CONTINUING MEDICAL EDUCATION

Alopecia areata update
Part I. Clinical picture, histopathology, and pathogenesis
Abdullah Alkhalifah, MD,a Adel Alsantali, MD,a Eddy Wang, BSc,a Kevin J. McElwee, PhD,aand Jerry Shapiro, MDa,bVancouver, British Columbia, Canada, and New York, New York
Alopecia areata (AA) is an autoimmune disease that presents as nonscarring hair loss, although the exact
pathogenesis of the disease remains to be clarified. Disease prevalence rates from 0.1% to 0.2% have been
estimated for the United States. AA can affect any hair-bearing area. It often presents as well demarcatedpatches of nonscarring alopecia on skin of overtly normal appearance. Recently, newer clinical variants
have been described. The presence of AA is associated with a higher frequency of other autoimmune
diseases. Controversially, there may also be increased psychiatric morbidity in patients with AA. Althoughsome AA features are known poor prognostic signs, the course of the disease is unpredictable and the
response to treatment can be variable. Part one of this two-part series on AA describes the clinicalpresentation and the associated histopathologic picture. It also proposes a hypothesis for AA development
based on the most recent knowledge of disease pathogenesis. ( J Am Acad Dermatol 2010;62:177-88.)
Learning objectives: After completing this learning activity, participants should be familiar with the mostrecent advances in AA pathogenesis, recognize the rare and recently described variants of AA, and be able
to distinguish between different histopathologic stages of AA.
Key words: alopecia areata; alopecia totalis; alopecia universalis; nonscarring alopecia; pathology;
pathogenesis.

DEMOGRAPHICS
Key pointdAbbreviations used:

Alopecia areata affects all age groups and different ethnicities, with equal sex distribution

AA:
APC:
APS:
AT:
AU:
CD4/8:
DEBR:
HLA:
HPA:
MHC:
SCID:
TE:

Alopecia areata (AA) occurs in populations worldwide.
It is a common disease encountered by dermatologists,
with a frequency ranging from 0.7% to 3.8% of patients
attending dermatology clinics.1,2 In the United States,
AA was estimated to occur in 0.1% to 0.2% of the general
population,3 with a lifetime risk of 1.7%.4 Overall, AA
likely affects males and females equally.5 Some studies
show a significant male preponderance in the adult age
group, although others identify contrasting results.6,7
From the Department of Dermatology and Skin Science,a University of British Columbia, Vancouver, and the Department of
Dermatology,b New York University.
Funding sources: None.
Conflicts of interest: Dr Shapiro is a consultant for Johnson andJohnson Inc. Drs Shapiro and McElwee are cofounders of
TrichoScience Innovations Inc. The other authors, editors, andpeer reviewers have no relevant financial relationships.
Reprint requests: Jerry Shapiro, MD, University of British Columbia
Skin Care Center, 835 W 10th Ave, Vancouver, BC, V5Z 4E8,
Canada. E-mail: jerry.shapiro@vch.ca.
0190-9622/$36.00ª 2009 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2009.10.032

alopecia areata
antigen presenting cell
autoimmune polyglandular syndrome
alopecia totalis
alopecia universalis
cluster of differentiation 4/8
Dundee experimental bald rat
human leukocyte antigen
hypothalamic-pituitary-adrenal
major histocompatibility complex
severe combined immunodeficient
telogen effluvium

Pediatric AA constitutes approximately 20% of AA
cases,8 and as many as 60% of patients with AA will
present with their first patch before 20 years of age.9
One study suggests that 85.5% of Asian patients with AA
have disease onset before 40 years of age.2 The diseaseprevalence peaks between the second and fourth
decades of life.10

