Etiopathogenesis of alopeciaareata: Why do our

patients get it?dth_1416 337..347

Eddy Wang* & Kevin J. McElwee*†*Department of Dermatology and Skin Science, University of BritishColumbia and †Vancouver Coastal Health Research Institute, Vancouver,British Columbia, Canada

ABSTRACT: Alopecia areata (AA) is a nonscarring, inflammatory skin disease that results in patchy hairloss. AA is unpredictable in its onset, severity, and duration making it potentially very stressful foraffected individuals. Currently, the treatment options for AA are limited and the efficacy of thesetreatments varies from patient to patient. The exact etiology of AA is unknown. This article providessome insights into the etiopathogenesis of AA and why some people develop it. The current knowledgeon the pathogenesis of AA is summarized and some of the recent hypotheses and studies on AA arepresented 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 typicallyinvolves sudden loss of circular patches of scalphair (1,2). The largest epidemiological study indi-cates a 1.7% lifetime risk of developing AA in theUnited States (3) and it is one of the more commonforms of hair loss encountered in the dermatologyclinic (4). A study of alopecia patients showed AAaccounted for 25% of all alopecia cases and themajority of the patients belonged to the 30 to59-year age group (5). The distribution of AA acrossboth sexes and different races is generally equiva-lent; however, it appears that female, black patientshave the highest frequencies of visits to clinicsbecause of AA (5).

AA can present anywhere on the body; however,in 90% of the cases seen in dermatology clinics,

the hair loss is predominantly on the scalp (6). It ischaracterized by the sudden loss of hair in oval-shaped patches with spontaneous remission, reoc-currence, and exacerbation (1,7). AA can developinto more severe forms; alopecia totalis (AT)involves the loss of all scalp hair and alopecia uni-versalis (AU) is the complete loss of all body hair.Approximately 5% of AA patients will progress intoAT/AU. Unlike other forms of hair loss, such ascicatricial alopecia, the AA lesion is nonscarring bynature. The areas of skin with hair loss are smooth,have a natural color or slightly pink/peach tone,and the hair fibers at the border of these patchesmay have an “exclamation mark” appearance:short, broken hair fibers with a broader distal endcompared to the proximal end (1,7). Nail abnor-malities such as pitting and longitudinal ridgingcan also be observed in 17% of AA patients (8). AAis usually a reversible disease but it can be recur-rent and abrupt, making it very unpredictable andemotionally disturbing despite it being nonlife-threatening (9). The presentation of AA and itstreatment are discussed in more detail elsewherein this publication.

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.

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Dermatologic Therapy, Vol. 24, 2011, 337–347Printed in the United States · All rights reserved

© 2011 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPYISSN 1396-0296

Alopecia areata – pathology

There are three key phases in the normal hair cycle:the anagen (growth) phase, the catagen (regres-sion) phase, and telogen (resting) phase (10).During the controlled shedding phase (exogen) inhealthy follicles, old hair fiber is typically shed fromthe hair follicle after a new growth cycle begins.Consequently, overall hair coverage is maintained.During the development of alopecias, exogen oftenoccurs before anagen is renewed or when anagen isdystrophic and this results in a state called kenogenwhere no visible hair fiber is left in the hair follicle(11). Essentially, AA-affected skin can be said to bein a state of kenogen (1).

The severity and duration of AA can result inseveral different abnormal hair cycle presenta-tions. As observed in AA skin lesions, in general,there is a “swarm of bees” infiltration of lympho-cytes into the peribulbar space of anagen stagehair follicles and some penetration of lymphocytesto intrafollicular locations (1,7,12). In all stages ofAA, there can also be a diffuse infiltration of eosi-nophils and mast cells into the AA-affected skin,the significance of which is unknown (13–15).However, the histological presentation of AA canbe very different as it progresses from acute tochronic (1).

