REVIEW
Hair Follicle Immune Privilege Revisited:
The Key to Alopecia Areata Management
Ralf Paus1, Silvia Bulfone-Paus1 and Marta Bertolini2
The collapse of the immune privilege (IP) of the ana-
gen hair bulb is now accepted as a key element in AA
pathogenesis, and hair bulb IP restoration lies at the
core of AA therapy. Here, we briefly review the es-
sentials of hair bulb IP and recent progress in under-
standing its complexity. We discuss open questions
and why the systematic dissection of hair bulb IP and
its pharmacological manipulation (including the clin-
ical testing of FK506 and a-melanocyte-stimulating
hormone analogs) promise to extend the range of
future therapeutic options in AA and other IP collapse-
related autoimmune diseases.
Journal of Investigative Dermatology Symposium Proceedings (2018) 19,
S12eS17; doi:10.1016/j.jisp.2017.10.014
HAIR FOLLICLE IMMUNE PRIVILEGE: INCEPTION AND
BASICS
Rupert Billingham recognized in the skin of guinea pigs that
transplanted heterologous epidermal melanocytes can
escape immune elimination when they migrate to the anagen
hair bulb epithelium of genetically incompatible host hair
follicles (HFs) (Billingham and Silvers, 1971). This striking
finding was largely ignored until Gill Westgate recalled
attention to the concept of HF immune privilege (IP)
(Westgate et al., 1991). This encouraged the proposal that
hair bulb IP collapse constitutes a crucial element in HF
pathobiology, namely in alopecia areata (AA) (Paus et al.,
1993) and triggered a series of studies to better define HF
immunology (e.g., Christoph et al., 2000; Hoffman et al.,
1996; Paus et al., 1994a, 1994b, 1994c, 1998, 2005; Wang
et al., 2014).
The central role of IP collapse in AA pathobiology has now
become widely accepted in the field (Gilhar et al., 1998;
Gilhar et al., 2012, 2016; Kang et al., 2010; McElwee
et al., 2013; Pratt et al., 2017; Wang et al., 2014), and
formal functional proof that anagen HFs do exhibit a relative
IP has been provided in mouse models (Alli et al., 2012; Gao
et al., 2017; Giangreco et al., 2012).
Since its first inception by Peter Medawar (1948) the term
IP has been extended to reflect a dynamic immunoinhibitory
1 catagen (Oh et al., 2016), and major HF dystrophy (Gilhar
Centre for Dermatology Research, University of Manchester, NIHR
Manchester Biomedical Research Centre and MAHSC, Manchester, UK;
and 2Department of Dermatology, University of Münster, Münster,
Germany
Correspondence: Ralf Paus, Centre for Dermatology Research, University of
Manchester, NIHR Manchester Biomedical Research Centre and MAHSC,
Stopford Building, Oxford Road, Manchester, M13 9PR, UK. E-mail: ralf.
paus@manchester.ac.uk
Abbreviations: AA, alopecia areata; HF, hair follicle; IP, immune privilege;
MHC, major histocompatibility complex; NK, natural killer
S12 Journal of Investigative Dermatology Symposium Proceedings (2018), Volume 19
state established by complex tissue-specific mechanisms that
suppress inflammation and promote immune tolerance
(Engelhardt et al., 2017). Although the few tissues that enjoy
IP differ in their IP state and characteristics, the most crucial
common mechanisms shared by them are (i) low or absent
expression of major histocompatibility complex (MHC) class
Ia/b2 microglobulin expression, thus rendering self-peptide
presentation ineffective or impossible, and (ii) the creation of
an immunoinhibitory milieu by the generation of secreted
immunosuppressants (Engelhardt et al., 2017; Joyce and
Fearon, 2015; Kinori et al., 2011; Nasr et al., 2005; Noso
et al., 2015; Paus et al., 2005; Taylor, 2016). Also, IP tissues
can induce a state of tolerance against antigens that manage to
escape immune sequestration (Taylor, 2016) and down-
regulate T-cell activation and proliferation (Eleftheriadis
et al., 2016; Ma et al., 2017; Tan and Bharath, 2009).
All of these mechanisms are established in the hair bulge IP
and hair bulb IP of murine and human HFs (Christoph et al.,
2000; Harrist et al., 1983; Meyer et al., 2008; Paus et al.,
2005), with the bulb IP being the one that is relevant to AA
pathogenesis. Although the functions of HF IP remain spec-
ulative, current evidence suggests that the main function of
the anagen hair bulb IP may be to sequester immunogenic,
melanogenesis-associated, and/or other HF antigens pro-
duced in the anagen hair bulb from immune recognition
(Paus et al., 1993, 2005). With increasing insights into the
immunological features of the HF over the past decade, the
understanding of HF IP has attained new layers of complexity
(Bertolini et al., 2016; Breitkopf et al., 2013; Ito and Tokura,
2014; Kang et al., 2010; Kinori et al., 2012; Paus et al., 2005;
Wang et al., 2014). These, and potential mechanisms for how
hair bulb IP is actively maintained, is threatened, collapses,
and may best be repaired during AA management are dis-
cussed below.
AA AS A STEREOTYPIC HAIR FOLLICLE RESPONSE
PATTERN
AA typically begins with focal hair loss in uninflamed skin,
which in some individuals progresses to universal hair loss.
Histologically, AA lesions show a dense inflammatory infil-
trate around the hair bulb of melanogenically active anagen
HFs (Miteva et al., 2012). This autoaggressive infiltrate causes
both premature termination of anagen, forcing the HF into
et al., 2012). Therefore, AA represents both an HF cycling
and a hair growth disorder.
