Am J Clin Dermatol (2018) 19:119–126

https://doi.org/10.1007/s40257-017-0312-y

SHORT COMMUNICATION

Evaluation of the Relationship between Alopecia Areata and Viral

Antigen Exposure
Christopher T. Richardson1 • Matthew S. Hayden2 • Elaine S. Gilmore3 •

Brian Poligone2,3

Published online: 11 August 2017

Ó Springer International Publishing AG 2017

Abstract presence of AA and these conditions was higher than in

Background Alopecia areata (AA) is an autoimmune dis-
ease characterized by non-scarring alopecia with T-cell
infiltration at the affected hair follicle.
Objective Our aim was to study the potential link between
hepatitis B virus (HBV) antigen exposure and AA.
Methods Two pediatric patients with AA following hep-
atitis B vaccination were identified in a general dermatol-
ogy clinic. A bioinformatics analysis and an electronic
medical record (EMR) database query were performed at
the University of Rochester Medical Center to identify
patients with AA, coexisting viral infections, vaccinations,
or interferon (IFN) therapy in order to determine if the
Elaine S. Gilmore and Brian Poligone contributed equally to this
work.
Electronic supplementary material The online version of this
article (doi:10.1007/s40257-017-0312-y) contains supplementary
material, which is available to authorized users.
AA patients without these associated conditions or therapy.
Results An increased frequency of AA among those who
received the HBV surface protein antigen [odds ratio (OR)
2.7, p \ 0.0001] was identified, and an independent anal-
ysis revealed an increased frequency of AA in those
receiving IFN-b treatment (OR 8.1, p \ 0.05). One
potential antigenic target identified was SLC45A2, a
melanosomal transport protein important in skin and hair
pigmentation. The longest potential vaccine peptide frag-
ment match (8-mer) was to a segment of natural killer (NK)
cell inhibitory receptors, KIR3DL2 and KIR3DL1. Pre-
dictive modeling of major histocompatibility complex
(MHC)-peptide binding demonstrated potential binding of
this peptide to MHC relevant to AA.
Limitations The results will need to be verified in addi-
tional patient databases allowing analysis of temporal
relationships, and with molecular experiments of the
identified antigens.
Conclusions Our data confirm associations between viral
infection and IFN treatment with AA. It establishes that the
hepatitis B surface protein antigen has shared epitopes with
human killer immunoglobulin-like receptors.

& Elaine S. Gilmore

egilmore@rocderm.com
& Brian Poligone
bpoligone@roclymphoma.com
1
Division of Allergy, Immunology and Rheumatology,
University of Rochester School of Medicine, 601 Elmwood
Avenue, Rochester, NY 14642, USA
2
Rochester General Hospital Research Institute, 1425 Portland
Avenue, Rochester, NY 14621, USA
3
Universal Dermatology, PLLC, 6800 Pittsford Palmyra Rd,
Suite 150, Fairport, NY 14450, USA
120 C. T. Richardson et al.