In the acute phase, when both CD8+ and CD4+ Tlymphocytes infiltrate into the peribulbar area, thecell density is an indication of active disease pro-gression (16). The net effect of the initial inflamma-tory cell infiltrate may not modify the hair cycle,but rather it adversely affects hair follicle activityand results in a “dystrophic anagen” state. Thoughanagen is maintained, the infiltration of inflamma-tory cells apparently disrupts the ability of the hairfollicles to produce hair fibers of sufficient size orintegrity (17). The exogen event may occur nor-mally as part of the overall hair cycle, but due to theanagen dystrophy, the expelled hair fiber is notreplaced by fiber that can provide equivalent scalpcoverage.

As the number of inflammatory cells in andaround the hair follicles increases, miniaturizationof the hair follicles can occur and the hair cycle canbecome truncated with rapid cycling of anagenand telogen phases (so-called “nanogen” hair fol-licles). As the process continues, progressively upto 50% of total hair follicles can be observed innanogen in tissue biopsies (1,18). The number ofcatagen/telogen stage hair follicles increases withtime. Notably, the amount of inflammation in theskin decreases as more hair follicles move into atelogen phase (18).

Finally, in the chronic stages of AA, most affectedhair follicles are forced into prolonged telogen andno attempt at reentering anagen or new growth ofhair is observed (17). The number of terminal scalphair follicles will decrease to about the samenumber of vellus hair follicles (18). At this point,any inflammation present will typically be local-ized in the papillary dermis around miniaturizedhair follicles. From these observations, AA is cir-cumstantially an inflammation driven diseasewhere changes to the hair follicle are closely corre-lated with changes in the peri- and intrafollicularinflammatory infiltrate.

Alopecia areata – role of the immune system

Although the AA phenotype is restricted to the skinand its appendages, there is evidence that much ofthe disease mechanism and the “decision” ondisease activation occurs away from the skin in theimmune system and its organs. To fully explain AA,one must consider events that can occur both inand beyond the skin. Inflammatory cells that com-prise the skin immune system (SIS) are transitory.On antigenic challenge, SIS antigen-presentingcells typically migrate to lymphoid organs toeducate and to be educated (19–21). Lymphocytesare not normally resident in healthy skin in largenumbers. The intense inflammatory infiltrateobserved in association with AA suggestsin-migration of activated cells from the centralimmune system. Studies with mice confirm thatblocking lymphocyte skin-homing receptors orimpeding antigen-presenting cell migration toskin-draining lymph nodes can prevent AA devel-opment and modulate its progression (22–25). Inshort, we are dealing with the whole of the immunesystem and not just the SIS when we investigateand elucidate AA disease mechanisms.

Alopecia areata – autoimmunity

It is generally accepted that AA is an autoimmunedisease. However, the research data produced thusfar is best described as “consistent with” anautoimmune mechanism in AA. Incontrovertibleevidence of autoimmunity would require the iden-tity of the primary antigen target(s) in the inflam-matory cell attack to be characterized as self-antigen(s) derived from the hair follicle unit, butthis remains to be proven (26). Nevertheless, anautoimmune scenario is currently the best expla-nation for the clinical research data we have for themajority of AA patients. Using animal models,functional evidence has been produced that dem-

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onstrates the dominance of the immune system inthe AA disease mechanism (27–32). Essentially, ifthere is no functional immune system and/or focalhair follicle inflammation, then AA does not occurin these disease models.

Alopecia areata – autoantibody activity

The presence of hair follicle specific autoantibodiesin AA patients suggests that AA is an autoimmunedisease (10). Hair follicle specific IgG antibody con-centration is increased in the peripheral blood ofAA patients and it can be found localized aroundthe periphery of hair follicles, especially near theborder of the active lesions (10,33). In a recentstudy, it was found that the antigens bound by someof these serum antibodies are keratin 16 and hairfollicle specific trichohyalin (34–36). However, thespecificity of hair follicle autoantibody targets canbe very variable between AA-affected individuals(37–40). Further, studies involving the injection ofautoantibodies in different models have not shownthe autoantibodies to have a significant pathogeniceffect (41). This suggests the AA disease mechanismis more likely cell mediated rather than antibodymediated. However, the presence of hair folliclespecific autoantibodies does suggest an autoim-mune mechanism is active and such autoantibod-ies may provide clues as to the antigenic targets forT cells.