The preference of AA for fully pigmented anagen VI HFs
has been used to explain the sparing of white HFs and has
invited the hypothesis that melanogenesis-associated auto-
antigens are the chief targets in AA (Paus et al., 1993). In AA,
these autoantigens are most likely to be presented by
MHC class Iaþ cells in the anagen hair bulb epithelium
ª 2017 The Authors. Published by Elsevier, Inc. on behalf of the
Society for Investigative Dermatology.

(Bertolini et al., 2014, 2016, 2017; Christoph et al., 2000; Ito
et al., 2004; Kinori et al., 2012).
It has long been recognized that AA reflects a wide spec-
trum of hair loss phenotypes (Gilhar et al., 2012; Ikeda, 1965;
Tosti et al., 2006). Moreover, AA clinical subtypes show some
shared gene associations, fitting the model of AA as a poly-
genic disease with different presentations arising from a
combination of genetic and environmental factors (Betz
et al., 2015; Fischer et al., 2016; Petukhova et al., 2010).
However, a phenocopy of AA lesions can be experimentally
induced in healthy human scalp skin xenotransplants onto
SCID mice under conditions where an antigen-specific
autoimmune attack on the anagen HF and a genetic predis-
position to AA are quite unlikely (Gilhar et al., 2013, 2016).
Therefore, we have argued that AA should be considered
as a stereotypic response pattern that any anagen HFs will
show, irrespective of the genetic predisposition and the pre-
existence of autoreactive CD8þ T cells, provided that HF IP
collapses and that excessive IFN-g signaling causes cytotoxic
HF damage (Paus, in: McElwee et al., 2013). According to
this concept, only a certain percentage of AA patients reflects
the presence of an (auto)antigen-specific and CD8/NKG2D-
dependent autoimmune disease, which is best termed auto-
immune AA (AAA). Instead, other AA patients—perhaps
those with the greatest likelihood of spontaneous remission—
may mainly exhibit the hair loss-triggering consequences of
nonspecific, IFN-geinduced HF IP collapse, dystrophy, and
premature catagen (Ito et al., 2005); therefore, AA patients
may require personalized medicine management strategies
(Paus, in: McElwee et al., 2013).
HF IP COLLAPSE AS THE CENTRAL PREREQUISITE OF THE
AA HAIR LOSS PHENOTYPE
Regardless of whether or not AA is only a stereotypic HF
response pattern, AA cannot develop without the following
(Gilhar et al., 2012):
 the occurrence of a perifollicular inflammation around the
anagen hair bulb;
 the induction of HF dystrophy, which leads to hair shaft
breakage or shedding and/or production of a dysfunctional
hair shaft; and, most important,
 hair bulb IP collapse.
The bulb IP exists only in anagen, because most of the
MHC class Ia/b2 microglobulin-negative HF keratinocytes
are deleted via apoptosis during catagen (Paus et al., 1994a,
2005). Therefore, once an inflammation-damaged anagen HF
(Ito et al., 2004, 2005; Peters et al., 2007; Zarbo et al., 2017)
has entered into catagen and has resided in telogen (Oh
et al., 2016), it has the chance to completely reconstruct its
bulb IP with entry into the next anagen phase—unless the
newly developing anagen HF is attacked again.
Circumstantial evidence suggests that spontaneous resto-
ration of HF IP is promoted by the intrafollicular production
of endogenous IP guardians by outer root sheath keratino-
cytes (Breitkopf et al., 2013; Ito et al., 2004; Paus et al., 2005)
and the release of immunoinhibitory neuropeptides from
perifollicular sensory nerve fibers (Bertolini et al., 2016;
Kinori et al., 2012). Therefore, the interindividual
R Paus et al.
Immune Privilege in Alopecia Areata
differences in susceptibility to AA, in course of the hair loss
phenotype, in response to AA therapy, and in likelihood of
spontaneous remission (Gilhar et al., 2012) may very well
reflect constitutive, genetically determined differences in
how easily the hair bulb IP collapses and how effectively HFs
manage to repair their IP.
HF IP RESTORATION AS THE CORNERSTONE OF
SUCCESSFUL AA MANAGEMENT
Thus, if one manages to protect and restore HF IP more
effectively, AA progression can be stopped, and spontaneous
hair regrowth is predicted to occur, because the HF damage
associated with AA remains fully reversible.
However, the current standard therapy for AA (Kassira
et al., 2017) may do little to restore HF IP. Although un-
equivocal placebo-controlled evidence that JAK/STAT in-
hibitors are effective in AA therapy is not yet available, one
main reason why these therapeutics promote hair regrowth in
many, though not all, AA patients (Alves de Medeiros et al.,
2016; Jabbari et al., 2015; Kennedy Crispin et al., 2016;
Liu et al., 2017; Mackay-Wiggan et al., 2016) may be
because they block IFN-gemediated signaling (Xing et al.,
2014) and thus the promotion of HF IP collapse, besides
affecting HF cycling (Harel et al., 2015).
The relapse of hair loss often seen after AA patients have
discontinued therapy with these promising new therapeutics
and the development of refractoriness to this therapy in some
patients over time (Kennedy Crispin et al., 2016; Mackay-
Wiggan et al., 2016) underscore the ultimate goal of any
successful AA therapy, that is, to help the HF restore its IP—
the most effective safeguarding mechanism against AA
relapse. Moreover, long-term therapy with potent JAK/STAT
inhibitors, which block T- and natural killer (NK)-cell func-
tions (Xing et al., 2014), must be expected to severely
compromise intracutaneous tumor immunosurveillance and
the defense against viral infection—concerns that are not
circumvented by topical drug application (Kostovic et al.,
2017). Therefore, caution is still advised regarding the long-
term administration of JAK/STAT inhibitors to AA patients.