mechanisms, including molecular mimicry, superantigens,

Key Points and epitope spreading. Molecular mimicry has been
described for multiple autoimmune diseases [8].
A bioinformatics analysis was performed showing a Vaccination could trigger autoimmunity through the
correlation between alopecia areata and hepatitis B same mechanisms. The hepatitis B vaccine is the most
virus (HBV) vaccination, hepatitis A virus commonly reported vaccine trigger of AA. From 1978 to
vaccination, cytomegalovirus infection, and 1995, 60 cases of hair loss after routine immunizations
interferon (IFN) treatment. were reported to the US FDA, including 46 cases following
hepatitis B vaccination [29]. Sixteen of these cases were
Through analysis of peptide sequences from the
positive after rechallenge with the vaccine. However, it is
HBV vaccine and virus, potential antigens were
unknown whether antigenic hepatitis B virus (HBV) pep-
identified, which may activate T cells after HBV
tides are similar in structure to melanocyte or hair follicle-
infection.
related proteins.
Taken together, the results presented are suggestive We identified two cases in which HBV vaccination was
of a link between robust IFN-driven immune associated with the onset of AA. Based on these cases and
responses and the development of AA, and point to existing literature, we sought to determine whether HBV
specific viral antigens for future investigation. antigen exposure and AA were correlated in a larger pop-
ulation through an analysis of the University of Rochester
Medical Center electronic medical records (EMRs). We
identified a correlation between HBV vaccination and AA,
and therefore performed a bioinformatics analysis to
identify potential HBV antigens sharing epitope cutaneous
1 Introduction
proteins. We identified antigens with potential relevance to
AA that should be further studied in both animal models
Alopecia areata (AA) is a complex autoimmune disease in
and patients with HBV-associated onset of AA.
which hair-bulb inflammation and loss of hair follicle
immune privilege (HFIP) leads to non-scarring hair loss
1.1 Cases
[1, 2]. Pathogenesis may be driven by antigen-specific
T-cell responses against hair follicle-associated proteins
Patient 1 presented as a 3-year-old female with hair loss of
[3, 4], as evidenced by a mouse model using melanocyte
several weeks’ duration (Fig. 1a). Alopecia began 4 days
peptide-stimulated T cells [5] and reports of human
after receiving the third dose of the hepatitis B vaccine.
leukocyte antigen (HLA) associations with AA [6]. While
The patient also developed transient joint pain of the
genetics contribute to AA development [7], the initial
wrists, arms, and right knee without associated swelling.
triggering events are not well-defined. Potential triggers
She had a positive antinuclear antibody (ANA) (1:320
include emotional stress, metabolic or endocrine disorders,
speckled/homogenous pattern). Complete blood count
infections, drugs, and vaccines, several of which induce an
(CBC), erythrocyte sedimentation rate (ESR), C-reactive
interferon (IFN) response.
protein (CRP), and rheumatoid factor were normal, and she
A strong IFN gene expression signature has been found
had no significant medical history. Her family history
in AA lesions in both humans and mouse models [8–13].
included a mother with positive ANA and AA, and a sister
Case reports of alopecia following treatment with IFN-a or
with positive thyroid antibodies. Physical examination
IFN-b also implicate type I IFNs in initiating hair loss
revealed widespread and well-demarcated alopecic patches
[14–17]. In addition, type I IFN-related proteins have been
on the scalp without scarring, erythema, or scale. There
found to be upregulated in inflammatory scalp lesions of
were no nail changes. The patient was prescribed clobe-
patients with AA [18]. Furthermore, Janus kinase (JAK)
tasol 0.05% solution applied once daily to the affected
inhibitors, which inhibit IFN and common c cytokine sig-
areas o fthe scalp, alternating weekly with tacrolimus
naling, have recently been shown to be effective in both
0.03% ointment.
animal models and patients with AA [13, 19–22].
At 6 weeks her scalp examination was largely unchan-
The loss of HFIP may be due to a non-specific bystander
ged and therapy was continued. After 2 more months, an
effect of the IFN response to viral infection. Several reports
ophiasis pattern had developed, in addition to persistent
have suggested a link between viral infection and the
alopecia on the crown. Clobetasol and tacrolimus were
development of AA [15, 17, 23–26], although others dis-
discontinued, and tretinoin 0.1% cream was applied once
agree [27, 28]. Alternatively, viral infection might con-
daily, with which there was minimal response over
tribute to the onset of AA through several other potential
4 months. Five months later, at which time the patient had
Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure
Fig. 1 Cases of alopecia areata following hepatitis B vaccination.
a 3-year-old female who presented with concern for hair loss of
several weeks’ duration. b 21-month-old female who presented with
concern for hair loss of sudden onset, beginning at age 15 months
stopped all prescription medications and had started a
South American herbal remedy called Suelda con Suelda
(likely Phoradendron spp.), examination revealed diffuse
new hair growth on the scalp of a few inches in length, with
one patch of alopecia on the right scalp and some irregu-
larity of the hair line.
Patient 2 presented as a 21-month-old female with hair
loss of sudden onset beginning at age 15 months
(Fig. 1b). Hair loss began 2 weeks after receiving the
third dose of the hepatitis B vaccine. Approximately
1 month prior to presentation at our clinic, the patient was
evaluated by a dermatologist and was noted to have
approximately 80% hair loss of the scalp, with downy
brown hair on the temples and occiput. The body was
without hair, although the eyebrows and eyelashes were
intact. No nail changes were noted. Work-up, including
121
ANA, double-stranded DNA (dsDNA) antibody (Ab),
thyroid-stimulating hormone (TSH), antithyroglobulin Ab,
rheumatoid factor, veneral disease research laboratory test
(VDRL), and glucose, was normal. Her medical history
and family history were non-contributory. Examination
revealed diffuse alopecia of the scalp, with a few sparse
hairs on the occiput. No other changes from prior
examination were noted. Treatment was begun with
pimecrolimus 1% cream once daily. At 3 months
her examination was unchanged. The patient was
instructed to continue the pimecrolimus and to start tri-
amcinolone 0.1 % cream daily for 1 week each month.
2 Materials and Methods
2.1 Electronic Medical Record Database Search
The EMR at the University of Rochester Medical Center
was evaluated for patients with AA and coexisting medical
conditions. The search was performed according to uni-
versity policy and was exempt per the Research Subjects
Review Board (RSRB). The following portions of the EMR
were included: problem list, past medical history, and
encounter diagnosis. The following Current Procedural
Terminology (CPT) or International Classification of Dis-
ease, Ninth Revision (ICD-9) codes were used to search the
database: alopecia areata (704.1), hepatitis B vaccination
(90731, 90740, 90743, 90744, 90745, 90746, 90747),
hepatitis A vaccination (90632, 90633, 90634, 90730),
hepatitis B infection (070.2, 070.3), hepatitis C virus
infection (070.41, 070.44, 070.51, 070.54, 070.70, 070.71),
Epstein–Barr virus (EBV) infection (075), cytomegalovirus
(CMV) infection (078.5), IFN-a treatment (J9212, J9213,
J9214, J9215), IFN-b treatment (J1826, J1830), and IFN-c
treatment (J9216). Alopecia totalis (AT) and alopecia
universalis (AU) are coded as ‘alopecia other’ (704.09),
which was not used in this database search since it includes
many miscellaneous alopecia conditions. There were 656
cases of AA in the database, 1897 cases of HBV exposure,
and 243,294 HBV vaccinations. Of these, 243,249 were
vaccine only, 749 were virus only, and 1148 were indi-
viduals with both.
2.2 Basic Local Alignment Search Tool (BLAST)
Query
Queries were performed against the human non-redundant
protein sequences (NR) database using blastp (protein-
protein BLAST) using all 221 potential 6-mers from the
Merck Recombivax hepatitis B vaccine peptide (menits-
gflgpllvlqagfflltriltipqsldswwtslnflggspvclgqnsqsptsnhsptsc
ppicpgyrwmclrrfiiflfilllclifllvlldyqgmlpvcplipgstttstgpcktct
122 C. T. Richardson et al.