Alopecia areata – immune cell activity

In both animal models of AA and in humans, folli-cular inflammation is mainly comprised of CD4+

and CD8+ T cells. However, a clear difference in thelocation of these cells is observed. From immuno-histological analysis, it is observed that activatedCD8+ T cells can be found infiltrated into hair fol-licles, whereas CD4+ T cells are almost exclusivelylocated in the perifollicular area (16,42–44). Due tothe cytotoxic nature of most CD8+ T cells, theirpresence inside hair follicles could easily disruptthe growth of hair. Various molecules are producedby activated cytotoxic T lymphocytes in AA such astumor necrosis factors, granzymes and Fas ligand(32,42,45–48). Potentially, these molecules maytrigger apoptosis in AA-affected hair follicle cellsand 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). Inthe rat model, depletion of CD8+ T cells yields abetter hair growth response compared to depletionof CD4+ T cells, and AA quickly redevelops whenthe cell depletion protocol is stopped (28,29). The

subcutaneous injection of activated CD8+ T cellswill quickly induce localized hair loss exclusively atthe site of injection while the injection of CD4+ Tcells does not induce local hair loss but will even-tually promote a systemic hair loss (multiple alope-cia patches) beyond the immediate site of injection(31). These studies suggest that CD8+ cells are theprimary instigators of hair follicle disruption andalopecia while CD4+ cells are likely to promote AAthrough their classic “helper” role.

Alopecia areata – hair follicle immune privilege

It is suggested that the hair follicle is an immuneprivileged site where there is an absence ofimmune cells (1,10,51–54). In a healthy hair fol-licle, the epithelium does not express majorhistocompatibility complex (MHC) class I and IImolecules. There is also a high expression level ofvarious immunosuppressive molecules such asTGF-b, IGF-1, and a-MSH (55–57). In contrast, theepithelium of hair follicles in both AA patients andC3H/HeJ mice with AA shows an increased expres-sion of MHC-I and II and a decrease in immuno-suppressive molecules; a sign of possible changein immune modulation in the AA-affected skin(7,53). It has also been shown that there is a higherexpression of adhesion molecules (ICAM-2 andELAM-1) in the perivascular and peribulbar zoneof AA-affected skin in a progressive disease stage.Adhesion molecules bind leukocytes to the endot-helial cells and mediate the trafficking of leuko-cytes into the dermis (58). This evidence has led tothe hypothesis of immune privilege collapse in thehair follicle leading to targeting of the hair follicleby inflammatory cells and the onset of AA(51,53,55).

A recent brief study has suggested there is down-regulated expression of several immunoregulatorygenes in association with AA of which at least one(Red/IK) is significantly downregulated in advanceof overt hair loss (57). This has been taken as evi-dence in support of the immune privilege collapsehypothesis (59). However, the putative immuneprivilege deficiencies were present when the samehair follicles were not under inflammatory attacksuggesting that immune privilege deficiencies ofthemselves are not enough to elicit AA. Further,where AA is transferred from affected to unaffectedmice by skin grafting (27), injury to folliclesthrough the sham grafting of normal skin in com-parative control mice, and the associated induc-tion of follicle damage and MHC I and IIexpression, 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 otherevents must also occur to launch the diseasemechanism.