From a drug safety and IP restoration efficiency perspec-
tive, well-documented “IP guardians” such as synthetic
a-MSH analogs (melanotan, alfamelanotide) need to be tested
clinically in AA. These not only potently down-regulate MHC
class Ia/b2 microglobulin expression in human anagen HFs
(Ito et al., 2004), but they may also stimulate production of
other HF IP guardians, besides exerting direct immunoinhibi-
tory effects themselves (Brzoska et al., 2008; Chang et al.,
2008). Although this strategy has long been advocated
(Gilhar et al., 2012; Ito et al., 2004) and despite the intro-
duction of a-MSH analogs into clinical dermatology, industry
has not yet advanced these agents for clinical testing in AA.
Although glucocorticoids suppress T-cell functions, MHC
class II expression, and many proinflammatory signaling
pathways, they are much less effective in down-regulating
MHC class Ia/b2 microglobulin expression (Truckenmiller
et al., 2005) and stimulating the production of HF IP guard-
ians, possibly explaining why glucocorticoids often disap-
point in AA management.
Instead, FK506 (tacrolimus), ideally in a topical prepara-
tion that facilitates penetration and drug accumulation
www.jidsponline.org S13
 R Paus et al.
Immune Privilege in Alopecia Areata
around affected anagen hair bulbs, is more attractive than
glucocorticoids. FK506 not only is a potent T- and NK-cell
immunosuppressant and promotes regulatory T cell activ-
ities (Arroyo Hornero et al., 2017; Shoughy, 2017), but it also
down-regulates MHC class Ia/b2 microglobulin expression in
human anagen hair bulbs, protects human HFs from IFN-
geinduced IP collapse, and can even restore the latter
ex vivo (Ito et al., 2004). Moreover, FK506 inhibits catagen
development and promotes anagen in mice (Maurer et al,
1997b; Paus et al., 1996). A recent case report further en-
courages pursuit of this avenue of clinical investigation
(Kanameishi et al., 2016).
RECENT DEVELOPMENTS AND MAJOR OPEN
QUESTIONS IN HF IP RESEARCH
The IP hair bulb epithelium must avoid constant attack by NK
cells, which recognize and eliminate MHC class Ia-negative
cells. Therefore, one key HF IP characteristic is that
NKG2D-activating ligands, such as MICA or ULBP3 (Elsner
et al., 2010), are expressed at low levels in healthy HFs,
while these are greatly up-regulated in lesional AA HFs (Ito
et al., 2008a; Ito et al., 2008b; Petukhova et al., 2010; Xing
et al., 2014). Recent evidence supports that overexpression
of both MICA and ULBP3 plays a role in AA pathobiology in
different patient cohorts (Li et al., 2016; Moftah et al., 2016)
and therefore greatly increases the risk of HF IP collapse (Ito
et al., 2008a; Ito et al., 2008b). Most recently, we have found
that stressed human scalp HFs that overexpress MICA also
attract, activate, and induce IFN-g release from dermal
Vd1þT cells, leading to AA-like HF dystrophy and premature
catagen induction ex vivo (Uchida et al., 2016).
Therefore, once the HF IP fails to avoid the stimulation of
NKG2Dþ immunocytes, massive influx of IFN-gesecreting
T cells may suffice to trigger the AA damage response
pattern—perhaps even in the absence of antigen-dependent
autoimmunity. Thus, it has become a central AA research
challenge to search for pharmacological strategies to down-
regulate the HF expression of activating NKG2D ligands
and to inhibit excessive activities of perifollicular NKG2Dþ
cells (Ito et al., 2008a; Xing et al., 2014).
If the location of the AA inflammatory infiltrate is linked to
the presence of melanogenesis-associated (auto-)antigens in
the hair bulb (Paus et al., 1993), it is important to understand
whether interindividual differences in the robustness of the
bulb IP (e.g., different constitutive expression levels of MHC
class Ia/b2 microglobulin, “IP guardian,” MICA, and che-
mokine and chemokine receptors [Dai et al., 2016; Ito et al.,
2013b, 2013c; Nagao et al., 2012], and intrafollicular ac-
tivity of AIRE-regulated signaling [Kumar et al., 2011;
Wengraf et al., 2008]) determine one’s personal risk of
developing the AA response pattern once HF IP comes under
threat, for example, after skin or HF trauma, viral infection, or
psychoemotional stress.
Another important open question is whether and how the
HF mesenchyme is involved in HF IP, besides harboring
immunoinhibitory immunocytes like mast cells that may
contribute to the maintenance of HF IP (Bertolini et al.,
2014). Although the HF mesenchyme is clearly MHC class
Ia/b2 microglobulin-positive, allotransplants of human HF
mesenchyme are not rejected (Reynolds et al., 1999) and can
S14 Journal of Investigative Dermatology Symposium Proceedings (2018), Volume 19
even be transplanted into other tissues to create an immune
rejection-preventive milieu (Wang et al., 2015).
