Bullous pemphigoid (BP) is an autoimmune blistering disease which carries a significant mortality and morbidity. While historically BP has been characterized as an IgG driven disease mediated by anti-BP180 and BP230 IgG autoantibodies, developments in recent years have further elucidated the role of eosinophils and IgE autoantibodies. In fact, eosinophil infiltration and eosinophilic spongiosis are prominent features in BP. Several observations support a pathogenic role of eosinophils in BP: IL-5, eotaxin, and eosinophil-colony stimulating factor are present in blister fluid; eosinophils line the dermo-epidermal junction (DEJ) in the presence of BP serum, metalloprotease-9 is released by eosinophils at the site of blisters; eosinophil degranulation proteins are found on the affected basement membrane zone as well as in serum corresponding with clinical disease; eosinophil extracellular DNA traps directed against the basement membrane zone are present, IL-5 activated eosinophils cause separation of the DEJ in the presence of BP serum; and eosinophils are the necessary cell required to drive anti-BP180 IgE mediated skin blistering. Still, it is likely that eosinophils contribute to the pathogenesis of BP in numerous other ways that have yet to be explored based on the known biology of eosinophils. We herein will review the role of eosinophils in BP and provide a framework for understanding eosinophil pathogenic mechanisms in mucocutaneous disease.

/pdf/the-role-of-eosinophils-in-bullous-pemphigoid-a-developing-4lh4hu8s6y.pdf

The Role of Eosinophils in Bullous Pemphigoid: A Developing Model of Eosinophil Pathogenicity in Mucocutaneous Disease.

Background
Bullous pemphigoid (BP) is an autoimmune bullous disease of the skin characterized by subepidermal blister formation due to tissue-bound and circulating autoantibodies to the hemidesmosomal antigens BP180 and BP230. Although eosinophils and their toxic mediators are found abundantly in BP lesions, their role in blister formation has remained unclear.

Objective
To investigate the role of eosinophils in the pathogenesis of BP with a specific focus on blister formation and to define conditions inducing dermal–epidermal separation (DES).

Methods
In an ex vivo human model of BP, normal human skin cryosections were incubated with purified human peripheral blood eosinophils with or without activation in the presence or absence of BP autoantibodies, brefeldin A, diphenyleneiodonium, DNase or blocking F(ab′)2 fragments to CD16, CD18, CD32 and CD64. Dermal–epidermal separation was assessed by light microscopy studies and quantified using Fiji software.

Results
Following activation with IL-5 and in the presence of BP autoantibodies, eosinophils induced separation along the dermal–epidermal junction of ex vivo skin. Dermal–epidermal separation was significantly reduced by blocking any of the following: Fcγ receptor binding (P = 0.048), eosinophil adhesion (P = 0.046), reactive oxygen species (ROS) production (P = 0.002), degranulation (P < 0.0001) or eosinophil extracellular trap (EET) formation (P = 0.048).

Conclusions
Our results provide evidence that IL-5-activated eosinophils directly contribute to BP blister formation in the presence of BP autoantibodies. Dermal–epidermal separation by IL-5-activated eosinophils depends on adhesion and Fcγ receptor activation, requires elevated ROS production and degranulation and involves EET formation. Thus, targeting eosinophils may be a promising therapeutic approach for BP.

/pdf/evidence-for-a-role-of-eosinophils-in-blister-formation-in-2ez4rkgrlc.pdf

Evidence for a role of eosinophils in blister formation in bullous pemphigoid.