Alopecia areata – disordered antigenpresentation

The immune privilege hypothesis of AA develop-ment is attractive, but it disregards many generallyaccepted immune system conventions. Typi-cally, lymphocyte-mediated inflammation is onlyinduced after active antigen epitope presentationin association with multiple costimulatory ligandson antigen-presenting cells (23,42,48). The infiltra-tion of immune cells in AA might be due to inap-propriately presented antigenic peptides derivedfrom within the hair follicles. Catagen regression ofhair follicles involves significant apoptosis andtissue remodeling (60) during which immune cellsnormally infiltrate around the hair follicles (61–64).This process may constantly expose the immunesystem to hair follicle-derived antigens. Autoim-munity is not an all or nothing event. It is a progres-sive scale of response with a threshold level abovewhich overt autoimmune disease is observed (65).Evidence of this may be the low level of hair follicle-specific autoantibodies found in some people androdents in the absence of overt AA (37–39,66).Langerhans cells and dendritic cells are capableof presenting cell apoptosis-derived antigens tolymphocytes and have been shown to promoteautoimmunity (19–21). Potentially, a disorderlyregression of catagen may involve hair follicleantigen uptake and presentation to lymphocytes,along with inappropriate expression of costimula-tory factors, to induce the onset of overt AA (10,67–69). Studies with mice reveal pro-inflammatoryevents occur in skin draining lymph nodes severalweeks in advance of alopecia onset or even infiltra-tion of the skin by lymphocytes (42,47,70). As such,the fate decision for AA onset likely occurs not inthe skin but in the draining lymph nodes (67,68).

Alopecia areata – atopy and otherautoimmune diseases

Studies have reported the association of AA with thedevelopment of other diseases. AA is found to beassociated with an increased frequency, and possi-bly an increased severity, of allergies (atopy) com-pared to the general population (10). Hay fever,asthma, and/or atopic dermatitis, are found in10–60% of AA patients (71–73). Association of AAwith other autoimmune diseases including thyroiddisorders (18%), anemia (0.9%), and psoriasis

(0.4%) has been observed (71,72,74,75). It can alsobe associated with autoimmune diseases like ulcer-ative colitis and multiple sclerosis according toindividual case reports (1,76). Notably, the develop-ment of AA seems to decrease the incidence of TypeI diabetes while being associated with an increase inthe incidence of diabetes in healthy relatives (77).

A recent retrospective study has revealed that asubject with a history of atopy or other autoim-mune disease has an increased risk of subsequentAA development (71). These apparent associationsbetween AA and atopy and other autoimmune dis-eases could be the result of a nonspecific increasein immune system sensitivity coupled to geneticpredispositions. For example, gene alleles codingfor higher general levels of immunosurveillance, orincreased levels of costimulation in associationwith antigen presentation to lymphocytes, couldmake an individual more susceptible to the devel-opment of aberrant immune responses. It is alsopossible the link is more direct. Atopy or presenceof other autoimmune diseases could be causalevents that lead to the destabilization of theimmune system which then enable the onset of AA.The role of atopy and non-AA autoimmunity in AAis still to be elucidated (10).

Alopecia areata – environmental input

The onset and progression of AA probably requiresinput from multiple factors including; genetics(65), stress (78), hormones (79), diet (80), infectiousagents (81), vaccinations (82), and several otherpossible inputs. Potentially, these factors mayincrease or reduce susceptibility to AA onset, influ-ence the disease pattern, severity, duration, andresponse to treatment, by modifying the physicaland biochemical status of the immune systemand/or hair follicles (10). Different factors may beprevalent for different individuals with AA. Thepotential impact of genetics on AA is describedelsewhere in this issue and will not be consideredhere; it suffices to say that specific genes are likelyto play very important roles in AA (65). However,the influence may vary from person to person. Forsome, genetics may play the dominant role withlittle environmental input. For others, environ-mental influence may be more dominant whilegenetics makes a relatively minor contribution.Thus, when dermatologists and scientists argue insupport of “stress” being a trigger versus “infectiousagents” versus “genetic susceptibility,” each ofthese factors may be important for different subsetsof patients. Many hypotheses have been raised as towhat may trigger and modulate AA but the specific

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environmental risk factors and their relative contri-butions are still largely to be determined.

Alopecia areata – stress

One of the most commonly cited causes of AA ispsychological stress. However, in controlled clini-cal studies, no correlations between reported stresslevels and AA have been observed (83–85). Studieson specific stressful events experienced by AApatients have revealed contradicting results onwhether it is causal (86–88) or unrelated (89–91) tothe development of AA. As such, the clinical data insupport of the claim that stress can trigger AA onsetis not strong.