Several immunocyte populations are now known to
actively participate in hair growth regulation, namely regu-
latory T cells (Ali et al., 2017; Bae et al., 2017; Castela et al.,
2014; Conteduca et al., 2014; Han et al., 2015; Petukhova
et al., 2010), gd T-cells (Kloepper et al., 2013), macro-
phages (Castellana et al., 2014), and mast cells (Bertolini
et al., 2014; Maurer et al., 1997a; Paus et al., 1994c;
Zhang et al., 2015). One important open question is
whether and how these immunocytes also affect HF IP. For
example, perifollicular mast cells may help to maintain
physiological HF IP (Bertolini et al., 2014) but may switch to
a proinflammatory phenotype in AA that could both activate
pathogenic CD8þ T cells and present autoantigens to them
(Stelekati et al., 2009), thus contributing to triggering HF IP
collapse in AA. Indeed, antihistamines can reduce T-cell
chemotaxis in AA patients (Ito et al., 2013a). Furthermore,
the role of resident, perifollicular memory T cells (Nasr et al.,
2005) and innate lymphoid cells (Klose and Artis, 2016) in
HF IP maintenance and collapse remains an important, as yet
unexplored AA research frontier.
Another crucial, but to our knowledge entirely unexplored
research area, is how the microbiome of human HFs
(Scharschmidt et al., 2017) affects the HF IP. For example,
interindividual differences in the composition of the HF
microbiome may modulate the balance between chemokine
and IP guardian secretion by HF keratinocytes and therefore
play a significant role in determining the personal risk of
developing AA and response to therapy.
Finally, it has recently been hypothesized that HF IP may
have been established as a mechanism to promote the de
novo induction of peripheral tolerance to neo-antigens
occurring outside of the thymus that have thus escaped
central tolerance (Oelert et al., 2016). If confirmed, proper
functioning of the HF IP would be of fundamental importance
for the maintenance of self-tolerance.
IP-CENTERED FUTURE AA MANAGEMENT
Although therapy with JAK/STAT inhibitors has become a
booming field of translational AA research (Jabbari et al.,
2015; Kennedy Crispin et al., 2016; Mackay-Wiggan et al.,
2016), this must not detract from exploring other promising
agents for AA management, namely candidate HF IP pro-
tectants and restorers, which present an attractive cost-
benefit-risk ratio.
Besides synthetic a-MSH analogs and FK506, these include
Kv1.3 channel inhibitors (Gilhar et al., 2013), PDE4
inhibitors (Keren et al., 2015), substance P receptor antago-
nists (Lindström et al., 2007), and VIP receptor (Bertolini
et al., 2016) and CGRP receptor agonists (Kinori et al.,
2012). Mono- or combination therapy with these agents
may enhance the efficacy of HF IP restoration, thus sup-
porting hair regrowth, and/or may protect the HF IP from
collapse, thus blocking AA progression.
More systematic research is also needed to clarify whether
contact sensitizers (Lamb et al., 2016) restore HF IP, given
that hair regrowth after diphenylcyclopropenone therapy is
associated with increased expression of the HF IP guardian
IL-10 (Hoffmann et al., 1994; Ito et al., 2004) and an altered

number of peribulbar CD8þ T cells, possibly indicating a
change in CD8þ T-cell reactivity/function (Wasyłyszyn et al.,
2007). Could contact sensitizer therapy in AA be replaced
with some of the agents described earlier to achieve more
effective HF IP restoration and longer-lasting hair regrowth?
Finally, because low-dose IL-2 treatment has been report-
edly beneficial in a small cohort of recalcitrant AA patients,
along with an increase in the number of regulatory T cells in
AA lesions (Castela et al., 2014), it will be interesting to
investigate how this IL-2 therapy affects HF IP.
To establish a truly curative AA therapy, identification of
the autoantigens in AA (more precisely, in AAA [see above])
and of the T-cell receptor clonotypes of autoreactive CD8þ T-
cells is required, at least for the subgroup of patients for
whom the AA response pattern reflects an antigen-specific
autoimmune response. The ongoing attempts to identify
either (e.g., Bertolini et al., 2015, 2017; Gilhar et al., 2001;
Ito et al., 2014; Wang et al., 2016) are of the utmost impor-
tance. However, if the hypothesis is correct that AA is just a
stereotypic response pattern of anagen HFs to excessive
proinflammatory signals triggered by several distinct patho-
mechanisms, of which autoantigen- and CD8þ T-
celledependent autoimmunity is only one among others
(Paus, in: McElwee et al., 2013), one must conclude that
curative AA therapy based on tolerization against identified
AA autoantigens or elimination of autoreactive T cells is
attainable for only some patients: those in whom genuine
anti-HF autoimmunity underlies the AA hair loss phenotype
(AAA).
In contrast, all AA patients will benefit from therapy that
manages to rapidly and lastingly restore HF IP, ideally at
minimal risk of adverse effects. Therefore, investigators
interested in developing more effective AA therapy are
encouraged to turn their full attention to understanding the
mechanisms that jointly maintain HF IP, while patient advo-
cacy groups such as NAAF (www.naaf.org) should persuade
policy makers to invest more funding into HF IP research.
Beyond AA, other patients with IP collapse-related autoim-
mune diseases are likely to benefit from having these ques-
tions answered in this model disease.
CONFLICT OF INTEREST
The authors state no conflict of interest.
ACKNOWLEDGMENTS
Writing of this review was made possible by grants from NAAF (USA) to RP
and MB, from National Institute of Health Research Manchester Biomedical
Research Centre (Inflammatory Hair Diseases Programme) to RP and SBP, and
from Associazione Mediterranea Alopecia Areata (Italy) to MB.
Funding for the Summit and the publication of this article was provided by
the National Alopecia Areata Foundation. Funding for this Summit was also
made possible (in part) by a grant (1 R13AR071266) from the National
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). The
views expressed in written conference materials or publications and by
speakers and moderators do not necessarily reflect the official policies of the
Department of Health and Human Services; nor does mention of trade names,
commercial practices, or organizations imply endorsement by the U.S.
Government.