Fig. 2 Association of alopecia Prevalence of Alopecia Areata

areata with other medical
conditions. a Prevalence and A 350
b odds ratio of alopecia areata
associated with several 300 ***
vaccinations, infections, and
*

Prevalence (per 100,000)

treatments. *p \ 0.05,
**p \ 0.005, ***p \ 0.0005. 250
CMV cytomegalovirus, EBV
Epstein–Barr virus, HAV 200
hepatitis A virus, HBV hepatitis
B virus, HCV hepatitis C virus,
150
IFN interferon
***
***
100

50

0
Total HBV HAV HBV EBV CMV HCV IFN-B
Population Vaccine Vaccine Infection Infection Infection Infection Treatment
(1865415) (n=61576) (n=29042) (n=1897) (n=1914) (n=412) (n=5119) (n=687)

Association with Alopecia Areata

B 100

**

10
Odds Ratio

8.06
6.71
*** ***
2.73 3.01 2.91 2.89

HBV HAV HBV EBV CMV HCV IFN-B

Vaccine Vaccine Infection Infection Infection Infection Treatment
0.1 (n=61576) (n=29042) (n=1897) (n=1914) (n=412) (n=5119) (n=687)
Paent Populaon (n=1865415)

tpaqgnsmfpsccctkptdgnctcipipsswafakylwewasvrfswlsllvpf B*12, B*18, B*52, C*0401, C*0702, C*1502, Cw*0704

vqwfvglsptvwlsaiwmmwywgpslysivspfipllpiffclwvyi). [5, 30–37].

