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150 DISC

Veterinary Dermatology 2000, 11, 1724

Morphologic and immunologic characterization of a


canine isthmus mural folliculitis resembling
pseudopelade of humans
THELMA LEE GROSS,* THIERRY OLIVRY{ and DESMOND J. TOBIN{
California Dermatopathology Service and IDEXX Veterinary Services, West Sacramento, CA 95605, USA
{North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27606, USA
{University of Bradford, Bradford, West Yorkshire, DB7 1DP, UK
(Received 21 July 1998; accepted 30 September 1998)

Abstract The clinical, histopathologic and immunopathologic features of a novel form of isthmus mural
folliculitis in dogs, which resembles pseudopelade in humans, were characterized. Clinically, dogs exhibited
variably distributed foci of alopecia that persisted without treatment or did not respond to
immunosuppressive therapy. Histopathologically, mixed mononuclear cell inltrates, largely lymphocytes,
inltrated the follicular isthmus. Occasionally, inammation extended above and below the follicular isthmus
but did not involve the hair bulb or the epidermis. Severe follicular atrophy and variable atrophy of sebaceous
glands occurred in all dogs. Folliculotropic lymphocytes exhibited most commonly CD3 and CD8 (cytotoxic
T cells). Autoantibodies specic for the lower hair follicle were detected in the serum of aected patients.
Western immunoblotting demonstrated binding of these antibodies to multiple follicular keratinocyte
proteins, including hair keratins and trichohyalin. Lack of hair regrowth (in contrast to canine alopecia
areata), as well as location of inammation and extreme atrophy of adnexal units are similar to ndings seen
in human pseudopelade.

Ahed
Bhed
Ched
Keywords: alopecia, dog, mural folliculitis, pseudopelade.
Dhed
Ref marker
Fig marker
Table marker
Ref end
ndings of this novel form of mural folliculitis in
INTRODUCTION
Ref start
ve dogs.
Mural folliculitis is a histopathologic pattern of
inammation, aecting the follicular wall, that has
CASE SUMMARIES
been reported recently in dogs and cats.1,2 Several
histopathologic subtypes have been described, inFive dogs developed patchy alopecia that was
cluding interface, inltrative, pustular, and necrotizclinically noninamed, and usually accompanied by
ing.1 Inltrative mural folliculitis is characterized by
ne scale. Dog 1, a 2-year-old, castrated male
inammation of the outer root sheath which centres
German Shepherd dog, presented with multiple,
predominantly on the follicular isthmus. Inammasmall (24 cm) foci of alopecia, developing rst on
tion may extend above and below this level, but
the chin and base of the right ear, and subsequently
spares the follicular bulb.
spreading to the left ear. Skin scrapings and a
Pseudopelade of Brocq is an alopecic disorder of
dermatophyte culture were negative. The lesions
humans that is characterized, histologically, by severe
remained static and did not change over a period of
follicular atrophy and variable inammation. Clini8 months; no therapy was given. Dog 2, a 1-year-old,
cally, the alopecic skin is smooth and noninamed;
spayed female Maltese, developed diuse alopecia
the hair loss is permanent.3,4 Recently, a unique form
over 75% of the body, sparing the head and feet
of inltrative mural folliculitis, leading to severe
(Fig. 1). Skin scrapings and a dermatophyte culture
follicular atrophy, and resembling pseudopelade of
were negative. Based on initial biopsy results, an
humans, has been observed in dogs. A similar entity
autoimmune mechanism was suspected for the hair
also has been observed in a cat; cytotoxic T cells were
loss. However, alopecia persisted over the next 6
demonstrated targeting the follicular isthmus (H.
months despite immunosuppressive therapy with
Power, T. Olivry et al., unpublished observations).
corticosteroids and chlorambucil. Dog 3, a 1-yearThe purpose of this study was to characterize the
old, spayed female Border Collie, had an irregular
clinical, histomorphologic and immunopathologic
focus of alopecia on the shoulder accompanied by
hyperpigmentation and mild scaling. The lesion
measured 6 6 8 cm and slowly expanded over the
Correspondence: T. L. Gross.
Reprint requests to: T. Olivry.
next 15 months (Figs 2 and 3). Skin scrapings and a
# 2000 Blackwell Science Ltd