REFERENCES
Ali N, Zirak B, Rodriguez RS, Pauli ML, Truong HA, Lai K, et al. Regulatory
T cells in skin facilitate epithelial stem cell differentiation. Cell 2017;169:
1119e29.
R Paus et al.
Immune Privilege in Alopecia Areata
Alli R, Nguyen P, Boyd K, Sundberg JP, Geiger TL. A mouse model of clonal
CD8þ T lymphocyte-mediated alopecia areata progressing to alopecia
universalis. J Immunol 2012;188:477e86.
Alves de Medeiros AK, Speeckaert R, Desmet E, Van Gele M, De Schepper S,
Lambert J1. JAK3 as an emerging target for topical treatment of inflam-
matory skin diseases. PLoS One 2016;11:e0164080.
Arroyo Hornero R, Betts GJ, Sawitzki B, Vogt K, Harden PN, Wood KJ.
CD45RA distinguishes CD4þCD25þCD127-/low TSDR demethylated
regulatory T cell subpopulations with differential stability and susceptibility
to tacrolimus-mediated inhibition of suppression. Transplantation
2017;101:302e9.
Bae JH, Hwang WS, Jang YJ, Lee YH, Jang DE, Kim JS, et al. CD80CD86
deficiency disrupts regulatory CD4þFoxP3þT cell homeostasis and
induces autoimmune-like alopecia [e-pub ahead of print]. Exp Dermatol
2017;26:1053e9.
Bertolini M, Pretzlaff M, Sulk M, Bähr M, Gherardini J, Uchida Y, et al.
Vasoactive intestinal peptide, whose receptor-mediated signalling may be
defective in alopecia areata, provides protection from hair follicle immune
privilege collapse. Br J Dermatol 2016;175:531e41.
Bertolini M, Rossi A, Paus R. Cover Image: Are melanocyte-associated pep-
tides the elusive autoantigens in alopecia areata? Br J Dermatol 2017;176:
1106.
Bertolini M, Uchida Y, Paus R. Toward the clonotype analysis of alopecia
areata-specific, intralesional human CD8þ T lymphocytes. J Investig Der-
matol Symp Proc 2015;17:9e12.
Bertolini M, Zilio F, Rossi A, Kleditzsch P, Emelianov VE, Gilhar A, et al.
Abnormal interactions between perifollicular mast cells and CD8þ T-cells
may contribute to the pathogenesis of alopecia areata. PLoS One 2014;9:
e94260.
Betz RC, Petukhova L, Ripke S, Huang H, Menelaou A, Redler S, et al.
Genome-wide meta-analysis in alopecia areata resolves HLA associations
and reveals two new susceptibility loci. Nat Commun 2015;6:5966.
Billingham RE, Silvers WK. A biologist’s reflections on dermatology. J Invest
Dermatol 1971;57:227e40.
Breitkopf T, Lo BK, Leung G, Wang E, Yu M, Carr N, et al. Somatostatin
expression in human hair follicles and its potential role in immune privi-
lege. J Invest Dermatol 2013;133:1722e30.
Brzoska T, Luger TA, Maaser C, Abels C, Böhm M. Alpha-melanocyte-
stimulating hormone and related tripeptides: biochemistry, antiin-
flammatory and protective effects in vitro and in vivo, and future
perspectives for the treatment of immune-mediated inflammatory diseases.
Endocr Rev 2008;29:581e602.
Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, et al.
Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells
in alopecia areata. JAMA Dermatol 2014;150:748e51.
Castellana D, Paus R, Perez-Moreno M. Macrophages contribute to the cyclic
activation of adult hair follicle stem cells. PLoS Biol 2014;12:e1002002.
Conteduca G, Rossi A, Megiorni F, Parodi A, Ferrera F, Tardito S, et al. Single
nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG
genes are associated with Alopecia areata. Clin Exp Med 2014;14:91e7.
Chang SH, Jung EJ, Lim DG, Park YH, Wee YM, Kim JH, et al. Anti-
inflammatory action of alpha-melanocyte stimulating hormone (alpha-
MSH) in anti-CD3/CD28-mediated spleen and CD4(þ)CD25(-) T cells and
a partial participation of IL-10. Immunol Lett 2008;118:44e8.
Christoph T, Müller-Röver S, Audring H, Tobin DJ, Hermes B, Cotsarelis G,
et al. The human hair follicle immune system: cellular composition and
immune privilege. Br J Dermatol 2000;142:862e73.
Dai Z, Xing L, Cerise J, Wang EH, Jabbari A, de Jong A, et al. CXCR3 blockade
inhibits T cell migration into the skin and prevents development of alopecia
areata. J Immunol 2016;197:1089e99.
Elsner L, Flügge PF, Lozano J, Muppala V, Eiz-Vesper B, Demiroglu SY, et al.
The endogenous danger signals HSP70 and MICA cooperate in the acti-
vation of cytotoxic effector functions of NK cells. J Cell Mol Med 2010;14:
992e1002.
Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Tsogka K, Sounidaki M,
et al. Differential effects of the two amino acid sensing systems, the GCN2
kinase and the mTOR complex 1, on primary human alloreactive CD4⁺
T-cells. Int J Mol Med 2016;37:1412e20.
Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune
privilege of the CNS. Nat Immunol 2017;18:123e31.
www.jidsponline.org S15
 R Paus et al.
Immune Privilege in Alopecia Areata
Fischer J, Degenhardt F, Hofmann A, Redler S, Basmanav FB, Heilmann-
Heimbach S, et al. Genome-wide analysis of copy number variants in
alopecia areata in a Central European cohort reveals association with
MCHR2. Exp Dermatol 2016;26:536e41.