However, some studies have linked aberrantpsychosocial traits with the development of AA andthese include depression, anxiety, and aggression(84,89,90). In a mouse model, AA was found to beassociated with altered hypothalamic-pituitary-adrenal (HPA) activity in a recent study (92). WhenAA was induced, affected mice were shown to havesignificantly higher active central and peripheralHPA tone compared to unaffected controls. Themice displayed a blunted systemic HPA response toacute physiological stress and also a decreasedhabituation response to chronic psychologicalstress (92). Differential expression of several stress-related genes was identified in the brains of theAA-affected mice.

In the skin of AA mice and human patients, thereis increased expression of local HPA horm-one receptors such as corticotrophin-releasinghormone receptor 2 (CRH-R2) at both mRNA andprotein levels (92,93). CRH-R2 is a major receptor indermal compartments and its aberrant expressioncould contribute to the local HPA axis and responseto inflammation (92,93). Estrogen receptor 1 (esr1)expression was also elevated in AA-affected mousehair follicles and esr1 is known to regulate the HPAresponse to stress (92,94). This suggests that theobserved changes to the local skin HPA and theaberrant central HPA activity are a consequence ofthe immune system activity in AA and may beexpressed as an inability to cope with stress.

The evidence that stress can modulate AA is lessclear, but the functional data thus far suggests it ispossible. CRH can induce mast cell differentiationfrom hair follicle mesenchyme (95,96) and theabove suggests CRH/receptor activity is high in AAskin. Differences in neuropeptide substance Pexpression occur with AA development (97,98).Applying substance P to the skin of AA-affectedmice induces mast cell degranulation, accelerateshair follicle catagen regression, and increases

numbers of CD8+ T cells-expressing granzyme B(99). These and other data suggest that there is afeedback loop; inflammatory activity in AA canmodify the HPA axis and stress responses, but inturn, increased HPA activity may accentuateinflammatory activity. Whether the effect is enoughto actually induce AA onset remains to be proven.

Alopecia areata – diet

AA might also be modulated by dietary intake. Incross-sectional studies, it is reported that iron defi-ciency is associated with various forms of hair lossincluding AA (100). As revealed in these studies, irondeficiency is mainly observed in females such that24–71% of the females presenting with AA were irondeficient (101,102). The mechanism by which irondeficiency could lead to AA is not known. One pos-sible explanation is that iron deficiency hinders therate-limiting enzyme for DNA synthesis and hencediminishes the proliferative capacity of hair folliclematrix cells (100). There is argument as to the truesignificance, if any, of dietary iron intake in hair lossand AA (103). However, some dermatologists evalu-ate iron deficiency as an aid to diagnosis and ironsupplements are sometimes used as a adjunctivetreatment for women with hair loss (100).

In mice, it was found that dietary soy oilincreases resistance to the development of AA (80).A high soy oil content diet was given to micegrafted with AA skin and regrowth of hair on theskin graft was observed while comparative controlson a normal diet developed AA. The antioxidantenzyme enhancement and estrogen receptor-binding properties of soy derivatives might blockthe onset of AA in mice (79,104). In studies on AAdevelopment in populations in different geo-graphical settings, the lifetime risk of AA in theUnited Kingdom and the United States is 1.7% (3),whereas the lifetime risk in Japan has been esti-mated at less than 1% (80). However, it has beenobserved that the Japanese population living inHawaii, where a Westernized non-soy diet pre-dominates, has disproportionally higher AA inci-dence (105). Whether these observational studiesdone on human populations truly reflect a signifi-cant difference in environmental or dietary influ-ence remains to be seen.