CLINICAL PICTURE
Key pointsd

AA classically presents as asymptomatic,well defined patches of nonscarring alopecia
with no overt epidermal changes
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the disease duration becomes chronic. Initial hair
Patches can be mildly reddened or peachy inregrowth, whether spontaneous or induced by treatcolord Acute diffuse and total alopecia is a newment, is typically non- or hypopigmented (Fig 8), but
the color usually returns with time.10 The disease isvariant of AA with favorable prognosis
frequently asymptomatic, although a few patients
AA can occur on virtually any hair-bearing area,
report pruritus, burning sensations, or pain before
but it affects the scalp in approximately 90% of cases
hair loss begins.11
seen in dermatology clinics.5 The disease can be
The use of videodermoclassified based on the extent
scopy with a magnification ofor pattern of the hair loss.11,12
CAPSULE SUMMARY
20 to 70 times may be a
The hair loss can present
valuable, noninvasive tool
as single delimited patches of
Alopecia areata pathogenesis is not fullyin equivocal AA cases. The
hair loss (most common),understood.
presence of numerous yelmultiple patches, or extenA new variant of alopecia areata with alow dots and short regrowing
sive hair loss. Based on thefavorable prognosis was recently
hairs is suggested to be aextent of hair loss, the disdescribed.
characteristicfeature.16,17
ease is clinically classified as
Yellow dots, however, canfollows: patchy AA, in which
The histopathologic picture varies
also be seen in androgenic
there is a partial loss of scalp
depending on the stage of disease and,alopecia.18 Close examinahair (Fig 1); alopecia totalis
in the absence of classic inflammation, ittion of the hair shafts at the(AT), in which 100% of scalp
can be puzzling to the inexperienced
edge of lesions, particularly
hair is lost (Fig 2); or alopecia
dermatopathologist.
exclamation mark hairs, may
universalis (AU), in which
reveal subtle defects in thethere is a 100% loss of all
structure and cuticle.19
scalp and body hair. Approximately 5% of cases will
progress to AT/AU.13
The pattern of hair loss observed in AA can vary
DIFFERENTIAL DIAGNOSIS
considerably, and less common presentations can be
Key points
observed in a minority of patients, including reticulard Trichotillomania and tinea capitis are thepatches of hair loss; ophiasis type, band-like hair loss
most important differential diagnoses inin parieto-temporo-occipital area (Fig 3); ophiasis
childreninversus (sisapho), very rare band-like hair loss ind Diffuse AA can be easily misdiagnosed as
the fronto-parieto-temporal area (Fig 4); and atelogen effluvium
diffuse thinning over part or all of the scalp.
Another variant that should be considered is acute
In children, the most important entities to rule out
diffuse and total alopecia, which was first describedaretinea capitis and trichotillomania. Tinea capitis
by Sato-Kawamura et al14 and was reported more
can be differentiated by the presence of inflammation
recently by Lew et al15 in a larger series of patientsor at least mild scaling. Trichotillomania may involvewith similar characteristics. This new variant is charirregular or bizarrely shaped lesions. The presence ofacterized by its rapid progression and extensive
broken hairs with varying lengths gives lesions a
involvement, along with a favorable prognosis.
rough texture, unlike the smooth surface of AA. The
Classic AA lesions are well demarcated, round ordifferentiation of diffuse AA from telogen effluvium
oval, completely bald, smooth-surfaced patches(TE) can be challenging. The patient’s history may(Fig 5).11 The skin within the patch is usually normal
reveal a triggering factor that may point towards aon the first examination; however, it is not uncomdiagnosis of TE. In diffuse AA, the hair pull test may
mon to see a slightly peachy11 (Fig 6) or reddened10
show some dystrophic anagen hairs compared to thecolor. A characteristic finding that is frequently seen
pure telogen hairs found in TE. Ultimately, a scalpin (or at the border of) the patches is ‘‘exclamation
biopsy may be required to correctly differentiate
mark hairs.’’5 These are short hairs that are tapered
diffuse AA and TE. Lupus and secondary syphilis
proximally and wider distally (Fig 7). In active
may also be considered in the differential diagnosis
disease, where alopecia patches are expanding, aof AA and may require serology testing or a scalp
hair pull test may be positive at the periphery ofbiopsy for confirmation. Where a strong family assolesions.11 An interesting feature of AA is its initialciation of universal hair loss is observed, the differsparing of white hairs in patients with graying hair.10
ential diagnosis may include a rare inherited genetic
However, eventually white hair is also often lost as
hair loss condition called congenital atrichia.20
d

d

d

d

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Fig 3. Ophiasis pattern of alopecia areata.

Fig 1. Patchy alopecia areata in the right frontotemporal
area. Note eyebrow involvement.

Fig 4. Ophiasis inversus (sisapho), a rare variant that can
mimic male pattern hair loss.

Autoimmune diseases, particularly thyroiditis, are the most significant associationd The presence of such abnormalities is one ofthe poor prognostic factors
d Other reported abnormalities include psychiatric and asymptomatic ophthalmologicchangesd

Fig 2. Alopecia totalis with a 100% loss of scalp hair.

