Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita

Abstract

Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous autoimmune skin blistering disease. The pathogenic relevance of autoantibodies targeting type VII collagen (COL7) has been well-documented. Therefore, EBA is a prototypical autoimmune disease with a well-characterized pathogenic relevance of autoantibody binding to the target antigen. EBA is a rare disease with an incidence of 0.2 new cases per million and per year. The current treatment of EBA relies on general immunosuppressive therapy, which does not lead to remission in all cases. Therefore, there is a high, so far unmet medical need for the development of novel therapeutic options. During the last 10 years, several novel in vitro and in vivo models of EBA have been established. These models demonstrated a critical role of the genetic background, T cells, and cytokines for mediating the loss of tolerance towards COL7. Neutrophils, complement activation, Fc gamma receptor engagement, cytokines, several molecules involved in cell signaling, release of reactive oxygen species, and matrix metalloproteinases are crucial for autoantibody-induced tissue injury in EBA. Based on this growing understanding of the diseases' pathogenesis, several potential novel therapeutic targets have emerged. In this review, the clinical presentation, pathogenesis, diagnosis, and current treatment options for EBA are discussed in detail.

Figure 1

Mean age of EBA onset in Korea, Netherlands, and blacks with African descent. Mean (SEM) patient age (years) at the diagnosis of EBA in 3 large cohorts of patients from Korea, Netherlands, and France (blacks with African descent) [–8]. ∗ indicates P < 0.05 (ANOVA).

Figure 2

Fine mapping of the autoantibody reactivity in epidermolysis bullosa acquisita. (a) Schematic structure of COL7. In vivo, COL7 chains form a trimer. Single COL7 chain consists of one central collagenous domain, flanked by 2 noncollagenous (NC) domains. The N-terminal NC-1 domain consists of several subdomains with high homologies to adhesion proteins (CMP: cartilage matrix-like, Fn3: fibronectin 3-like, and vWFA2: von Willebrand factor A-like). The C-terminal NC2 domain contains conserved cysteine residues, which accompany an antiparallel assembly of these collagen molecules. The COL7 gene (COL7A1) maps to the locus 3p21 [–72]. (b) Summary of epitope mapping studies performed within the NC1 domain. The percentages indicated in the figure correspond the percentage of patients with autoantibodies to their regions.

Figure 3

Demonstration of the pathogenicity of anti-type VII collagen antibodies. (a) Immune complexes (IC) of anti-COL7 IgG (Ab) and COL7 (AG) are able to activate neutrophils isolated from either healthy humans or mice. Endpoint measurement is the release of reactive oxygen species (ROS) by chemiluminescence. Detection of elastase by ELISA is an additional measurement for neutrophil activation in this assay. For AIBD, this assay was first described for type XVII collagen and anti-type XVII collagen antibodies obtained from patients with bullous pemphigoid [73]. Later, the same method was adopted for EBA [61]. The figure shows a schematic result (ROS release) from neutrophils activated with either antigen or antibody alone, or with immune complexes. (b) Incubation of cryosections of normal human or mouse skin with antibodies targeting COL7, followed by incubation with neutrophils from healthy donors induces dermal-epidermal separation. This so-called “cryosection assay” also allows to investigate neutrophil activation. This assay was initially developed using sera from BP patients [74, 75] and was later adopted for EBA [60]. Shown are H&E stained sections of cryosections of normal human skin incubated with either normal human serum (NHS) or IgG from an EBA patient. After the washing of antibodies, neutrophils from healthy human donors were added to the sections. While no pathology is observed in the section incubated with NHS, a clear separation of the epidermis from the underlying dermis is present in the section incubated with anti-COL7 IgG. ∗ indicates split formation. (c) Injection of rabbit or human anti-COL7 IgG into mice leads to IgG and complement (C3) deposition along the dermal-epidermal junction (arrow heads). Subsequently, subepidermal blistering (∗) accompanied with a dermal leukocyte infiltration (arrow heads) develops. Clinically, mice present with erythema, crusts, and alopecia. Fresh blisters are rarely observed, most likely due to the thin epidermis in mice. This antibody transfer (passive) EBA mouse model was first described independently in 2005 by two groups [44, 63]. The histology and images are from C57Bl/6 mice injected with rabbit anti-COL7 IgG, 12 days after the first antibody injection. (d) Immunization of susceptible mouse strains with recombinant proteins located within the NC1 domain leads to autoantibody production, which can be detected by direct IF microscopy from skin biopsies. Subsequent to autoantibody deposition at the dermal-epidermal junction, complement activation (evidenced by C3 deposition at the dermal-epidermal junction) and histological and clinical findings duplicating the human disease are observed.

Figure 4

Pathogenesis of autoantibody-induced tissue injury in EBA. (a) In EBA, blister formation is induced by antibody binding to COL7 located at the dermal-epidermal separation. (b) This leads to the activation of the complement system. Cleavage products of complement activation, for example, C5a, mediate CD18-dependent neutrophil extravasation into the skin. (c) Subsequently, cytokines are released from yet to be defined cells. This can either contribute to tissue injury (GM-CSF, IL-1, CXCL1, and CXCL2) or have potent anti-inflammatory effects (IL-6, IL-1ra). (d) Blister formation is mediated by MMP such as elastase and reactive oxygen species (ROS) released from neutrophils after binding to the immune complexes. (e) Recent attention has focused on the resolution of inflammation in EBA. Flightless I (Flii) has potent anti-inflammatory and proresolving effects in experimental EBA.

Figure 5

Modulation of complement-driven inflammation through FcgRIIB and dectin-1. Highly galactosylation IgG1 immune complexes bind to FcgRIIB. Galactosylation links FcgRIIB to dectin-1 resulting in tyrosine phosphorylation of the ITAM-like motif downstream of dectin-1 and transient phosphorylation of Syk. This pathway inhibits C5a-mediated ERK1/2 phosphorylation and several cellular effector functions of C5aR.

Figure 6

u-serrated pattern in direct IF microscopy in EBA. Direct IF microscopy from perilesional EBA skin (staining for IgG, 400x original magnification). A linear binding along the dermal-epidermal junction is evident. The insert further magnifies the u-serrated binding of the autoantibodies (highlighted in red), which can also be observed in the original direct IF microscopy photograph.