17

150 DISC
18

T. L. Gross, T. Olivry and D. J. Tobin

Figure 1. Diuse alopecia of dog 2, with


sparing of the head and feet.

patchy alopecia, which began on the head and


subsequently involved the entire haircoat; a few hairs
were spared on the head. Additional clinical data
were not available. Initially, erythema was observed,
but ultimately no evidence of inammation was
present. The alopecia persisted over the next year;
no therapy was administered.
MATERIALS AND METHODS
Biopsy specimens from aected cutaneous areas were
obtained and routinely xed and processed for
histopathology. Frozen sections of biopsy specimens
obtained from aected skin of dogs 1 and 2 were
stained via an immunohistochemical technique using
a limited panel of monoclonal antibodies specic for
canine leucocyte antigens (CD3, CD21, CD4, CD8,
CD1c).5 In dogs 14, an indirect immunouorescent
technique using normal canine, feline, and equine
haired skin was used to look for circulating IgG
antifollicular antibodies.5 Western immunoblotting
was performed using the sera from dogs 1, 2 and 3,
with plucked human scalp anagen hair follicle
extracts, and an anticanine IgG antiserum, as
previously described.6
Figure 2. Focal alopecia of the shoulder in dog 3.

dermatophyte culture were negative. There was no


response to anti-inammatory doses of systemic
corticosteroids. Dog 4, a 10-year-old, female spayed
Chihuahua, developed patchy alopecia, accompanied
by hyperpigmentation, which was rst observed on
the head and subsequently became generalized (Fig.
4). Skin scrapings and a dermatophyte culture were
negative. The alopecia persisted over the next 14
months. Therapy, other than antibiotics to control
concurrent pyoderma, was not given. Dog 5, an 11year-old, intact male Doberman Pinscher, developed
# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 1724

RESULTS
Histopathologically, lesional skin biopsy specimens
obtained from all dogs demonstrated similar features.
There was variably intense, often tightly focused
inammation of the follicular isthmus (Fig. 5).
Inammation also extended to the perifollicular
dermis at that level. The folliculotropic inammation
was not uniform and had a tendency to skip some
follicular units (Fig. 6). In most cases, lymphocytes
predominated and fewer histiocytes/dendritic cells
were observed. Apoptosis of follicular epithelial cells
was not observed. Plasma cells were seen in three of

150 DISC
Pseudopelade in dogs

19

Figure 3. A closer view of the alopecic


focus of dog 3. The more chronic portion
of the lesion is hyperpigmented; note the
ne scaling.

Figure 4. Patchy, generalized alopecia of


dog 4.

Figure 5. Inammation is directed to the


follicular isthmus; dog 1 (H&E; original
magnication 625).

# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 1724

150 DISC
20

T. L. Gross, T. Olivry and D. J. Tobin

Figure
6.
The
folliculotropic
inammation is aecting one follicle
within the unit; the adjacent follicles are
spared;
dog
3
(H&E;
original
magnication 625).

ve dogs (dogs 1, 3, and 5). Inammation extended to


the infundibulum and below the isthmus in three dogs
(dogs 2, 3, and 5), but spared the hair bulb and
peribulbar dermis. The epidermis was mildly inamed
in dog 3; this dog had the most severe inammation
overall. Hair follicles were often severely atrophic
(Figs 7 and 8); atrophy was often inversely proportional to the degree of inammation observed.
Sebaceous glands were often absent. However, they
were frequently spared, although often smaller than
normal, even in areas where severe follicular atrophy
prevailed (Fig. 9). There was slightly increased
supercial or infundibular keratin in three dogs (dogs
2, 4, and 5). Neither demodectic mites nor dermatophytes were found.
Immunohistochemical studies in dogs 1 and 2
characterized the lymphocytes inltrating the midfollicle as T cells which were more often CD8+ than
CD4+, indicating a preponderance of cytotoxic cells
(Fig. 10). Perifollicular mononuclear cells consisted
of a mixture of CD4+ and CD8+ T lymphocytes, as
well as CD1c+ dendritic antigen-presenting cells.
Sera from dogs 14 exhibited variable titres of IgG
autoantibodies specic for the lower hair follicle. In
all cases, the matrix, precortex and inner root sheath
seemed targeted by autoantibodies (Fig. 11). Hair
cortex and medulla were variably recognized. Western immunoblotting, performed with the sera of
dogs 13, conrmed the presence of an heterogeneous
antibody response directed against follicular keratinocytes (Fig. 12). This technique demonstrated that
circulating IgG autoantibodies recognized multiple
proteins including hair keratins (3550 kDa) and
trichohyalin (200220 kDa) (Table 1).
DISCUSSION
The ve dogs in this study demonstrate a clinically
and histopathologically novel form of isthmus mural
folliculitis. Isthmus mural folliculitis has been ob# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 1724