PROGNOSISKey points
The extent of AA involvement is probably
the most important prognostic factor
d In AT/AU, the chance of full recovery is lessthan 10%d

The course of AA is unpredictable. Up to 50% of
patients will recover within 1 year even without
treatment.12 However, most patients will have morethan one episode of hair loss. The most importantfactors indicating a poor prognosis are the extent of
hair loss presentation (extensive AA/AT/AU)21 or an
ophiasis pattern of hair loss.15 Other factors associated with a poor prognosis include a long duration of
hair loss,15 atopy, a positive family history, the presence of other autoimmune diseases, nail involvement, and young age of first onset.11 In children, thedisease may have a tendency towards worsening withtime, even if the initial presentation was mild.21 In
AT/AU, the chance of full recovery is less than 10%.22

ASSOCIATED ABNORMALITIESKey pointsdAA can be associated with nail changes in as
many as 66% of patients

Nail involvement may be observed in AA, with areported frequency ranging from 7% to 66%.23 Nailpitting is the most common nail abnormality observed.23,24 Other abnormalities include trachyonychia, Beau lines, onychorhexis, thinning or
thickening, onychomadesis, koilonychias, punctuate
or transverse leukonychia, and red spotted lunulae.11 Nails can be affected before, concurrent with,or after the resolution of hair loss. Several studies
have suggested that nail abnormalities are associatedwith more extensive hair loss.23,24
AA can be found in association with other autoimmune diseases. Thyroid autoimmunity is probably
the main association, with an incidence between 8%
and 28%.25 The presence of thyroid autoantibodies
has no clinical correlation with AA severity.26 Vitiligo
may be another important association, with a 3% to
8% incidence in AA patients compared to a prevalence of 1% in the US population.27 Atopy is twice ascommon in AA patients compared with the general
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Fig 5. Well-demarcated, smooth-surfaced patches ofalopecia areata.

Fig 6. Alopecia areata can present with peach coloredpatches. Note the color difference between the involved
and uninvolved hair bearing scalp.

reported to be associated with AA include Down
syndrome, Addison disease, autosomal recessive
autoimmune polyglandular syndrome (APS-1)(chronic
hypoparathyroidism-mucocutaneous
candidiasis-autoimmune adrenal insufficiency), pernicious anemia, psoriasis, lupus, celiac disease,ulcerative colitis, and multiple sclerosis. These lesscommon autoimmune diseases are more likely to be
associated with AT/AU.28 There may be an increased
risk of type 1 diabetes in family members of AA
patients; in contrast, the patients themselves may
have a reduced incidence compared to the general
population.29
There may be a high psychiatric morbidity in AA,
especially anxiety and mood disturbance.30 In one
report, ophthalmologic findings such as asymptomatic lens opacities and fundus changes occurred in
51% and 41% of AA patients, respectively.31

INVESTIGATIONS
Key pointdRoutine testing is not indicated in AA

Routine screening for autoimmune disease (thyroid disease in particular) is not generally indicatedbecause of insufficient clinical evidence.32 Olderpatients, patients with long disease duration,

Fig 7. A, Close view showing multiple exclamation markhairs. B, Exclamation mark hairs seen under Folliscopeexamination (Sometech Inc, Seoul, Korea). (Original
magnification, 350.)

females, patients with persistent patchy AA (ascompared to transient patchy AA), and patientswith AT/AU have been found to more likely havethyroid abnormalities.28 However, because AA severity and thyroid disease are neither correlated nor
causal, routine thyroid testing is not recommended
at our center.
Potassium hydroxide, fungal culture, lupus serology, syphilitic screening, and a scalp biopsy may benecessary in ambiguous or difficult to diagnose
cases. However, most presentations of AA are obvious, and further laboratory tests are not indicated in
the vast majority of cases.

PATHOLOGY
Key points
The histopathologic picture varies depending on disease durationd A peribulbar lymphocytic infiltrate ‘‘swarmof bees’’ characterizes the acute phase of AA
d In subacute cases, large numbers of catagen
and telogen hairs will be presentd Hair follicle miniaturization with minimal or
no inflammation is seen in chronic casesdThere is abnormal hair cycling in AA. Anagen
follicles may enter telogen prematurely, or some may
survive for some time in a dystrophic anagen state.33

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Fig 8. White hair regrowth after one session of intralesional triamcinolone acetonide.

