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Bullous pemphigoid followed by pustular psoriasis showing Th1, Th2, Treg and Th17 immunological changes

European Journal of Dermatology. Volume 19, Number 1, 69-71, January-February 2009, Clinical report

DOI : 10.1684/ejd.2008.0572

Summary

Author(s) : Shinsuke Yasukawa, Teruki Dainichi, Hisashi Kokuba, Yoichi Moroi, Kazunori Urabe, Takashi Hashimoto, Masutaka Furue , Department of Dermatology, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan, Department of Dermatology, Kurume University, School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan.

Summary : Psoriasis vulgaris is occasionally accompanied by autoimmune bullous diseases, but the opposite is very rare. We document here the first reported case of generalized pustular psoriasis that appeared during steroid therapy for bullous pemphigoid. The serum cytokine levels and the results of an immunohistochemical study over the disease course suggest that the immunological state was consistent with a shift from Th2-dominance to Th1-dominance. IL-17-producing cells appeared in the skin lesions when each disease was most exacerbated and disappeared after remission. Thus, the present case demonstrated a dynamic immunological state in which the appearances of Th1 and Th2 as well as Th17 varied during the course of the disease.

Keywords : pustular psoriasis, bullous pemphigoid, Th1, Th2, Th17

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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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