Figure 7. Severe follicular atrophy; dog 2 (H&E; original


magnication 625).

served in conjunction with demodicosis and dermatophytosis in dogs.1,7 These agents were not demonstrated in the ve dogs of this study. Isthmus mural
folliculitis may be a feature of sebaceous adenitis;1
although sebaceous glands were frequently absent in
areas of severe follicular atrophy in the dogs of this
report, they often were spared, even in foci of severe
follicular attenuation.
Distinctive clinical features included patchy and
grossly noninamed alopecia which persisted over a

150 DISC
Pseudopelade in dogs

Figure 8. A higher-power magnication of Fig. 7, demonstrating


severe follicular attenuation and residual mural inammation
(H&E; original magnication 650).

21

Figure 9. Small sebaceous glands are persisting in the face of


isthmus mural inammation; dog 3 (H&E; original magnication
650).

Figure
10.
Immunostaining
using
anticanine CD8 monoclonal antibody;
intrafollicular lymphocytes are cytotoxic
T cells (CD8+); dog 1 (original
magnication 680).

period of many months. The alopecia failed to


respond to immunosuppressive therapy and was
apparently permanent. Histopathologically, predominantly lymphocytic inammation was tightly orientated to the middle portion of the hair follicle. The
hair bulb was spared. In contrast, the inammation of
canine alopecia areata, although it may extend to the
middle portion of some follicles, predominantly

aects the hair bulb.5 Clinically, in the authors'


experience (T.L.G. and T.O.), alopecia areata often is
reversible. Spontaneous regrowth of hair over a
period of 26 months has been observed; thus, the
apparent `response' of alopecia areata to immunomodulating therapy in other cases may be questionable.
Clinically persistent alopecia characterized histologically by severe follicular atrophy is similar to
# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 1724

150 DISC
22

T. L. Gross, T. Olivry and D. J. Tobin

Figure 11. The hair follicle in normal


canine skin substrate is targeted by the
uorescene-labelled
(green-staining),
circulating IgG antibodies from the
serum of dog 3; (anti-IgG-FITC with
propidium iodine counterstain; original
magnication 6200).

Table 1. Follicular antigens recognized by autoantibodies


(Western immunoblotting). Circulating autoantibodies target a
wide array of follicular antigens

Figure 12. Immunoblotting using canine pseudopelade sera and


human anagen hair follicle extract. IgG antibodies bind to multiple
hair follicle proteins, including, most likely, hair keratins (4552
kDa), trichohyalin (200210 kDa), and other noncharacterized
antigens (75150 kDa); A = dog 2; B = dog 3; C = dog 1;
D = control serum.

pseudopelade of humans.3,4 Originally named `pseudopelade of Brocq' after the author of its original
description in 1885, pseudopelade has been classied
as a `scarring' alopecia because hair loss is permanent.8
As scarring implies localized, nonspecic destruction
by a pre-existent disease or process, atrophy rather
than true scarring better characterizes the prominent
histopathologic feature of pseudopelade.3,9 Scarring
was not observed in the dogs of our study. Although
most reports of human pseudopelade describe mild to
absent inammation,3,4,9 early lesions demonstrate
dense accumulations of lymphocytes in and around
the upper hair follicle.8,10 Lymphocyte-associated
apoptosis has been described in human pseudopelade,10 but was not observed in the dogs of this study.
Histological dierences between the isthmus mural
folliculitis of the dogs of this report and pseudopelade
of humans include more transient inammation that is
less inltrative to the follicular wall in humans.
# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 1724

Antigens
(approx. kDa)

Dog 1

Dog 2

Dog 3

200220
150
125
110
90
80
50
46
44
38
35

+
+
+
+
+
++
+++
+
++
++
+

+
+
++
++
+
+
+

++
+++
+++
+
++
++

+
+
+
+

, no reactivity; +, faint reactivity; ++, moderate reactivity;


+++ strong reactivity.