Fig 10. Abnormal hair shaft formation (trichomalacia): asign of active alopecia areata. (Hematoxylineeosin stain;
original magnification: 320.)

Fig 9. Classic peribulbar ‘‘swarm of bees’’ inflammation inalopecia areata. Some eosinophils are present within theinfiltrate. (Hematoxylineeosin stain; original magnification: 320.)

Fig 11. Catagen transformation in subacute alopecia areata.
(Hematoxylineeosin stain; original magnification: 320.)

Consequently, the histopathologic appearance of AA
varies depending on disease duration.34 However,increased numbers of eosinophils can be present inregions of AA affected skin in any stage of AA and area useful diagnostic feature.35,36
In the acute stage, a peribulbar lymphocytic infiltrate ‘‘swarm of bees’’ preferentially targets anagen
stage follicles (Fig 9).34 The infiltrate is composed ofboth CD41 and CD81 cells with the CD41/CD81 ratio
being higher in clinically active disease.37 As a consequence, edema, microvesiculation, apoptosis, necrosis, macrophages, and foreign body giant cells canbe seen in and around the affected hair follicles.38
The root sheaths and hair matrix are infiltrated bylymphocytes and there may be hair follicle pigmentincontinence, keratinocyte cell necrosis, and vacuolar damage.5,39 Focal matrix cell vacuolization andnecrosis, a relatively uncommon event, is claimed to
be a characteristic feature of AA.40 Ultrastructural
studies showed that keratinocytic degeneration may
affect layers of matrix cells in AA, unlike the apoptosisof scattered outer root sheath cells in normal catagen.41 Anagen arrest, shortly followed by catagen,weakens the hair shaft and causes breakage at thesurface of the skin. As the follicle goes into telogen,the fractured widened tip will further extrude, resulting in the typical exclamation point hair.38
Trichomalacia (Fig 10) with marked narrowing of
the hair shafts (‘‘pencil point hair’’) results in fragile
hairs that fall from the scalp in great numbers.40
In the subacute stage, large numbers of catagen
hairs, followed by telogen hairs, can be observed.38
The percentage of catagen/telogen is markedly
increased (Fig 11) and often exceeds 50% of the totalfollicles.40 Some remnant inflammation may persist
in or around fibrous streamers as the follicles ascend
to telogen level.38
In the chronic stage, there is marked hair follicle
miniaturization (Fig 12). The terminal to vellus scalp
hair follicle ratio is reduced and is likely to be 1:1.38
These miniaturized anagen follicles are situatedslightly deeper than normal vellus follicles.40
Chronic lesions are characterized by the presenceof nanogen follicles (an intermediate stage between
terminal and vellus anagen; Fig 13).5 Nonsclerotic
fibrous tracts (streamers) extend along the originalsite of the previous terminal follicles into the subcutis.34 The inflammatory infiltrate, if present, islikely to be in the papillary dermis around miniaturized follicles.38

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Fig 12. Marked miniaturization: a feature of long-standing
alopecia areata. (Hematoxylineeosin stain; original magnification: 34.)

In the recovery stage, the terminal to vellus ratio
reverts to normal, the percentage of anagen hairs
increases, and there is little or no inflammation.38
The total number of follicles are normal or decreasedin AA compared to normal scalp.40,42

ALOPECIA AREATA PATHOGENESIS
Key points
AA is a lymphocyte cellemediated inflammatory form of hair loss with research evidence
suggesting an underlying autoimmune
etiopathogenesis
d The development of hair loss involves aberrant modulation of the hair growth cycle,
resulting in dystrophic anagen hair follicles
and/or increased frequency of telogen statefollicles
d Genetic susceptibility to the development of
AA involves specific alleles of the HLA region
though other non-HLA genes are also likely
to be involvedd Susceptibility to the development of AA may
be modified by environmental factors, including exposure to proinflammatory agentsand possibly other modulators, including
stress and dietdHair follicle growth cycling modulation inalopecia areata
There are three key phases of the hair cycle: thegrowth phase (anagen), the regression phase (catagen), and the resting phase (telogen).43 The cyclingof these phases is finely coordinated by the expression of hormones, cytokines, transcription factors,
and their corresponding receptors and is carefully
regulated through endocrine, paracrine, and autocrine routes. The disruption of these finely tuned
pathways can result in the development of hairdiseases. Exogen is a hair follicle cycle event that
describes the controlled shedding of club hair fibers.

