Autoimmunity, February 2012; 45(1): 55–70 q Informa UK, Ltd. ISSN 0891-6934 print/1607-842X online DOI: 10.3109/08916934.2011.606447 Pemphigoid diseases: Pathogenesis, diagnosis, and treatment MICHAEL KASPERKIEWICZ1, DETLEF ZILLIKENS1, & ENNO SCHMIDT1,2 1Department of Dermatology, University of Lu¨beck, Lu¨beck, Germany, and 2Comprehensive Center for Inflammation Medicine, University of Lu¨beck, Lu¨beck, Germany (Submitted 25 June 2011; accepted 12 July 2011) Abstract Pemphigoid diseases (including bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA dermatosis, lichen planus pemphigoides, and anti-p200 pemphigoid) are a subgroup of autoimmune bullous skin diseases characterized by an autoantibody response toward structural components of the hemidesmosome resulting in subepidermal blistering. By the use of different in vitro systems and experimental animal models, the pathogenic relevance of these autoantibodies has been demonstrated. Recent advances in the understanding of autoantibody responses have led to novel diagnostic tools and a more differentiated therapeutic approach for these disorders. This review covers the most recent understanding of the pathophysiology, diagnosis, and treatment of this group of autoimmune diseases. Keywords: Pemphigoid, skin, antibody, antigen Introduction may be due to the increasing age of the general population and/or an increased awareness leading to The pemphigoid group of diseases is characterized by further diagnostic steps. MMP and PG have been For personal use only. subepidermal blisters due to autoantibody-induced disruption of the components of the dermal– identified as the second most frequent pemphigoid epidermal anchoring complex. Pemphigoid diseases diseases in central Europe with an incidence of two include bullous pemphigoid (BP), mucous membrane new patients/million/year [1]. pemphigoid (MMP), pemphigoid gestationis (PG), For the correct diagnosis of pemphigoid diseases, linear IgA dermatosis (LAD), lichen planus pemphi- the detection of tissue-bound and circulating auto- goides (LPP), and anti-p200 pemphigoid. In particu- antibodies is pivotal [7]. Although direct immuno- lar, disorders with anti-BP180 (type XVII collagen) fluorescence (IF) microscopy differentiates pemphigus reactivity, including BP, PG, LAD, LPP, and a from pemphigoid disorders, serological analyses are subgroup of MMP may form a continuous spectrum necessary to separate pemphigoid diseases from each Autoimmunity Downloaded from informahealthcare.com by Goteborgs University on 11/20/12 of subepidermal autoimmune blistering dermatoses. other and from epidermolysis bullosa acquisita (EBA). BP is not only the most common disorder within In fact, while direct IF microscopy is still the gold the pemphigoid group, but also represents the most standard for the diagnosis of pemphigoid diseases, in frequent autoimmune blistering disease in general the great majority of patients, diagnosis can be made [1,2]. The incidence of BP has been estimated between serologically today [7]. 4.5 and 14 new cases/million/year in central Europe By indirect IF microscopy on 1 M NaCl-split [1–5]. A higher incidence of 42.8/million/year has human skin, anti-laminin 332 MMP and anti-p200 recently been reported in Great Britain based on a pemphigoid can be distinguished from BP, LAD, PG, data registry established on the general practitioner and anti-BP180 MMP, but final diagnosis can only level [6]. Interestingly, in Germany and Great Britain, be made by more sophisticated methods, i.e. use it has been shown that the incidence of BP has of cell-derived or recombinant forms of the target considerably increased within the last 10 years (2-fold antigens (Figure 1). In recent years, various novel and 4.8-fold, respectively) [1,6]. This development detection systems for serum antibodies have been Correspondence: M. Kasperkiewicz, Department of Dermatology,University of Lu¨beck, Ratzeburger Allee 160, 23538 Lu¨beck, Germany. Tel: 0049-451-500-5844. Fax: 0049-451-500-5162. E-mail: [email protected] 56 M. Kasperkiewicz et al. (a) Disease Main target antigens Bullous pemphigoid BP180, BP230 Mucous membrane BP180, BP230, pemphigoid α6β4 integrin Pemphigoid gestationis BP180, BP230 Linear IgA dermatosis BP180, BP230 Lichen planus BP180, BP230 pemphigoides (b) Disease Main target antigens Mucous membrane Laminin 332 pemphigoid Anti-p200 Laminin γ1 pemphigoid Figure 1. Indirect IF microscopy on 1 M NaCl split human skin and main target autoantigens of pemphigoid diseases. Differentiation of the diseases and target molecules is based on the binding pattern with either (a) epidermal or (b) dermal binding of circulating autoantibodies on the artificial split. developed, some of which are also commercially avail- epitopes