probably requires input from multiple factors including; genetics (65), stress (78), hormones (79), diet (80), infectious agents (81), vaccinations (82), and several other possible inputs. Potentially, these factors may increase or reduce susceptibility to AA onset, inuence the disease pattern, severity, duration, and response to treatment, by modifying the physical and biochemical status of the immune system and/or hair follicles (10). Different factors may be prevalent for different individuals with AA. The potential impact of genetics on AA is described elsewhere in this issue and will not be considered here; it sufces to say that specic genes are likely to play very important roles in AA (65). However, the inuence may vary from person to person. For some, genetics may play the dominant role with little environmental input. For others, environmental inuence may be more dominant while genetics makes a relatively minor contribution. Thus, when dermatologists and scientists argue in support of stress being a trigger versus infectious agents versus genetic susceptibility, each of these factors may be important for different subsets of patients. Many hypotheses have been raised as to what may trigger and modulate AA but the specic

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environmental risk factors and their relative contributions are still largely to be determined. Alopecia areata stress One of the most commonly cited causes of AA is psychological stress. However, in controlled clinical studies, no correlations between reported stress levels and AA have been observed (8385). Studies on specic stressful events experienced by AA patients have revealed contradicting results on whether it is causal (8688) or unrelated (8991) to the development of AA. As such, the clinical data in support of the claim that stress can trigger AA onset is not strong. However, some studies have linked aberrant psychosocial traits with the development of AA and these include depression, anxiety, and aggression (84,89,90). In a mouse model, AA was found to be associated with altered hypothalamic-pituitaryadrenal (HPA) activity in a recent study (92). When AA was induced, affected mice were shown to have signicantly higher active central and peripheral HPA tone compared to unaffected controls. The mice displayed a blunted systemic HPA response to acute physiological stress and also a decreased habituation response to chronic psychological stress (92). Differential expression of several stressrelated genes was identied in the brains of the AA-affected mice. In the skin of AA mice and human patients, there is increased expression of local HPA hormone receptors such as corticotrophin-releasing hormone receptor 2 (CRH-R2) at both mRNA and protein levels (92,93). CRH-R2 is a major receptor in dermal compartments and its aberrant expression could contribute to the local HPA axis and response to inammation (92,93). Estrogen receptor 1 (esr1) expression was also elevated in AA-affected mouse hair follicles and esr1 is known to regulate the HPA response to stress (92,94). This suggests that the observed changes to the local skin HPA and the aberrant central HPA activity are a consequence of the immune system activity in AA and may be expressed as an inability to cope with stress. The evidence that stress can modulate AA is less clear, but the functional data thus far suggests it is possible. CRH can induce mast cell differentiation from hair follicle mesenchyme (95,96) and the above suggests CRH/receptor activity is high in AA skin. Differences in neuropeptide substance P expression occur with AA development (97,98). Applying substance P to the skin of AA-affected mice induces mast cell degranulation, accelerates hair follicle catagen regression, and increases

numbers of CD8+ T cells-expressing granzyme B (99). These and other data suggest that there is a feedback loop; inammatory activity in AA can modify the HPA axis and stress responses, but in turn, increased HPA activity may accentuate inammatory activity. Whether the effect is enough to actually induce AA onset remains to be proven. Alopecia areata diet AA might also be modulated by dietary intake. In cross-sectional studies, it is reported that iron deciency is associated with various forms of hair loss including AA (100). As revealed in these studies, iron deciency is mainly observed in females such that 2471% of the females presenting with AA were iron decient (101,102). The mechanism by which iron deciency could lead to AA is not known. One possible explanation is that iron deciency hinders the rate-limiting enzyme for DNA synthesis and hence diminishes the proliferative capacity of hair follicle matrix cells (100). There is argument as to the true signicance, if any, of dietary iron intake in hair loss and AA (103). However, some dermatologists evaluate iron deciency as an aid to diagnosis and iron supplements are sometimes used as a adjunctive treatment for women with hair loss (100). In mice, it was found that dietary soy oil increases resistance to the development of AA (80). A high soy oil content diet was given to mice grafted with AA skin and regrowth of hair on the skin graft was observed while comparative controls on a normal diet developed AA. The antioxidant enzyme enhancement and estrogen receptorbinding properties of soy derivatives might block the onset of AA in mice (79,104). In studies on AA development in populations in different geographical settings, the lifetime risk of AA in the United Kingdom and the United States is 1.7% (3), whereas the lifetime risk in Japan has been estimated at less than 1% (80). However, it has been observed that the Japanese population living in Hawaii, where a Westernized non-soy diet predominates, has disproportionally higher AA incidence (105). Whether these observational studies done on human populations truly reect a signicant difference in environmental or dietary inuence remains to be seen. Alopecia areata other factors Cytomegalovirus (CMV) has been suggested as a potential promoter of AA (106), but several subsequent studies were not able to conrm the potential association (107110). Yet intriguingly, latest