Fig 13. Nanogen follicle (intermediate stage, between
terminal and vellus anagen) is very typical of alopecia
areata. (Hematoxylineeosin stain; original magnification:
360.)

In healthy individuals, shedding normally occurs
during the subsequent anagen growth phase as a
new hair fiber is produced. In the development ofalopecias, exogen occurs in advance of renewedanagen growth, leaving a hair follicle devoid ofvisible hair fiber—a state called kenogen.44
In AA, significant disruption of the hair growth
cycle clearly occurs, but different perturbations inhair growth occur depending on the pattern, severity,and duration of AA in each patient. There are several
possible presentations of AA. First, the anagen phaseof a hair follicle can become inflamed and maintainedin a dystrophic anagen state, unable to produce hairfiber of significant size or integrity.45 When there is agreater intensity of inflammation, the hair follicles
may be forced into a telogen phase and may thencycle through multiple anagenetelogen phases ofbrief duration. Correspondingly, inflammatory cell
infiltration occurs in early anagen follicles without
migration to draining lymph nodes as follicles capitulate and return to telogen.43,45 Finally, when AA ischronic, the hair follicles tend to persist in a prolonged telogen phase without an apparent attempt toreturn to an anagen growth phase (Fig 14).38,43,45
Autoimmune activity in alopecia areata
The pathogenesis of AA and the molecular mechanisms that lead to hair loss are poorly understood.
In the past, AA was believed to be of infectious orneurotrophic origin.46 Recent research studies haveindicated that AA is an inflammation-driven disease
and is likely an autoimmune disorder.47-49
Circumstantial evidence in support of an autoimmune mechanism underlying AA comes from several
sources. The association of AA with other autoimmune diseases has been reported.25 The presence of
inflammatory lymphocytes around and within affected hair follicles and the ability to promote hairregrowth with the use of immunosuppressive agents

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Fig 14. Hair growth cycle patterns in alopecia areata. A, Hair follicles held in dystrophic
anagen by mild inflammatory insult unable to produce significant hair fiber. B, Anagen growthphases truncated by moderate inflammatory insult resulting in rapid cycling and brief hair fiber
growth. C, Hair follicles enter prolonged telogen dormancy with development of chronic
alopecia areata.

is consistent with an autoimmune hypothesis.50 The
infiltration of antigen presenting cells (APCs) such as
macrophages and Langerhans cells both around andwithin the dystrophic hair follicles has also been
observed.47 This is potentially consistent with a
response to autoantigens within the hair follicles
and attraction of these APCs.

A major proinflammatory event in AA is suggested
to be the abnormal expression of class I and II major
histocompatibility complex antigens in hair follicle
epithelia.50 There is also an increase in proinflammatory markers such as intercellular cell adhesion
molecule and endothelial cell selectin in the bloodvessels around the hair follicles. The presence of hair184 Alkhalifah et al