Alopecia areata – other factors

Cytomegalovirus (CMV) has been suggested as apotential promoter of AA (106), but several subse-quent studies were not able to confirm the poten-tial association (107–110). Yet intriguingly, latest

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genetic research suggests a possible role for a CMV-binding protein in natural killer cell activation(111). Vaccinations have also been implicated inthe development of AA (82,112). However, a large-scale study using the AA mouse model was unableto demonstrate a significant correlation betweenhepatitis B vaccination and AA (113). Hormones,while not directly environment derived, can bemodified by other environmental factors. Onesmall study with AA-affected mice suggested estro-gens may accelerate AA progression while test-osterone might reduce AA susceptibility (79).

Conundrums in understandingmechanisms of alopecia areata

Alopecia areata is a complex and poorly under-stood entity. There is much that we do not under-stand about the pathogenesis of the various clinicalpresentations. Previously in a review on scarringalopecia, several questions were posed, theanswers to which would significantly help inunderstanding disease etiopathogenesis (114).With modification, some of these issues also applyto understanding AA. The questions below may beprimary points to address in building a frameworkfor further research investigation of AA.

What comes first, an inflammatory infiltrate or ahair follicle defect?

Animal model research confirms that the immunesystem is the driving force for overt hair loss and inthe absence of a functional immune system AAdoes not develop (27–32). However, the initiatingmechanism for the first onset of AA is not clear.Defects in the immune system, such as inappropri-ate antigen presentation, or failed immunoregula-tion, could elicit AA onset. Equally, hair follicledefects, such as a failure of immune privilege orinappropriate expression of altered antigenepitopes, could initiate the disease with inflamma-tion as a response event. Which comes first is notan easy question to answer without extensive useof animal models. However, answering the ques-tion will be important as it could determinewhether the main focus of treatment developmentshould be on modulating the immune system orthe hair follicle unit.

Where and what is the target of attack inAA-affected hair follicles?

In cicatricial alopecias, the inflammatory infiltratefocuses on the permanent region of the hair fol-

licle suggesting that the target of interest tothe inflammatory infiltrate resides in the perma-nent portion of the hair follicle (115,116). In con-trast, the primary location of the inflammatoryinfiltrate in AA focuses on the transient region ofanagen stage hair follicles. Logically, this suggeststhe location of the target of interest in AA ispresent in the transient region and is notexpressed in the permanent portion of the hairfollicle. Assuming that the antigen target of attackis close to the location of the immune cell infil-trate, then there are multiple candidates assources for the inciting agent; keratinocytes con-stitute the root sheaths and hair matrix, dermalpapilla and dermal sheath cells are mesenchymederived, and melanocytes in the hair bulb are allpossible targets.

Several studies have circumstantially suggestedmelanocytes could be the candidate source ofantigen epitopes. In the rat model for AA, ratscan sometimes lose the pigmented hair aroundtheir necks before the onset of AA occurs innonpigmented pelage areas on their trunks(117). There are also case reports of selectivepigmented hair loss during the development of AAin humans (118–120). It is therefore possible thatproteins involved in pigmentation may be associ-ated with the development of AA. Melanoma-associated antigens such as GP100 and MART-1have been used to stimulate T cells in culture andthese lymphocytes were able to reinduce AAwhen injected into previously AA-affected skinbiopsies grafted to severe combined immuno-deficient (SCID) mice (121). However, the intrafol-licular inflammatory cells in AA do not seem tofocus on melanocytes as one might anticipateif they were the primary target. Rather, theylocate themselves among root sheath and matrixkeratinocytes (1,18,70). The humoral immunesystem also seems to be focused on kerati-nocytes as keratinocyte proteins like K16 andtrichohyalin are found to be targeted by autoanti-bodies (36) and studies have not been able toidentify autoantibody targeting of melanocytes. Itis possible that lymphocytes from patients withAA may also target these keratinocyte antigens orsimilar.

What distinguishes nonscarring AA fromscarring alopecia?