The permanent follicular atrophy that occurs in


both humans and dogs may relate to the putative
location of the germinative region within the isthmus
region of the hair follicle. Identied as the `bulge'
region in mice and humans, follicular stem cells reside
in the upper follicle.11,12 Although a localized bulge
region has not been shown, to date, in the dog,
regenerative cells do occur above the level of the hair
bulb, within the isthmus and infundibulum.13 Failure
to regrow hair when the isthmus portion of the hair
follicle is the primary target, as in pseudopelade of
humans and the dogs of this report, is remarkable,
particularly when contrasted with the usual recovery
of hair growth that characterizes hair bulb-targeted
alopecia areata.
Cytotoxic T cells and antifollicular antibodies were
identied in two and four dogs, respectively, of this
study. Similar immunological ndings characterize
canine alopecia areata.5,6 Results of this study, as well
as previous studies of canine alopecia areata, indicate
that cytotoxic T-cell attack is accompanied by
production of similar autoantibodies in both dis-

150 DISC
Pseudopelade in dogs
eases.5,6 The autoantibody response appears to be
more heterogeneous in canine pseudopelade (Table 1)
than in alopecia areata in which antibody production
to trichokeratins predominates.6 The presence of
follicular autoantibodies may represent a nonspecic
epiphenomenon that results from exposure of follicular antigens due to folliculocentric inammation of
any cause. Immunologic studies in dogs with other
forms of folliculitis are required to determine the
specicity of follicular autoantibody formation.
Although autoantibodies to follicular antigens
occur in both pseudopelade and alopecia areata in
dogs, the level of lymphocyte homing to the hair
follicle is dierent. Thus, antigen-specic cytotoxic Tcell damage may be the initiating event. A central role
for cytotoxic T cells also has been demonstrated in
human alopecia areata.14,15 Detailed immunological
studies have not been performed for pseudopelade in
humans; a previous report proposed lymphocytemediated apoptosis as a mechanism for the alopecia.10
Apoptosis was not observed in the dogs of this report.
A cause for the variability of the clinical distribution of alopecic lesions in the dogs of this study was
not determined. In humans, permanent alopecia may
be an endpoint for various immunological triggers,
including lichen planopilaris and discoid lupus
erythematosus.3 It is possible that dierent immunological events may initiate this form of mural
folliculitis in dogs. Dog 3 was of particular interest
in that lesions occurred over the shoulder, a common
site for vaccination in animals. One of the authors
(T.L.G.) has seen isthmus mural folliculitis in a cat
with a similar clinical distribution.
In conclusion, this distinctive form of isthmus
mural folliculitis in dogs is probably immunological
in origin and leads to apparently permanent hair loss
that fails to respond to immunosuppressive therapy.
Further studies are needed to elucidate the immunological sequence of events and their roles in the
pathogenesis of this condition.
ACKNOWLEDGEMENTS
The authors would like to thank Drs Rainee Johnson,
Mitchell Song, Helen Power, Caroline de Jaham, and
Marianne Heimann for clinical case material, as well
as clinical photographs (Song, Power and de Jaham).
We are also grateful to Dr Peter F. Moore for
providing the monoclonal antibodies specic for
canine leucocyte antigens.