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genetic research suggests a possible role for a CMVbinding protein in natural killer cell activation (111). Vaccinations have also been implicated in the development of AA (82,112). However, a largescale study using the AA mouse model was unable to demonstrate a signicant correlation between hepatitis B vaccination and AA (113). Hormones, while not directly environment derived, can be modied by other environmental factors. One small study with AA-affected mice suggested estrogens may accelerate AA progression while testosterone might reduce AA susceptibility (79).

Conundrums in understanding mechanisms of alopecia areata

Alopecia areata is a complex and poorly understood entity. There is much that we do not understand about the pathogenesis of the various clinical presentations. Previously in a review on scarring alopecia, several questions were posed, the answers to which would signicantly help in understanding disease etiopathogenesis (114). With modication, some of these issues also apply to understanding AA. The questions below may be primary points to address in building a framework for further research investigation of AA. What comes rst, an inammatory inltrate or a hair follicle defect? Animal model research conrms that the immune system is the driving force for overt hair loss and in the absence of a functional immune system AA does not develop (2732). However, the initiating mechanism for the rst onset of AA is not clear. Defects in the immune system, such as inappropriate antigen presentation, or failed immunoregulation, could elicit AA onset. Equally, hair follicle defects, such as a failure of immune privilege or inappropriate expression of altered antigen epitopes, could initiate the disease with inammation as a response event. Which comes rst is not an easy question to answer without extensive use of animal models. However, answering the question will be important as it could determine whether the main focus of treatment development should be on modulating the immune system or the hair follicle unit. Where and what is the target of attack in AA-affected hair follicles? In cicatricial alopecias, the inammatory inltrate focuses on the permanent region of the hair fol-

licle suggesting that the target of interest to the inammatory inltrate resides in the permanent portion of the hair follicle (115,116). In contrast, the primary location of the inammatory inltrate in AA focuses on the transient region of anagen stage hair follicles. Logically, this suggests the location of the target of interest in AA is present in the transient region and is not expressed in the permanent portion of the hair follicle. Assuming that the antigen target of attack is close to the location of the immune cell inltrate, then there are multiple candidates as sources for the inciting agent; keratinocytes constitute the root sheaths and hair matrix, dermal papilla and dermal sheath cells are mesenchyme derived, and melanocytes in the hair bulb are all possible targets. Several studies have circumstantially suggested melanocytes could be the candidate source of antigen epitopes. In the rat model for AA, rats can sometimes lose the pigmented hair around their necks before the onset of AA occurs in nonpigmented pelage areas on their trunks (117). There are also case reports of selective pigmented hair loss during the development of AA in humans (118120). It is therefore possible that proteins involved in pigmentation may be associated with the development of AA. Melanomaassociated antigens such as GP100 and MART-1 have been used to stimulate T cells in culture and these lymphocytes were able to reinduce AA when injected into previously AA-affected skin biopsies grafted to severe combined immunodecient (SCID) mice (121). However, the intrafollicular inammatory cells in AA do not seem to focus on melanocytes as one might anticipate if they were the primary target. Rather, they locate themselves among root sheath and matrix keratinocytes (1,18,70). The humoral immune system also seems to be focused on keratinocytes as keratinocyte proteins like K16 and trichohyalin are found to be targeted by autoantibodies (36) and studies have not been able to identify autoantibody targeting of melanocytes. It is possible that lymphocytes from patients with AA may also target these keratinocyte antigens or similar. What distinguishes nonscarring AA from scarring alopecia? Both scarring and nonscarring alopecias can involve folliculocentric inammation by lymphocytes. In cicatricial alopecias, there is relatively quick and irreversible hair follicle destruction