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follicleespecific IgG autoantibodies in the peripheral blood of AA patients also further reinforces the
hypothesis that the development of AA could be
autoimmune related.47
Animal models of alopecia areata
Two inbred rodent models have been developedfor use in AA research: the Dundee experimental
bald rat (DEBR) and the C3H/HeJ mouse.45,51,52
These two models have shown AA to be an autosomal polygenic trait with incomplete penetrance. By
studying the breeding patterns of C3H/HeJ mice, it
was found that the segregation pattern of the AA
phenotype is under the control of one or more
dominant gene alleles.45 In C3H/HeJ mice, AA
develops after 4 months in females and 10 months
in males and affects up to 20% of a colony.47,53 DEBR
females develop AA after 5 to 8 months; DEBR males
develop AA in 7 to 10 months. More than 40% of a
DEBR colony will be affected, and the condition ismore likely to affect females than males with a 3:1
ratio.52 Both rodent models express an AA phenotype as multifocal sites of hair loss, often withsymmetrical distribution.51,52 Histologically, theskin of mice and rats shows an infiltration of CD41
and CD81 T cells, macrophages, and dendritic cells
in and around the hair follicles.54
Functional studies in animal models further support the notion of AA as an autoimmune disease andprovide information on the mechanisms of AA
development. AA can be transferred from spontaneously affected mice to healthy mice with an almost
100% success rate by using a skin grafting technique.55 This allows the study of AA with predictable
onset and progression. The grafting of affected skinpromotes an induction of anagen stage hair follicle
inflammation in a skin graft recipient. This infiltration
is progressive over time and begins several weeks inadvance of hair loss onset.56 Infiltration of the hairfollicles and inhibition of AA onset can be blocked bytargeting activated lymphocyte markers or by blocking costimulatory receptors.57,58
When AA affected mouse skin is grafted to severe
combined immunodeficient (SCID) mice, in theabsence of CD41 and CD81 T cells, hair regrowthis observed in grafted skin and no loss of hair isobserved in the host skin.55 This is a strong indicationthat CD41 and CD81 T cells are directly involved in
the hair loss promotion mechanism. Further, partial
restoration of hair growth is observed by depleting
CD41 or CD81 T cell subsets by using monoclonal
antibodies in AA affected DEBR and C3H/HeJ
mice.47,59,60 Most significantly, subcutaneous injection into normal haired mice of lymphocyte cellsubsets isolated from AA affected mice shows thatthese cells induce the disease. CD81 cells quickly
induced localized patches of hair loss. CD41 cells did
not induce local hair loss, but they were shown toactivate the host’s immune system to promote multiple AA patches after several weeks. It was concluded that CD81 cells are the direct modulators ofhair loss while CD41 cells play a classic ‘‘helper’’ rolein AA onset.61
A further SCIDehuman mouse model has beendeveloped. AA affected human skin regrows hairafter grafting to SCID mice. Using a cell transfer
method, hair loss can be reinduced by injecting
patient CD41 and CD81 T cells into the human skingraft.62 To successfully reinduce AA, the cells must
be previously activated in vitro using antigenic
peptides which may or may not reflect the naturalin vivo disease mechanism. All of these diseasemodels have significantly helped in understanding
the pathogenesis of AA, and they should proveinvaluable in the development of new treatments63
and understanding the mechanisms by which current treatments are effective.64,65
Role of genetics in alopecia areata
The genetics of an individual can play a role in thedevelopment of AA. That AA can be inherited isbased on observations on monozygotic twins; AA in
twins can have similar times of onset and patterns ofhair loss.66,67 Some patients with AA have a strong
family history that spans many generations, and thisalso suggests that AA can be inherited. Between 4%
and 28% of patients who have AA will have at least
one other affected family member.48
Gene association studies have indicated that human leukocyte antigen (HLA) genes play a role in AA
and multiple HLA class I (A, B, and C) alleles
conferring susceptibility have been identified indifferent cohorts of AA patients.47 MHC (HLA) class
I molecules are present on almost all nucleated cells
and they present antigens to CD81 T cells. There isan aberrant expression of HLA antigens found within
the follicles of AA affected patients.50 However, theevidence in support of an association of HLA class Iwith AA is inconsistent with different susceptibility
alleles identified in different cohorts, while somestudies were unable to confirm any significant
association.68
A much more consistent and stronger association
between HLA class II alleles and AA development
has been observed. HLA class II antigens are constitutively expressed on specific immune cells and may
be upgregulated on nonimmune cells in response to
injury. They are responsible for presenting antigenic
peptides to CD41 T cells. HLA class II antigens areaberrantly highly expressed on AA affected hair