in BP and is recognized by autoantibodies in able. These now allow for a more accurate diagnosis, 80–90% of BP patients [16–19]. The importance of which is becoming increasingly important to guide anti-BP180 NC16A reactivity is further highlighted For personal use only. treatment decisions, while our knowledge about the by the observation that serum levels of BP180 therapeutic arsenal of these disorders has also NC16A-specific antibodies correlate with the disease expanded. In this review, we focus on recent progress activity in BP patients [20]. in our understanding of the pathogenesis, diagnosis, In addition, it was reported that autoantibodies and treatment of the different pemphigoid diseases. preferentially recognize the phosphorylated BP180 ectodomain [21,22]. Recent studies have identified Bullous pemphigoid the presence of memory B cells specific for the NC16A domain, which can be induced in vitro to synthesize Pathogenesis autoantibodies [23]. These cells belong to the short- Autoimmunity Downloaded from informahealthcare.com by Goteborgs University on 11/20/12 Two hemidesmosomal proteins, the 230 kDa protein lived plasma blast population [24]. The BP180 (BP230 or BPAG1), and 180 kDa antigen (BP180, NC16A-specific autoantibodies are not only of the BPAG2, or type XVII collagen) have been identified IgG isotype (mainly IgG1 and IgG4 subclasses), but as the major antigenic targets of BP autoantibodies also of the IgE class [25–27]. In fact, patients with [8–10]. BP230 is an intracellular plakin protein member BP frequently have IgE autoantibodies binding to the showing homology with plectin and desmoplakins I NC16A domain of BP180 [28]. and II and promotes the association of hemidesmo- The presence of IgE autoantibodies has recently somes with keratin intermediate filaments [11–13]. been correlated with a severe form of BP, and BP In contrast, BP180 is a transmembrane protein with a patients, positive for IgE anti-BP180 antibodies, type II orientation that spans the lamina lucida and required longer duration for remission, higher dosage projects into the lamina densa of the epidermal basal of prednisolone, and more intensive therapies for membrane zone (BMZ). The extracellular region remission [29]. Interestingly, one study showed that a consists of 15 collagen domains separated from one recombinant NC16A fusion protein degranulated another by noncollagen sequences [14,15]. basophils opsonized with IgE from patients with BP The noncollagenous 16A domain (NC16A), [30], further supporting the pathophysiological role located at the membrane-proximal region of BP180, of IgE antibodies in BP. In addition, other antigenic is considered to harbor major pathogenically relevant sites exist on both the extracellular and intracellular Update on pemphigoid 57 domain of BP180, which are recognized by IgE and are important in human BP is supported by the IgG autoantibodies in BP patients [16–18,31–34]. increased frequency of cutaneous lymphocyte-associ- BP patients also exhibit significant reactivity with ated antigen-positive IL-4- and IL-13-producing cells BP230, which is thought not to be involved in the in the peripheral blood [56]. Furthermore, analysis of initiation of the inflammatory response in BP due to cell subsets with immunoregulatory functions in its intracellular localization [8,35–40]. Currently, it is BP patients has shown that while the number of unclear whether anti-BP230 autoantibodies in BP circulating CD4 þ CD25 þ FOXP3 þ regulatory T patients directly contribute to blister formation or cells, natural killer T cells, and natural killer cells are whether they are just a result of keratinocyte injury normal, gd T cells are reduced in BP patients [57,58]. and determinant spreading of the autoimmune Our knowledge about the functionally relevant response. Very recently, two retrospective studies with pathogenic mechanisms in BP is based on in vitro a large series of 138 and 190 patients with active BP, studies using cultured human keratinocytes, ex vivo respectively, have determined the outcome of BP230 studies using cryosections of human skin as well as autoantibody detection using commercial enzyme- various mouse models [59,60]. When cultured human linked immunosorbent assays (ELISAs) [39,40]. keratinocytes were treated with anti-BP180 IgG, dose- In the first-mentioned study, 59% of patients had a and time-dependent increases of both mRNA and positive BP230 ELISA result and 86% had a positive protein levels of IL-6 and IL-8 were observed, BP180 ELISA result, while only 5% had anti-BP230 pointing to a signal-transducing event via BP180 autoantibodies without anti-BP180 autoantibodies [61]. In the same model, decreased expression of [39]. In the second study, anti-BP230 and anti- BP180 and