2.3 RANKPEP Analysis 2.4 Statistics

RANKPEP (imed.med.ucm.es/Tools/rankpep.html) was A two-sample t test between proportions was performed to

used to predict major histocompatibility complex (MHC)-
peptide binding of the 218 possible 9-mers from the hep-
atitis B vaccine peptide. The following HLA relevant to
AA in various patient populations were evaluated: DPw4,
DQ1,DQ7 (B1*0301), DR1, DR4 (B1*0401), DR5, DR11
(B1*1104), A*0101, A*0201, A*0301, B*2701, B*62,
Cw*0702. However, the following MHCs relevant to AA
could not be evaluated by RANKPEP: DQ3 (B1*03),
determine whether there was a significant difference
between the prevalence of those with AA in the general
population and the prevalence of those with various vac-
cinations, infections, and treatments. Odds ratios (ORs)
were calculated for the association of AA with various
vaccinations, infections, and treatments. 95% confidence
intervals were determined and the Pearson’s Chi-square
test with Yates’ correction was used to determine p values.
Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure 123

Table 1 Hepatitis B vaccine Human protein (gene) Peptide

peptide sequence homology to
human peptides
Killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) IFLFILLL
Killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) IFLFILLL
Membrane-associated transporter protein (SLC45A2) SLYSIV
BLAST query results revealed three 8-mers, eight 7-mers, and 169 6-mers from the vaccine peptide with
exact sequence homology to human peptides
A full listing of identifed proteins are presented in the Electronic Supplementary Material
BLAST Basic Local Alignment Search Tool