23

2. Declercq, J. Lymphocytic mural folliculitis in two cats.


Vlaams Diergeneeskundig Tijdschrift 1995; 64: 17780.
3. Sahl, W.J. Pseudopelade: an inherited alopecia.
International Journal of Dermatology 1996; 35: 7159.
4. Braun-Falco, O., Imai, S., Schmoeckel, C., Steger, O.,
Bergner, T. Pseudopelade of Brocq. Dermatologica
1986; 172: 1823.
5. Olivry, T., Moore, P., Naydan, D., Puget, B., Gross,
T.L., Kline, A. Antifollicular cell-mediated and
humoral immunity in canine alopecia areata.
Veterinary Dermatology 1996; 7: 679.
6. Tobin, D.J., Olivry, T. Anti-trichohyalin antibodies in
canine alopecia areata. In: Kwochka, K.W., Willemse,
T., Von Tscharner, C., eds. Advances in Veterinary
Dermatology, Volume 3 . Butterworth-Heinemann,
Oxford: 1998: 35562.
7. Caswell, J.L., Yager, J.A., Ferrer, L., Weir, J.A.M.
Canine demodicosis: a re-examination of the
histopathologic lesions and description of the
immunophenotype of inltrating cells. Veterinary
Dermatology 1995; 6: 919.
8. Templeton, S.F., Solomon, A.R. Scarring alopecia: a
classication based on microscopic criteria. Journal of
Cutaneous Pathology 1994; 21: 97109.
9. Collier, P.M., James, M.P. Pseudopelade of Brocq
occurring in two brothers in childhood. Clinical and
Experimental Dermatology 1994; 19: 614.
10. Pierard-Franchimont, C., Pierard, G.E. Massive
lymphocyte-mediated apoptosis during the early stage
of pseudopelade. Dermatologica 1986; 172: 2547.
11. Cotsarelis, G., Sun, T.-T., Lavker, R.M. Labelretaining cells reside in the bulge area of
pilosebaceous unit: implications for follicular stem
cells, hair cycle, and skin carcinogenesis. Cell 1990;
61: 132937.
12. Yang, J.-S., Lavker, R.M., Sun, T.-T. Upper human
hair follicle contains a subpopulation of keratinocytes
with superior in vitro proliferative potential. Journal of
Investigative Dermatology 1993; 101: 6529.
13. Credille, K.M., Petersen, A.D., Nachreiner, R.F.,
Butler, K.L., Dunstan, R.W. The use of hair plucking
to assess canine hair follicle regeneration: implications
for the bulge activation hypothesis. Proceedings of the
14th Annual Meeting of the American Academy and
American College of Veterinary Dermatology, 1998:
11920.
14. Dressel, D., Brutt, C.H., Manfras, B. et al. Alopecia
areata but not androgenetic alopecia is characterized
by a restricted and oligoclonal T-cell receptorrepertoire among inltrating lymphocytes. Journal of
Cutaneous Pathology 1997; 24: 1648.
15. Paus, R., Slominski, A., Czarnetzki, B.M. Is alopecia
areata an autoimmune-response against melanogenesisrelated proteins, exposed by abnormal MHC class I
expression in the anagen hair bulb? Yale Journal of
Biology and Medicine 1994; 66: 54154.

REFERENCES
1. Gross, T.L., Stannard, A.A., Yager, J.A. An
anatomical classication of folliculitis. Veterinary
Dermatology 1997; 8: 14756.

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150 DISC
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T. L. Gross, T. Olivry and D. J. Tobin