Gao Z, Jin YQ, Wu W. SOCS3 treatment prevents the development of alo-
pecia areata by inhibiting CD8þ T cell-mediated autoimmune destruction.
Oncotarget 2017;8:33432e43.
Giangreco A, Hoste E, Takai Y, Rosewell I, Watt FM. Epidermal Cadm1
expression promotes autoimmune alopecia via enhanced T cell adhesion
and cytotoxicity. J Immunol 2012;188:1514e22.
Gilhar A, Etzioni A, Paus R. Alopecia areata. N Engl J Med 2012;366:
1515e25.
Gilhar A, Keren A, Shemer A, Ullmann Y, Paus R. Blocking potassium
channels (Kv1.3): a new treatment option for alopecia areata? J Invest
Dermatol 2013;133:2088e91.
Gilhar A, Landau M, Assy B, Ullmann Y, Shalaginov R, Serafimovich S, et al.
Melanocyte-associated T cell epitopes can function as autoantigens for
transfer of alopecia areata to human scalp explants on Prkdc(scid) mice.
J Invest Dermatol 2001;117:1357e62.
Gilhar A, Schrum AG, Etzioni A, Waldmann H, Paus R. Alopecia areata:
Animal models illuminate autoimmune pathogenesis and novel immuno-
therapeutic strategies. Autoimmun Rev 2016;15:726e35.
Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS. Autoimmune hair loss
(alopecia areata) transferred by T lymphocytes to human scalp explants on
SCID mice. J Clin Invest 1998;101:62e7.
Han YM, Sheng YY, Xu F, Qi SS, Liu XJ, Hu RM, et al. Imbalance of T-helper
17 and regulatory T cells in patients with alopecia areata. J Dermatol
2015;42:981e8.
Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, et al. Pharmacologic inhi-
bition of JAK-STAT signaling promotes hair growth. Sci Adv 2015;1:
e1500973.
Harrist TJ, Ruiter DJ, Mihm MC Jr, Bhan AK. Distribution of major
histocompatibility antigens in normal skin. Br J Dermatol 1983;109:
623e33.
Hoffman U, Tokura Y, Nishijima T, Takigawa M, Paus R. Hair cycle-dependent
changes in skin immune functions: anagen-associated depression of
sensitization for contact hypersensitivity in mice. J Invest Dermatol
1996;106:598e604.
Hoffmann R, Wenzel E, Huth A, van der Steen P, Schäufele M, Henninger HP,
et al. Cytokine mRNA levels in Alopecia areata before and after treatment
with the contact allergen diphenylcyclopropenone. J Invest Dermatol
1994;103:530e3.
Ikeda T. A new classification of alopecia areata. Dermatologica 1965;131:
421e45.
Ito T, Bertolini M, Funakoshi A, Ito N, Takayama T, Biro T, Paus R, et al. Birth,
life, and death of the MAGE3 hypothesis of alopecia areata pathobiology.
J Dermatol Sci 2013a;72:327e30.
Ito T, Fujiyama T, Hashizume H, Tokura Y. Antihistaminic drug olopatadine
downmodulates T cell chemotaxis toward CXCL10 by reducing CXCR3
expression, F-actin polymerization and calcium influx in patients with
alopecia areata. J Dermatol Sci 2013b;72:68e71.
Ito T, Hashizume H, Shimauchi T, Funakoshi A, Ito N, Fukamizu H, et al.
CXCL10 produced from hair follicles induces Th1 and Tc1 cell infiltration
in the acute phase of alopecia areata followed by sustained Tc1 accumu-
lation in the chronic phase. J Dermatol Sci 2013c;69:140e7.
Ito T, Ito N, Bettermann A, Tokura Y, Takigawa M, Paus R. Collapse and
restoration of MHC class-I-dependent immune privilege: exploiting the
human hair follicle as a model. Am J Pathol 2004;164:623e34.
Ito T, Ito N, Saathoff M, Bettermann A, Takigawa M, Paus R. Interferon-gamma
is a potent inducer of catagen-like changes in cultured human anagen hair
follicles. Br J Dermatol 2005;152:623e31.
Ito T, Ito N, Saatoff M, Hashizume H, Fukamizu H, Nickoloff BJ, et al.
Maintenance of hair follicle immune privilege is linked to prevention of NK
cell attack. J Invest Dermatol 2008a;128:1196e206.
Ito T, Meyer KC, Ito N, Paus R. Immune privilege and the skin. Curr Dir
Autoimmun 2008b;10:27e52.
Ito T, Tokura Y. The role of cytokines and chemokines in the T-cell-
mediated autoimmune process in alopecia areata. Exp Dermatol
2014;23:787e91.
S16 Journal of Investigative Dermatology Symposium Proceedings (2018), Volume 19
Jabbari A, Dai Z, Xing L, Cerise JE, Ramot Y, Berkun Y, et al. Reversal of
alopecia areata following treatment with the JAK1/2 inhibitor baricitinib.
EBioMedicine 2015;2:351e5.
Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor
microenvironment. Science 2015;348:74e80.
Kanameishi S, Dainichi T, Endo Y, Otsuka A, Tanioka M, Kabashima K.
Successful hair regrowth in an acute diffuse form of alopecia areata during
oral tacrolimus treatment in a patient with rheumatoid arthritis. J Eur Acad
Dermatol Venereol 2016;31:3137e8.
Kang H, Wu WY, Lo BK, Yu M, Leung G, Shapiro J, et al. Hair follicles from
alopecia areata patients exhibit alterations in immune privilege-associated
gene expression in advance of hair loss. J Invest Dermatol 2010;130:
2677e80.