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(115,116). In contrast, in AA, there is either no permanent destruction of the hair follicles, or at least it takes many years of inammatory attack for scarring alopecia to develop (122). This disparity is currently explained by the difference in location of the inammatory inltrate focus and the potential for stem cells or progenitor cells to be the target of attack in cicatricial alopecia (114). In addition, in AA, it is suspected that under inammatory attack, the hair follicle regresses to a telogen state and in doing so, the hair follicle may avoid irreversible destruction (10). As hair follicles enter telogen, the AA inammatory inltrate largely disappears while in scarring alopecias, the inammation persists regardless of changes in the hair cycle. However, anagen stage hair follicles in AA can be surrounded and inltrated by an intense inammatory inltrate such that one would anticipate rather more follicular destruction than is actually observed. So why are anagen stage hair follicles not quickly destroyed? The answer may be that not all inammatory inltrates are created equal. For cell apoptosis to occur, there must be signicant cytotoxic activity mediated by the inammatory inltrate. In AA however, the inammatory cells may not possess high levels of cytotoxic activity as compared to inammatory cells in cicatricial alopecia (123). Therefore, an important study in understanding AA may be to characterize the cellular composition of the inammatory inltrate, the nature of its activated state, and the potency of its total cytotoxic activity. Is alopecia areata really just one disease? This is potentially an issue that could cause signicant problems with the interpretation of clinical research data and the study of genetic contribution. It is unlikely that what we describe today as a single disease will be shown to have a common disease pathogenesis in all cases of AA. AA is found in several different phenotypic presentations from the classic distinct patches, through diffuse AA, to exclusive ophiasis AA, and nevoid AA (1). These different presentations may indicate different underlying disease development mechanisms or variations thereof. It is also possible that individuals presenting with similar AA phenotypes will be shown to have different causal disease pathogenesis mechanisms. It is unlikely that exactly the same mechanism is involved in every case identied within the AA disease collective.

Are animal models of AA a satisfactory reection of the human clinical disease? The best model of a human disease is another human with the same disease. Animal models may not be perfect representations of the human condition, but it would be folly to ignore potentially important information. Data should be considered from any and every source; animal models, cell culture, clinical studies, historical perspective, etc., and synthesized into realistic hypotheses. Ethical issues temper the ability to involve patients in many forms of research, particularly those requiring proactive interventions with unknown consequences. Here, animal models become invaluable. For example, targeted deletion or overexpression of specic genes in a rodent model can enable a signicant insight into disease development that cannot be obtained using human observation alone (46,69,124127). Animal models may also enable rapid and extensive screening of candidate treatments for AA (117).

Conclusion
AA is an unpredictable disorder that has varying histopathological characteristics at different stages. There are many hypotheses for the etiopathogenesis of AA and it is probable that it involves very diverse input factors ranging from the genetics of the immune system to autoantigen specicity and expression patterns. Combining recent studies, it is likely that the time of onset and severity of AA is determined by interaction between an individuals genetic predisposition and exposure to environmental triggers. Currently, the hypotheses for AA development mostly focus on the collapse of immune privilege properties of the hair follicles and the nature of self-antigen presentation that result in the induction and subsequent attack of activated lymphocytes. Studies are being conducted to look for the autoantigens that may be associated with the development of AA but the exact nature of the inciting antigen epitope(s) remains to be elucidated.

Acknowledgements
This work was supported by grants from the Canadian Dermatology Foundation (CDF) and the Canadian Institutes of Health Research (CIHR) to KJM (MOP-82927). EW is a recipient of a CIHR Skin Research Training Center (CIHR-SRTC) award. KJM is a recipient of CIHR (MSH-95328) and Michael Smith Foundation for Health Research (MSFHR) investigator awards.

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