Autoimmune bullous skin disorders are rare but meaningful chronic inflammatory diseases, many of which had a poor or devastating prognosis prior to the advent of immunosuppressive drugs such as systemic corticosteroids, which down-regulate the immune pathogenesis in these disorders Glucocorticoids and adjuvant immunosuppressive drugs have been of major benefit for the fast control of most of these disorders, but their long-term use is limited by major side effects such as blood cytopenia, osteoporosis, diabetes mellitus, hypertension, and gastrointestinal ulcers In recent years, major efforts were made to identify key elements in the pathogenesis of autoimmune bullous disorders, leading to the identification of their autoantigens, which are mainly located in desmosomes (pemphigus) and the basement membrane zone (pemphigoids) In the majority of cases, immunoglobulin G, and to a lesser extent, immunoglobulin A autoantibodies directed against distinct cutaneous adhesion molecules are directly responsible for the loss of cell-cell and cell-basement membrane adhesion, which is clinically related to the formation of blisters and/or erosions of the skin and mucous membranes We describe and discuss novel therapeutic strategies that directly interfere with the production and regulation of pathogenic autoantibodies (rituximab), their catabolism (intravenous immunoglobulins), and their presence in the circulation and extravascular tissues such as the skin (immunoadsorption), leading to a significant amelioration of disease Moreover, we show that these novel therapies have pleiotropic effects on various proinflammatory cells and cytokines Recent studies in bullous pemphigoid suggest that targeting of immunoglobulin E autoantibodies (omalizumab) may be also beneficial In summary, the introduction of targeted therapies in pemphigus and pemphigoid holds major promise because of the high efficacy and fewer side effects compared with conventional global immunosuppressive therapy

Targeted Therapies for Autoimmune Bullous Diseases: Current Status

Various sections of the manuscript reviewed by: O.E. Araujo, Department of Pharmacy Practice, University of Florida, Gainesville, Florida, USA; M. Bagot, Department of Dermatology, Henri Mondor Hospital, Creteil, France; J. Berth-Jones, Department of Dermatology, Leicester Royal Infirmary, Leicester, England; M.F. Holick, Boston University School of Medicine, Boston, Massachusetts, USA; G. Jones, Departments of Biochemistry and Medicine, Queen's University, Kingston, Ontario, Canada; L. Kemeny, Albert Szent-Gyorgyi Medical University, Szeged, Hungary; J. Keski-Oja, Department of Virology, University of Helsinki, Helsinki, Finland; M.R. Klaber, Dermatology Department, Broomfield Hospital, Chelmsford, England; HM. Lewis, Department of Dermatology, General Hospital, Birmingham, England; H.I. Maibach, Department of Dermatology, UCSF School of Medicine, San Francisco, California, USA; T.F. Poyner, Queens Park Medical Centre, Stockton-on-Tees, England; CA. Ramsay, University of Toronto, Toronto, Ontario, Canada; J-H. Saurat, Clinique de Dermatologie, H6pital Cantonal Universitaire, Geneva, Switzerland; S.N. Tham, National Skin Centre, Singapore.

A Review of its Pharmacological Properties and Therapeutic Efficacy in the Management of Psoriasis

Infections by herpes simplex virus (HSV) types I and II are diverse and quite frequent. After primary infection, the virus establishes a life-long latency in the sensory ganglia and recrudescences may occur at an unpredictable rate. Recurrent labial and genital herpes infections represent the majority of clinical manifestations of HSV infections. Their management is currently well established using evidence-based medicine data. Primary labial herpes is generally not treated with antivirals in otherwise healthy children, although intravenous aciclovir may be offered in severe primary infections, particularly in the immunocompromised patient. The decision whether or not to treat recurrent labial herpes should be evaluated individually and depends on the frequency and severity of relapses, the impairment of the quality of life, and the cost of therapy. Patients with mild disease may benefit from topical therapy, and those with severe and frequent recurrences may be considered for intermittent or long-term oral antiviral therapy. Primary genital herpes is treated with oral or intravenous antivirals, depending on the severity of the infection and associated symptoms. Recurrent genital herpes can be managed with episodic short courses of oral antivirals in patients whose recurrences are moderate to severe and rare, and have a clear prodrome. Patients with >5 episodes/year, severe recurrences or unrecognisable prodromes may be best managed with long-term suppressive antiviral prophylaxis. HSV is also responsible for a variety of other clinical manifestations, including herpetic whitlow, neonatal infection, disseminated and atypical cutaneous infections, traumatic herpes, eczema herpeticum, and HSV— associated erythema multiforme. HSV infection may also represent a complication following cosmetic procedures of the oro-facial region, surgical and dental interventions, sun exposure and burns. Precise treatment guidelines for these HSV infections are not firmly established.