3 Results hepatitis A vaccination) and IFN-a, IFN-b, and IFN-c

3.1 Relationship of Alopecia Areata (AA)
with Hepatitis B Vaccination
The two case reports presented, along with similar reports
in the literature [8], suggest a potential relationship
between hepatitis B vaccination and AA. To examine this
potential relationship, the EMR database at the University
of Rochester Medical Center was queried to identify
patients who had received the hepatitis B vaccine and also
had AA. The odds of a patient receiving the hepatitis B
vaccine also having AA was significantly increased com-
pared with patients who had not received the vaccine (OR
2.73, p \ 0.0001). The OR is reported as opposed to rel-
ative risk as the temporal association between the occur-
rence of AA and hepatitis B vaccination was not
determined. An accurate analysis of this association with
AT or AU was not possible given that the ICD-9 code for
these two conditions is the same as for a wide variety of
differing forms of alopecia (704.09, ‘other alopecia’),
although a future analysis may be possible with ICD, Tenth
Revision (ICD-10).
3.2 Relationship of AA with Other Vaccinations,
Infections, and Interferon
One potential mechanism whereby vaccination might
trigger AA is through the induction of IFN. This mecha-
nism of induction of AA is non-specific, with any number
of vaccinations or infections potentially leading to hair
loss. Given that vaccination is known to lead to a type I
IFN response [38], a type I IFN signature was found in
scalp lesions of patients with AA [25], and alopecia is
associated with IFN-a and IFN-b treatments [14–17], one
potential mediating factor is type I IFN. In order to
examine this hypothesis, additional EMR database queries
were performed. Prevalence and associations of AA with
other DNA viruses (EBV, CMV), viral hepatitides and
vaccinations (hepatitis B infection, hepatitis C infection,
treatment were evaluated (Fig. 2a). Given that few patients
in the query received IFN-a (n = 72) or IFN-c (n = 4),
and none with AA, statistical analysis could not be per-
formed on these data. The prevalence of AA was signifi-
cantly higher in those vaccinated against HBV or hepatitis
A virus (HAV) (p \ 0.0001), as well as those with a his-
tory of CMV infection (p = 0.028) or treatment with IFN-
b (p = 0.0005). The prevalence of AA in those with a
history of HBV or EBV infections approached significance
(p = 0.11) but was limited by the small sample size. Of
note, no patients with a history of HCV infection had AA.
This could potentially be due to the fact that chronic HCV
infection does not induce type I IFNs [40]. The OR of
association of AA with the above conditions followed the
same general trend (Fig. 2b).
3.3 Hepatitis B Virus Vaccine Peptides with Human
Sequence Homology
A second potential mechanism whereby vaccination might
lead to AA is via molecular mimicry. In order to investi-
gate this possibility, all 221 potential 6-mers from the
hepatitis B peptide (226 amino acids) used in the vaccine
were queried against the human non-redundant protein
sequences (NR) database using BLASTP (protein-protein
BLAST). MHC I and II typically bind peptides 8–11 amino
acids in length. 6-mers were analyzed to allow for some
differences from human peptides. Although this does not
account for all of the potentially similar peptides, further
analysis was beyond the scope of the present study.
Using this method, no exact match larger than eight
peptides was found. Three 8-mers, eight 7-mers, and 169
6-mers from the vaccine peptide were found to have exact
sequence homology with human peptides (Table 1). One
potential antigenic target identified by the search is
melanosomal transport protein SLC45A2 (solute carrier
family 45 member 2), alternatively known as membrane-
associated transport protein (MATP) or antigen in mela-
noma 1 (AIM1). SLC45A2 has been found to be a key
regulator of melanogenesis [39], and is important in both
124 C. T. Richardson et al.