Kassira S, Korta DZ, W Chapman L, Dann F. Review of treatment for alopecia
totalis and alopecia universalis. Int J Dermatol 2017;56:801e10.
Kennedy Crispin M, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, et al.
Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with
alopecia areata. JCI Insight 2016;1:e89776.
Keren A, Shemer A, Ullmann Y, Paus R, Gilhar A. The PDE4 inhibitor, apre-
milast, suppresses experimentally induced alopecia areata in human skin
in vivo. J Dermatol Sci 2015;77:74e6.
Kinori M, Bertolini M, Funk W, Samuelov L, Meyer KC, Emelianov VU, et al.
Calcitonin gene-related peptide (CGRP) may award relative protection
from interferon-g-induced collapse of human hair follicle immune privi-
lege. Exp Dermatol 2012;21:223e6.
Kinori M, Kloepper JE, Paus R. Can the hair follicle become a model for
studying selected aspects of human ocular immune privilege? Invest
Ophthalmol Vis Sci 2011;52:4447e58.
Kloepper JE, Kawai K, Bertolini M, Kanekura T, Paus R. Loss of gd T cells
results in hair cycling defects. J Invest Dermatol 2013;133:1666e9.
Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflam-
mation and tissuehomeostasis. Nat Immunol 2016;17:765e74.
Kostovic K, Gulin SJ, Mokos ZB, Ceovic R. Tofacitinib, an oral janus
kinase inhibitor: perspectives in dermatology. Curr Med Chem 2017;24:
1158e67.
Kumar V, Pedroza LA, Mace EM, Seeholzer S, Cotsarelis G, Condino-Neto A,
et al. The autoimmune regulator (AIRE), which is defective in autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy patients, is
expressed in human epidermal and follicular keratinocytes and associates
with the intermediate filament protein cytokeratin 17. Am J Pathol
2011;178:983e8.
Lamb RC, Young D, Holmes S. Retrospective review of diphencyprone in the
treatment of alopecia areata. Clin Exp Dermatol 2016;41:352e8.
Li J, van Vliet C, Rufaut NW, Jones LN, Sinclair RD, Carbone FR. Laser capture
microdissection reveals transcriptional abnormalities in alopecia areata
before, during, and after active hair loss. J Invest Dermatol 2016;136:
715e8.
Lindström E, von Mentzer B, Påhlman I, Ahlstedt I, Uvebrant A, Kristensson E,
et al. Neurokinin 1 receptor antagonists: correlation between in vitro re-
ceptor interaction and in vivo efficacy. J Pharmacol Exp Ther 2007;322:
1286e93.
Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe
alopecia areata and variants: a study of 90 patients. J Am Acad Dermatol
2017;76:22e8.
Ma EH, Bantug G, Griss T, Condotta S, Johnson RM, Samborska B, et al.
Serine is an essential metabolite for effector T cell expansion. Cell Metab
2017;25:345e57.
Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise JE, Clark C, Ulerio G, et al.
Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe
alopecia areata. JCI Insight 2016;1:e89790.
Maurer M, Fischer E, Handjiski B, von Stebut E, Algermissen B, Bavandi A,
et al. Activated skin mast cells are involved in murine hair follicle regres-
sion (catagen). Lab Invest 1997a;77:319e32.
Maurer M, Handjiski B, Paus R. Hair growth modulation by topical immu-
nophilin ligands: induction of anagen, inhibition of massive catagen
development, and relative protection from chemotherapy-induced alope-
cia. Am J Pathol 1997b;150:1433e41.
McElwee KJ, Gilhar A, Tobin DJ, Ramot Y, Sundberg JP, Nakamura M, et al.
What causes alopecia areata? Exp Dermatol 2013;22:609e26.

Meyer KC, Klatte JE, Dinh HV, Harries MJ, Reithmayer K, Meyer W, et al.
Evidence that the bulge region is a site of relative immune privilege in
human hair follicles. Br J Dermatol 2008;159:1077e85.
Medawar PB. Tests by tissue culture methods on the nature of immunity to
transplanted skin. Q J Microsc Sci 1948;89:239e52.
Miteva M, Misciali C, Fanti PA, Tosti A. Histopathologic features of alopecia
areata incognito: a review of 46 cases. J Cutan Pathol 2012;39:596e602.
Moftah NH, El-Barbary RA, Rashed L, Said M. ULBP3: a marker for alopecia
areata incognita. Arch Dermatol Res 2016;308:415e21.
Nagao K, Kobayashi T, Moro K, Ohyama M, Adachi T, Kitashima DY, et al.
Stress-induced production of chemokines by hair follicles regulates the
trafficking of dendritic cells in skin. Nat Immunol 2012;13:744e52.
Nasr IW, Wang Y, Gao G, Deng S, Diggs L, Rothstein DM, et al. Testicular
immune privilege promotes transplantation tolerance by altering the bal-
ance between memory and regulatory T cells. J Immunol 2005;174:
6161e8.
Noso S, Park C, Babaya N, Hiromine Y, Harada T, Ito H, et al. Organ speci-
ficity in autoimmune diseases: thyroid and islet autoimmunity in alopecia
areata. J Clin Endocrinol Metab 2015;100:1976e83.
Oelert T, Gilhar A, Paus R. T cell “induced-self” MHC class I/peptide com-
plexes may enable “de novo” tolerance induction to neo-antigens occur-
ring outside of the thymus. Exp Dermatol 2016;26:529e31.
Oh JW, Kloepper J, Langan EA, Kim Y, Yeo J, Kim MJ, et al. A guide to studying
human hair follicle cycling in vivo. J Invest Dermatol 2016;136:34e44.
