ARTICLE
Auteur(s) : Shinsuke Yasukawa1, Teruki
Dainichi2, Hisashi Kokuba1, Yoichi
Moroi1, Kazunori Urabe1, Takashi
Hashimoto2, Masutaka Furue1
1Department of Dermatology, Graduate School
of Medical Sciences, Kyusyu University, Fukuoka, Japan
2Department of Dermatology, Kurume University,
School of Medicine, 67 Asahimachi, Kurume, Fukuoka
830-0011, Japan
accepté le 12 Août 2008
It has been reported that some patients with psoriasis, whose
disease was improved by treatment such as phototherapy,
occasionally suffered from bullous pemphigoid [1, 2]. These cases
may be based on an immunological shift from T helper cell type 1
(Th1) to Th2 [3]. It has been suggested that Th1 plays a central
role in the pathogenesis of psoriasis vulgaris as effector cells
for keratinocytes, whereas a Th2-predominant immunological profile
is observed in bullous pemphigoid [4-7]. However, it is
unsatisfactory to explain the pathogenesis and course of autoimmune
diseases such as psoriasis and bullous diseases simply within the
scheme of the Th1/Th2 hypothesis [8].
There are other types of T lymphocytes: Regulatory T lymphocytes
(Treg) can influence the expression and activation of helper T
lymphocytes and are suggested to suppress autoimmunity [9]. Most
recently, IL-17-producing T lymphocytes, Th17, have been accepted
as a fourth type of CD4-positive T lymphocytes. Th17 appear to
stimulate cytotoxic activity and exacerbate autoimmune diseases as
a counterpart of Treg with opposite function [10-13].
Here, we report the first case of generalized pustular psoriasis
that appeared during steroid therapy for bullous pemphigoid. We
followed the dynamics of Th1, Th2, Treg, and Th17 changes over the
disease course.
Patient and methods
Patient
A 37-year-old Japanese man was admitted to our hospital because of
a sudden appearance of bullae and erythema on almost the whole body
(figures 1A, B).
A direct immunofluorescence showed a linear deposition of IgG
(figure 1C) and
C3 (not shown) at the basement membrane zone. Indirect
immunofluorescence detected IgG antibodies to the basement membrane
zone in the patient’s serum at a titer of 640, which reacted with
the epidermal side of 1M sodium chloride split skin. Anti-BP180 IgG
autoantibodies were detected on immunoblot analysis using the
recombinant BP180 NC16a protein, which contains the most
immunogenic regions of the BP180. We diagnosed the patient as
having bullous pemphigoid. During treatment with oral betamethasone
5.5 mg daily and courses of plasmapheresis, systemic symptoms
improved and erythema and bullae quickly disappeared.
After the betamethasone was tapered to 1.0 mg daily,
erythema with pustules and severe edema appeared over the body
(figure 1D), and
fever with a temperature as high as 39 ˚C developed.
Histopathologically, a specimen from the skin lesion showed Kogoj’s
spongiform pustules in the upper part of the epidermis and
psoriasiform acanthosis with elongation of rete ridges (figure 1E). Direct
immunofluorescence showed a linear deposition of IgG and C3 at the
basement membrane zone. Indirect immunofluorescence with the
patient’s serum showed IgG anti-basement membrane zone antibodies
at a titer of 10. Immunoblot analysis using epidermal extracts
demonstrated that the patient’s serum reacted with BP180. We
diagnosed this patient as suffering from generalized pustular
psoriasis accompanying bullous pemphigoid. Combination therapy with
etretinate 20 mg daily and betamethasone 3.0 mg daily
improved his skin lesions. Even after the steroid dose was tapered,
a stable condition was maintained.
Quantification of serum interferon (IFN)-γ and tumor
necrosis factor (TNF)-α
Serum samples were collected at the beginning and during the
disease courses of both bullous pemphigoid and pustular psoriasis,
and were stored at – 80 ˚C until use. Quantification of
IFN-γ and TNF-α levels in the patient’s sera was performed by
enzyme-linked immunosorbent assays.