Table 2 RANKPEP analysis of hepatitis B vaccine peptide: MHC potential 9-mers from the vaccine based on potential
binding binding to specific MHC class I and class II. Given that
Peptide Rank RANKPEP predicts binding to MHC class II using 9-mers,
the two vaccine 9-mers containing the KIR peptide IFL-
Class I
FILLL, as well as all such 9-mers containing the shared
HLA-A*0301 IIFLFILLL 3 sequence from SLC45A2 (SLYSIV), were evaluated.
HLA-Cw*0702 IIFLFILLL 4 Similar analysis was performed for binding to MHC class I.
HLA-A*0201 IIFLFILLL 7 The rank results indicate that among all potential 9-mers
HLA-B*2701 IFLFILLLC 15 from the vaccine, the one matching the portion of the
HLA-A*0101 IIFLFILLL 77 human KIR receptor is the most likely portion of the
HLA-B*62 IFLFILLLC 183 vaccine to bind to HLA-DQ1. This 9-mer is also one of the
Class II most likely to bind to several other MHC class I and II
HLA-DQ1 IIFLFILLL 1 relevant to AA (Table 2). In addition, one of the 9-mers
HLA-DR11 (B1*1104) IIFLFILLL 3 containing the sequence match with SLC45A2 is the most
HLA-DPw4 IIFLFILLL 12 likely to bind to HLA-B*62. While not predicted to bind to
HLA-DR4 (B1*0401) IFLFILLLC 14 many other MHCs, it is also very likely to bind to HLA-
HLA-DR5 IFLFILLLC 27 A*0201. Results based on this modeling software do not
HLA-DR1 IFLFILLLC 57 guarantee binding or initiation of an immune response, but
HLA-DQ7 (B1*0301) IIFLFILLL 122 merely indicate that the possibility exists.
This online program ranked all 218 potential 9-mers from the vaccine
based on potential binding to a specific MHC. The rank results
indicate that of all potential peptides from the vaccine, the one 4 Conclusions
matching the portion of the human KIR receptor is one of the most
likely to bind to several different MHC class I and class II relevant to
alopecia areata The clinical cases and preliminary investigation presented
MHC major histocompatibility complex, KIR killer immunoglobulin-
here support the proposal that exposure to hepatitis B
like receptor antigens, through either infection or vaccination, are
associated with AA in a subset of patients. We have per-
formed a bioinformatics analysis that has identified multi-
ple epitopes that could link HBV infection or vaccination
skin and hair pigmentation [40]. It is the underlying defect to the onset of AA. The HBV components in the vaccine
in oculocutaneous albinism type 4 [41] and is a suscepti- share sequence homology to hair follicle protein SLC45A2,
bility gene in melanoma [42]. Melanocyte peptides have which might serve as the target of an antigen-specific
been postulated to be the antigenic targets in AA [5]. T-cell response due to molecular mimicry. In addition,
Killer immunoglobulin-like receptors (KIRs) represent a 9-mer peptides containing IFLFILLL from KIRs show
second potential antigenic target. Two of the three longest strong binding to MHC. Intriguingly, this peptide has
BLASTP matches were to the inhibitory KIR receptors previously been shown to be an antigenic component of the
KIR3DL2 and KIR3DL1. These receptors are found on HBV vaccine to which strong T-cell responses have been
both natural killer (NK) cells, a subset of cytotoxic CD8? identified [46]. This leads us to postulate that HBV infec-
T cells, and regulatory T cells (Tregs) [43–45]. One tion or vaccination has the potential to initiate an antigen-
hypothesized mechanism of AA pathogenesis is through a specific response targeting inhibitory receptors on NK cells
subset of cytotoxic CD8? T cells that express the NK cell and some T cells. Such a response, either by inhibiting
receptor NKG2D [14]. These T cells are necessary and KIR3DL1/2 function on NK or CD8 cells, or by increasing
sufficient for the induction of AA in the murine model of KIR signaling in Tregs, could theoretically predispose
the disease, and efficacy of recently published treatments towards development of autoimmune diseases such as AA.
for AA correlate with effects on this cellular compartment While our data provide evidence of a significantly
[14, 18]. Interestingly, it appears that most T cells that increased risk associated with HBV antigen exposure, the
express KIR3DL1 also express NKG2D [43]. results are correlative and are limited by the inability to
Not all peptides are able to bind to MHC with equal confirm a temporal association with the current database.
affinity, or at all. RANKPEP, an online tool that predicts Further prospective evaluation and controlled studies
peptide binding to MHC, was used to evaluate which would be necessary to conclude that exposure to specific
portions of the hepatitis B vaccine peptide are most likely HBV antigens leads to AA. Genetic associations between
to bind to MHC. Analysis focused on MHC described as specific HLA alleles and chronic HBV infection have been
relevant to AA [32–40]. This program ranked all 218 described [47–49]. A recent genome-wide meta-analysis of
Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure
AA suggested that HLA-DR is a key factor in AA devel-
opment [6]. Although this literature does not establish a
definitive link between HLA alleles, HBV, and AA, it does
appear that it would be worthwhile for future studies to
directly interrogate the potential correlation between
specific HLA alleles and the development of AA after
HBV antigen exposure. Therefore, it is not yet clear whe-
ther the association between AA and HBV vaccination or
infection is a result of specific antigens or whether this is a
general result of conditions producing a robust type I IFN
response in susceptible individuals. The finding that several
different infections, vaccinations, and the clinical use of
immunomodulatory treatments are all associated with both
robust type I IFN responses and increased AA incidence
points towards the latter. In contrast, our failure to identify
significant risk associated with other infectious events, the
lack of case reports of AA associated with other vaccines,
and the potential peptides identified in this study suggest
that there may be an antigen-specific aspect to the associ-
ation of AA with HBV.
Acknowledgements This study was supported by the Skin Cancer
Research and Education Fund from the Rochester General
Foundation.
Compliance with ethical standards
Conflicts of interest Christopher T. Richardson, Matthew S. Hayden,
Elaine S. Gilmore, and Brian Poligone report no conflicts of interest
relevant to this study.
The study was reviewed by the Institutional Review Board and
was found to be exempt.
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