Treatment of mucocutaneous presentations of herpes simplex virus infections.

BACKGROUND The importance of eosinophils in the pathogenesis of the major forms of pemphigoid (bullous pemphigoid, cicatricial pemphigoid, herpes gestationis) remains to be confirmed. METHODS To evaluate the role of eosinophilic infiltrates in these diseases and to detect the presence and activity of eosinophils, we compared the serum levels of eosinophil cationic protein (ECP), an eosinophil-derived protein, in 11 healthy subjects and in 10 patients with pemphigoid diseases (8 with bullous pemphigoid, one with cicatricial pemphigoid, and one with herpes gestationis). The serum of two patients with epidermolysis bullosa acquisita (EBA) and one with linear IgA bullous dermatosis (LABD) were utilized as a further control. RESULTS There was a significant difference between the mean of serum ECP levels in patients with pemphigoid diseases (25.1 +/- 12.3 micrograms/L, M = SD) and control subjects (2.30 +/- 2.41, micrograms/L +/- SD 2.41) (T = 4.272 P < 0.0001). The two patients with EBA (10.8 and 17.7 micrograms/L) showed contrasting results; the patient with LABD had normal ECP serum levels. The serum levels of ECP were not significantly correlated with the blood eosinophil count (R = 0.103; P = 0.777) in any of the cases. CONCLUSIONS In pemphigoid disease, the serum levels of ECP seem to be correlated with the activated secreting and tissue-damaging eosinophils found in the dermis, supporting the concept of an active participation of eosinophils in generating cutaneous lesions.

Serum eosinophil cationic protein (ECP) in bullous pemphigoid.

A 83-year-old man was seen in January 1993, because of a pruritic eruption, consisting of numerous erosions surrounded by erythema and covered by large crusts and scales with sharply defined margins (Fig. 1). The eruption was localized on the scalp, chest, abdomen, and back. A biopsy specimen taken from a lesion on the back revealed a subcorneal, acantholytic bulla. Direct immunofiuorescence (DIF) of a perilesional sample demonstrated IgG and C3 deposits in the epidermal intercellular space. Indirect immunofiuorescence (IIF) showed circulating antibodies directed against the intercellular substance (titer 1:80). A diagnosis of pemphigus foliaceus was made and prednisone therapy (60 mg per day) was instituted.

Kaposi's varicelliform eruption in pemphigus foliaceus.

Recent research has demonstrated the activity of calcipotriol, effective as a potent inhibitor of cellular proliferation and known to increase differentiation in a number of cell lines in the topical treatment of psoriasis. Vit D3 receptors are expressed in keratinocytes and vascular endothelial cells. We studied the alterations in basal keratinocytes (stem cells or anchoring cells) and endothelial cell modification in 6 patients with psoriasis treated with calcipotriol ointment twice a day for 4 weeks. The samples were embedded in Epon resin for thin section and ultrathin section examination by electron microscopy. A normal pattern of distribution of the two different types of basal keratinocytes was observed before treatment. After treatment, only anchoring cells were detected. The alterations of endothelial cells in capillary loop disappeared after treatment, presenting normal aspects. Our morphological findings suggest that calcipotriol is therapeutically effective, due principally to an inhibition of cellular proliferation.

Structural alterations of basal keratinocytes and capillary loop in psoriasis during treatment with topical calcipotriol.

Persistent hypereosinophilia, cardiac involvement and a recurrent erythematous-papular pruritic eruption histologically characterized by eosinophilic spongiosis are described in a 77-year-old man. This condition, suggestive of “idiopathic” hypereosinophilic syndrome, represented the prodromic phase of atypical bullous pemphigoid, which manifested 7 months later.

Hypereosinophilic syndrome as prodrome of bullous pemphigoid:report of a case

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Papers

Serum eosinophil cationic protein (ECP) in bullous pemphigoid.

Kaposi's varicelliform eruption in pemphigus foliaceus.

Structural alterations of basal keratinocytes and capillary loop in psoriasis during treatment with topical calcipotriol.

Hypereosinophilic syndrome as prodrome of bullous pemphigoid:report of a case