Paus R, Böttge JA, Henz BM, Maurer M. Hair growth control by immuno-
suppression. Arch Dermatol Res 1996;288:408e10.
Paus R, Eichmüller S, Hofmann U, Czarnetzki BM, Robinson P. Expression of
classical and non-classical MHC class I antigens in murine hair follicles. Br
J Dermatol 1994a;131:177e83.
Paus R, Hofmann U, Eichmüller S, Czarnetzki BM. Distribution and changing
density of gamma-delta T cells in murine skin during the induced hair
cycle. Br J Dermatol 1994b;130:281e9.
Paus R, Maurer M, Slominski A, Czarnetzki BM. Mast cell involvement in
murine hair growth. Dev Biol 1994c;163:230e40.
Paus R, Nickoloff BJ, Ito T. A ‘hairy’ privilege. Trends Immunol 2005;26:
32e40.
Paus R, Slominski A, Czarnetzki BM. Is alopecia areata an autoimmune-
response against melanogenesis-related proteins, exposed by abnormal
MHC class I expression in the anagen hair bulb? Yale J Biol Med 1993;66:
541e54.
Paus R, van der Veen C, Eichmüller S, Kopp T, Hagen E, Müller-Röver S, et al.
Generation and cyclic remodeling of the hair follicle immune system in
mice. J Invest Dermatol 1998;111:7e18.
Peters EMJ, Liotiri S, Bodó E, Hagen E, Bı́ró T, Arck PC, Paus R. Probing the
effects of stress mediators on the human hair follicle: substance P holds
central position. Am J Pathol 2007;171:1872e86.
Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y, et al.
Genome-wide association study in alopecia areata implicates both innate
and adaptive immunity. Nature 2010;466:113e7.
Pratt CH, King LE Jr, Messenger AG, Christiano AM, Sundberg JP. Alopecia
areata. Nat Rev Dis Primers 2017;16(3):17011.
R Paus et al.
Immune Privilege in Alopecia Areata
Reynolds AJ, Lawrence C, Cserhalmi-Friedman PB, Christiano AM,
Jahoda CA. Trans-gender induction of hair follicles. Nature 1999;402:
33e4.
Scharschmidt TC, Vasquez KS, Pauli ML, Leitner EG, Chu K, Truong HA, et al.
Commensal microbes and hair follicle morphogenesis coordinately drive
Treg migration into neonatal skin. Cell Host Microbe 2017;21:467e477.
e5.
Shoughy SS. Topical tacrolimus in anterior segment inflammatory disorders.
Eye Vis 2017;4:7.
Stelekati E, Bahri R, D’Orlando O, Orinska Z, Mittrücker HW, Langenhaun R,
et al. Mast cell-mediated antigen presentation regulates CD8þ T cell
effector functions. Immunity 2009;31:665e76.
Tan PH, Bharath AK. Manipulation of indoleamine 2,3 dioxygenase; a novel
therapeutic target for treatment of diseases. Expert Opin Ther Targets
2009;13:987e1012.
Taylor AW. Ocular immune privilege and transplantation. Front Immunol
2016;7:37.
Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long term follow-up study
of 191 patients. J Am Acad Dermatol 2006;55:438e41.
Truckenmiller ME, Princiotta MF, Norbury CC, Bonneau RH. Corticosterone
impairs MHC class I antigen presentation by dendritic cells via reduction of
peptide generation. J Neuroimmunol 2005;160:48e60.
Uchida Y, Gherardini J, Alam M, Keren A, Arakawa A, Rossi A, et al.
Vd1þT-cells are stress-sentinels in human skin and are implicated in alo-
pecia areata pathogenesis. J Invest Dermatol 2016;136(9 Suppl. 2):S228.
Wang EH, Yu M, Breitkopf T, Akhoundsadegh N, Wang X, Shi FT, et al.
Identification of autoantigen epitopes in alopecia areata. J Invest Dermatol
2016;136:1617e26.
Wang X, Marr AK, Breitkopf T, Leung G, Hao J, Wang E, et al. Hair follicle
mesenchyme-associated PD-L1 regulates T-cell activation induced
apoptosis: a potential mechanism of immune privilege. J Invest Dermatol
2014;134:736e45.
Wang X, Hao J, Leung G, Breitkopf T, Wang E, Kwong N, et al. Hair follicle
dermal sheath derived cells improve islet allograft survival without sys-
temic immunosuppression. J Immunol Res 2015;2015:607328.
Wasyłyszyn T, Kozłowski W, Zabielski SL. Changes in distribution pattern of
CD8 lymphocytes in the scalp in alopecia areata during treatment with
diphencyprone. Arch Dermatol Res 2007;299:231e7.
Wengraf DA, McDonagh AJ, Lovewell TR, Vasilopoulos Y, Macdonald-
Hull SP, Cork MJ, et al. Genetic analysis of autoimmune regulator haplo-
types in alopecia areata. Tissue Antigens 2008;71:206e12.
Westgate GE, Craggs RI, Gibson WT. Immune privilege in hair growth. J Invest
Dermatol 1991;97:417e20.
Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata
is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat
Med 2014;20:1043e9.
Zhang X, Zhao Y, Ye Y, Li S, Qi S, Yang Y, et al. Lesional infiltration of mast
cells, Langerhans cells, T cells and local cytokine profiles in alopecia
areata. Arch Dermatol Res 2015;307:319e31.
Zarbo A, Belum VR, Sibaud V, Oudard S, Postow MA, Hsieh JJ, et al. Immune-
related alopecia (areata and universalis) in cancer patients receiving
immune checkpoint inhibitors. Br J Dermatol 2017;176:1649e52.
www.jidsponline.org S17