Both scarring and nonscarring alopecias caninvolve folliculocentric inflammation by lympho-cytes. In cicatricial alopecias, there is relativelyquick and irreversible hair follicle destruction

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(115,116). In contrast, in AA, there is either nopermanent destruction of the hair follicles, or atleast it takes many years of inflammatory attackfor scarring alopecia to develop (122). This dispar-ity is currently explained by the difference in loca-tion of the inflammatory infiltrate focus and thepotential for stem cells or progenitor cells to bethe target of attack in cicatricial alopecia (114). Inaddition, in AA, it is suspected that under inflam-matory attack, the hair follicle regresses to atelogen state and in doing so, the hair follicle mayavoid irreversible destruction (10). As hair folliclesenter telogen, the AA inflammatory infiltratelargely disappears while in scarring alopecias, theinflammation persists regardless of changes in thehair cycle.

However, anagen stage hair follicles in AAcan be surrounded and infiltrated by an intenseinflammatory infiltrate such that one wouldanticipate rather more follicular destructionthan is actually observed. So why are anagen stagehair follicles not quickly destroyed? The answermay be that not all inflammatory infiltrates arecreated equal. For cell apoptosis to occur, theremust be significant cytotoxic activity mediatedby the inflammatory infiltrate. In AA however,the inflammatory cells may not possess highlevels of cytotoxic activity as compared to inflam-matory cells in cicatricial alopecia (123). There-fore, an important study in understanding AAmay be to characterize the cellular composition ofthe inflammatory infiltrate, the nature of its acti-vated state, and the potency of its total cytotoxicactivity.

Is alopecia areata really just one disease?

This is potentially an issue that could causesignificant problems with the interpretation ofclinical research data and the study of geneticcontribution. It is unlikely that what we describetoday as a single disease will be shown to have acommon disease pathogenesis in all cases of AA.AA is found in several different phenotypic pre-sentations from the classic distinct patches,through diffuse AA, to exclusive ophiasis AA, andnevoid AA (1). These different presentationsmay indicate different underlying disease devel-opment mechanisms or variations thereof. It isalso possible that individuals presenting withsimilar AA phenotypes will be shown to have dif-ferent causal disease pathogenesis mechanisms. Itis unlikely that exactly the same mechanism isinvolved in every case identified within the AAdisease collective.

Are animal models of AA a satisfactory reflectionof the human clinical disease?

The best model of a human disease is anotherhuman with the same disease. Animal models maynot be perfect representations of the human con-dition, but it would be folly to ignore potentiallyimportant information. Data should be consideredfrom any and every source; animal models, cellculture, clinical studies, historical perspective, etc.,and synthesized into realistic hypotheses. Ethicalissues temper the ability to involve patients inmany forms of research, particularly those requir-ing proactive interventions with unknown conse-quences. Here, animal models become invaluable.For example, targeted deletion or overexpressionof specific genes in a rodent model can enable asignificant insight into disease development thatcannot be obtained using human observationalone (46,69,124–127). Animal models may alsoenable rapid and extensive screening of candidatetreatments for AA (117).

Conclusion

AA is an unpredictable disorder that has varyinghistopathological characteristics at different stages.There are many hypotheses for the etiopathogen-esis of AA and it is probable that it involves verydiverse input factors ranging from the genetics ofthe immune system to autoantigen specificity andexpression patterns. Combining recent studies, it islikely that the time of onset and severity of AA isdetermined by interaction between an individual’sgenetic predisposition and exposure to environ-mental triggers. Currently, the hypotheses for AAdevelopment mostly focus on the collapse ofimmune privilege properties of the hair follicles andthe nature of self-antigen presentation that result inthe induction and subsequent attack of activatedlymphocytes. Studies are being conducted to lookfor the autoantigens that may be associated with thedevelopment of AA but the exact nature of the incit-ing antigen epitope(s) remains to be elucidated.

Acknowledgements

This work was supported by grants from the Cana-dian Dermatology Foundation (CDF) and theCanadian Institutes of Health Research (CIHR) toKJM (MOP-82927). EW is a recipient of a CIHR SkinResearch Training Center (CIHR-SRTC) award. KJMis a recipient of CIHR (MSH-95328) and MichaelSmith Foundation for Health Research (MSFHR)investigator awards.

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