Resume Les caracteristiques cliniques, histopathologiques et immunopathologiques d'une nouvelle forme de
folliculite murale de l'isthme, qui ressemble a la pseudopelade chez l'homme, sont presentees. Cliniquement,
les chiens presentaient des zones multifocales variables d'alopecie, qui persistaient sans traitement, ou n'ont
pas repondu a un traitement immunosuppresseur. Histopathologiquement, un inltrat mononuclee, a
predominance de lymphocytes, inltrait l'isthme folliculaire. Une extension de l'inammation au dessus ou en
dessous de l'isthme folliculaire a ete observee occasionnellement, mais sans jamais atteindre le bulbe
folliculaire ou l'epiderme. Une atrophie folliculaire severe, et une atrophie variable des glandes sebacees etait
presente pour tous les animaux. Les lymphocytes a tropisme folliculaire etaient le plus souvent de phenotype
CD3 et CD8 (cellules T cytotoxiques). Des autoanticorps speciques des portions profondes du follicule pileux
ont ete detectes dans le serum des patients. Un Western blott a demontre la xation des anticorps sur de
nombreuses proteines folliculaires de keratinocytes, incluant les keratines du poil et la trichohyaline.
L'absence de repousse des poils (a l'oppose de l'alopecia areata chez le chien), la localisation de l'inammation
et l'atrophie extreme des unites annexielles sont semblables aux donnees observees dans la pseudopelade chez
l'homme. [Gross, T. L., Olivry, T. et Tobin, D. J. (Caracteristiques morphologiques et immunologiques d'une
folliculite murale de l'isthme chez le chien ressemblant a la pseudopelade chez l'homme.) Veterinary
Dermatology 2000; 11: 1724.]
Resumen Se caracterizaron los hallazgos clinicos, histopatogicos e inmunopatologicos de una nueva forma
de foliculitis mural del istmo en el perro, parecida a pseudopelade de humanos. Clinicamente, los perros
mostraban focos de alopecia distribuidos de forma variable, que persist an sin tratamiento o no respond an a
la terapia de inmunosupresion. Histopatologicamente, inltrados mixtos de celulas mononucleares,
predominantemente linfocitos, inltraban el istmo folicular. Ocasionalmente, la inamacion se extend a por
encima y por debajo del istmo folicular pero no implicaba el bulbo folicular ni la epidermis. Exist a atroa
folicular intensa y atroa variable de las glandulas sebaceas en todos los perros. Los linfocitos foliculotropicos
mostraban mas frecuentemente CD3 y CD8 (celulas T citotoxicas). En el suero de los pacientes afectados se
detectaron anticuerpos espec cos para la parte profunda del fol culo. El western immunoblotting demostro la
union de estos anticuerpos a numerosas proteinas de queratinocitos foliculares, incluyendo queratinas del pelo
y tricohialina. La falta de nuevo crecimiento del pelo (a diferencia de la alopecia areata canina), as como la
localizacion de la inamacion y la extrema atroa de los anejos son similares a los hallazgos que se observan
en pseudopelade de los humanos. [Gross, T. L., Olivry, T. y Tobin, D. J. (Caracterizacion morfologica e
inmunologica de la foliculitis mural canina del istmo parecida a pseudopelade de la especie humana.)
Veterinary Dermatology 2000; 11: 1724.]
Zusammenfassung Die klinischen, histopathologischen und immunpathologischen Merkmale einer neuen
Form von muraler Isthmusfollikulitis, die humaner Alopecia atrophicans ahnelt, wurden beschrieben.
Klinisch zeigten die Hunde unterschiedlich verteilte haarlose Stellen, die ohne Behandlung persistierten und
nicht auf immunsuppressive Therapie ansprachen. Histopathologisch inltrierten gemischte mononukleare
Zellen (hauptsachlich Lymphozyten) den follikularen Isthmus. Gelegentlich erstreckte sich die Entzundung
oberhalb und unterhalb des Isthmus, betraf jedoch nicht die Haarzwiebel oder die Epidermis. Alle Hunde
hatten schwere follikulare Atrophie und unterschiedliche Atrophie der Talgdrusen. Folliculotrophe
Lymphozyten exprimierten am haugsten CD3 und CD8 (zytotoxische T-Zellen). Spezische
Autoantikorper gegen den unteren Teil des Haarfollikels wurden im Serum dieser Patienten entdeckt.
Western Immunoblotting demonstrierte eine Bindung dieser Antikorper gegen mehrere follikulare
Keratinozytenproteine wie Haarkeratine und Trichohyalin. Im Gegensatz zu kaniner Alopezia areata
wachsen die Haare nicht wieder nach, dieser Befund sowie die Lokalisierung der Entzundung und die extreme
Atrophie der Adnexae entsprechen den Befunden bei humaner Alopecia atrophicans. [Gross, T. L., Olivry, T.
und Tobin, D. J. (Morphologische und immunologische Charakterisierung einer der humanen Alopecia
atrophicans ahnelnden kaninen, muralen Isthmusfollikulitis.) Veterinary Dermatology 2000; 11: 1724.]

# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 1724

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