Immunohistochemistry
Skin biopsy samples were serially obtained from each lesion and
stored at –80˚C until use. The immunohistochemical procedures were
carried out using first antibodies as follows: Mouse monoclonal
anti-human IL-4 antibody, goat anti-human IL-17 antibody (R&D
Systems, Inc., MN, USA), and mouse monoclonal antibody [236A/E7] to
Foxp3 (Abcam, Cambridge, UK).
Results
In the present case, IFN-γ was not detectable (< 0.1 IU/mL) in
any of the serum samples over the studied course of the disease
(table 1). Serum TNF-α was elevated at
the time of the pustular psoriasis attack, and subsequently
remained at a detectable level even after the remission (table 1). Immunohistochemical analysis showed that
both IL-4- and IL-17-producing cells, as well as Foxp3-positive
cells, were detected in the upper dermis of the skin from a bullous
pemphigoid lesion (figure 2). On the other
hand, the specimen from the psoriasis lesion showed no evidence of
IL-4-producing cells or Foxp3+ cells. There were IL-17-producing
cells not only in the dermis, but also in the epidermis. The skin
specimen obtained at remission contained no IL-4- or
IL-17-producing cells, or Foxp3-positive cells. The immunological
dynamics over the course are summarized in table
1.
Table 1 The immunological dynamics over the disease
course of the present case
|
|
BP
|
Psoriasis
|
Remission
|
|
Serum: (pg/mL)
|
IFN-γ
|
n.d.
|
n.d.
|
n.d.
|
|
TNF-α
|
n.d.
|
45
|
24
|
|
Skin :
|
IL-4
|
+
|
–
|
–
|
|
IL-17
|
+
|
+
|
–
|
|
Foxp3
|
+
|
–
|
–
|
Discussion
We document the first reported case of generalized pustular
psoriasis accompanying bullous pemphigoid. Although there was no
published information available about the role of Th17 in
autoimmune bullous diseases, accumulating evidence suggests that
Th17 cytokines, including IL-22, play an important role in the
pathogenesis of psoriasis [14-16]. We have recently confirmed that
IL-17-producing lymphocytes were detected in the skin lesions of
both bullous pemphigoid and pemphigus vulgaris (manuscript in
preparation). The immunological profile of the present case was
ideal to support the hypothesis that the immunological dynamics in
autoimmune diseases should not be viewed as a one-dimensional
interaction between Th1 and Th2, but as a multiple-level
interaction among Th1, Th2, Treg and Th17.
The Th1/Th2 theory simply and elegantly explains various
immunological states in mice and humans [8]. However, this theory
is not suitable for understanding the pathogenesis of autoimmune
diseases because the mechanism of exacerbation and amelioration
cannot be simply explained as a switch from Th1 to Th2. Now we have
information about two new players involved in the multidirectional
immunological reactions: i.e., Treg and Th17. Accumulated evidence
suggests that Treg is responsible for the third direction of an
immunological reaction, and controls autoimmunity, tumor immunity
and resolution of immune reactions. Th17 is accepted as a
helper/effector cell subset responsible for cytotoxic reactions in
autoimmunity, a function that could not be assigned by the Th1/Th2
hypothesis.
The role of Th17 in the lesional skin in bullous pemphigoid is
unknown, but they may have a similar effector function to the one
they have in several other autoimmune diseases. It is also
conceivable that lesional Th17 may not be a cause but a result of
the disease: i.e., they may function in a non-specific protective
and repair response following damage in the epidermis. It would be
valuable to elucidate the precise mode of function of Th17.
It is, naturally, a limitation of this study that the immune
parameters investigated in a single patient do not provide
sufficient information to draw specific conclusions on the immune
profile of autoimmune diseases. Nevertheless, the multidimensional
immune reactions described here will help us to understand the
pathogenesis of autoimmune diseases and to discover new
therapies.
Acknowledgements
Financial support: None. Conflict of interest: None.
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