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follicles. Specific alleles, such as DQB1*03 andDRB1*1104, have been reported as markers forsusceptibility to AA.69 These findings suggest theimportance of specific HLA class II alleles in theonset and progression of AA and imply that antigen
presentation to CD41 cells plays a significant role in
AA development. Several association studies haveinvestigated non-HLA gene alleles, indicating thatmultiple genes may contribute to AA susceptibility.46
Genome-wide screening for AA susceptibility locihas been challenging. Linkage analysis with the AA
mouse model revealed that AA is a complex polygenic trait.70 Four intervals (Alaa1, 2, 3, and 4) on
mouse chromosomes 17, 9, 8, and 15, respectively,
were identified as regions of the genome conferring
AA susceptibility.70 Mouse gene associations were
found comparable to those in humans. In particular,
the equivalent MHC region in mice (Alaa1) wasstrongly associated with AA susceptibility. Studies to
identify the specific susceptibility genes within theseregions are underway.
A genome-wide study was completed on extended human families with multiple AA patients.
Intervals on human chromosomes 6, 10, 16, and 18
were identified as potential AA susceptibility loci.71
This study further confirmed that the HLA region onhuman chromosome 6 is associated with genetic
susceptibility to AA. However, there was at least one
significant genetic determinant of AA found at
6q.23.3 outside of the HLA gene cluster. Large scale,genome-wide screens using the AA registry and DNA
bank72 are nearing completion and should provide
significant new information on the potential geneactivity in AA development beyond the HLA region.
Environmental impact on alopecia areata
Environmental factors may also contribute to AA
development. Specific gene alleles might provide an
innate degree of susceptibility to AA for an individual, but environmental factors likely cumulatively
determine the actual onset, hair loss pattern, andseverity of the disease.47,68 However, the exact environmental stimuli required for AA expression are yet
to be determined. Hormonal fluctuation,68 infectious
agents,73 and vaccinations74 have all been cited as
possible triggers for AA. In the mouse model, dietary
soy oil increases resistance to AA development,suggesting that diet might also play a role in AA
susceptibility.56 It is likely that there are manypotential environmental inputs with different factors
involved in AA development for different individuals.
Stress is commonly cited as a cause for AA onset,
but controlled clinical studies have been inconclusive.75-77 Some did not find a significant correlationof hair loss onset with stressful life events,78-80 whileothers confirm stressful events in AA patients before
the onset of disease.30,79,81 In contrast, several studies have shown that individuals with AA are more
likely to exhibit aberrant psychosocial traits, such asincreased anxiety, depression, and aggression.76,78,80,82 Investigations on the skin of miceand humans have indicated increased presence ofmultiple factors associated with stress mediation.83,84
In a mouse model study, the development of AA wasstrongly associated with higher central and peripheral hypothalamic-pituitary-adrenal (HPA) tone.85
The AA affected mice had a significantly blunted
systemic HPA response to acute physiologic stressand a decreased habituation response to constantpsychological stress. Taken together, AA may impact
stress responses and HPA activity may be significantly involved in modulating the severity or courseof AA.
Hypothesis for alopecia areata development
Although many hypotheses to explain autoimmune disease development have been suggested
by immunologists,86-89 most of these scenarios havenot been seriously considered in the context of AA.
Currently, AA development hypotheses focus on hairfollicle immune privilege collapse or the inappropriate presentation of antigens to the immune system
during normal hair follicle cycling. Anagen stage hairfollicles retain immune privilege, and a breach inimmune privilege and exposure of unique hairfollicle antigens may result in targeting by the skinimmune system.90-92 This popular hypothesis ishighly ‘‘skin-centric’’ and largely ignores current
immunologic dogma, although it is attractive in its
simplicity.
An alternative hypothesis is based on the knowledge that hair follicle immunoprotection is transient,
limited to the anagen growth cycle stage. Regressionof the hair follicle in catagen involves significant
apoptosis93 and immune cell infiltration.94-97 This
normal hair follicle cycling event may continuously
expose the immune system to low levels of hairfollicleederived antigens. Hair follicleespecific autoantibodies found in humans and animal models in
the absence of AA98-100 may be a consequence of thisconstant low level exposure.
Langerhans cells and dendritic cells are capable ofpresenting cell apoptosisederived antigens to lymphocytes and stimulating autoimmunity.101-103 If
catagen regression became disordered, the associated immune cell infiltrate might inappropriately
coexpress antigenic peptides and costimulatory molecules and induce an immunologic response.47,56
Mouse studies have revealed that significant proinflammatory events occur in the lymph nodes in186 Alkhalifah et al

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Fig 15. Alopecia areata pathogenesis. Inappropriate excitation of antigen presenting cells during disorderedcatagen and migration of cells to draining lymph nodes
may lead to hair follicle antigenespecific lymphocyte
activation, migration, and infiltration of anagen stage hairfollicles.

advance of lymphocyte infiltration into the skin andsubsequent hair loss onset.56,57,104 As such, the onsetof AA may be initially triggered during routine
catagen because of inappropriate skin immune system signaling (Fig 15).

SUMMARY
Classic AA presents as well defined, completely
bald patches without changes in the skin’s color or
surface. AA is usually a clinical diagnosis and a skinbiopsy is generally not required. However, rare patterns and variants can be challenging to diagnose.
There is insufficient evidence to support routine blood
testing in AA. While there are some prognostic factors,
the course of the disease is unpredictable. The histopathologic picture varies according to the stage of AA
and can be difficult to recognize. Despite continuingresearch, the exact pathogenesis of AA is still to beclarified. However, the best available evidence supports an autoimmune targeting of hair follicles.
The authors would like to thank Magdalena Martinka,MD, for providing the histopathologic images.
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