A Review of Acquired Autoimmune Blistering Diseases in Inherited Epidermolysis Bullosa: Implications for the Future of Gene Therapy

Abstract

Gene therapy serves as a promising therapy in the pipeline for treatment of epidermolysis bullosa (EB). However, with great promise, the risk of autoimmunity must be considered. While EB is a group of inherited blistering disorders caused by mutations in various skin proteins, autoimmune blistering diseases (AIBD) have a similar clinical phenotype and are caused by autoantibodies targeting skin antigens. Often, AIBD and EB have the same protein targeted through antibody or mutation, respectively. Moreover, EB patients are also reported to carry anti-skin antibodies of questionable pathogenicity. It has been speculated that activation of autoimmunity is both a consequence and cause of further skin deterioration in EB due to a state of chronic inflammation. Herein, we review the factors that facilitate the initiation of autoimmune and inflammatory responses to help understand the pathogenesis and therapeutic implications of the overlap between EB and AIBD. These may also help explain whether corrections of highly immunogenic portions of protein through gene therapy confers a greater risk towards developing AIBD.

Keywords: autoimmune blistering disorder; autoimmunity; collagen XVII; epidermolysis bullosa; gene therapy.

Figure 1

(A) Collagen mutation profile and immunogenic domains of epitope reactivity. This schematic representation of collagen VII consists of noncollagenous-1 (NC1, shown as a blue elliptical bar), triple-helix collagenous (shown as a blue rectangular bar), and noncollagenous-2 domains (NC2, shown as a blue oval bar). A crucial region within NC1 is the fibronectin-III-like domains 1–9 (shown as blue vertical bars). The asterisks indicate the approximate location of the mutations alongside intervals of 100 amino acids within the collagen VII polypeptide chain. The size of the asterisk corresponds to the number of mutations detected within the specified interval. The second half of this image depicts the combined results of studies measuring the reactivity of sera from patients with epidermolysis bullosa acquisita to epitopes alongside collagen VII. The intensity of the color relates to the percent reactivity identified within the individual domains. The areas of highest immunogenicity in a majority of patients include fibronectin-III-like domains 4–6 of collagen VII (approximately AA 500–800), and various regions within the NC1 and collagenous domains. As such, gene therapy must target the greatest number of mutations, while avoiding highly immunogenic areas of epitope binding [6,7,8]. (B) In this schematic representation of collagen XVII, the extracellular domain consists of stretches of noncollagenous domains and a series of 15 collagenous domains (shown as blue vertical bars). Also represented are the intracellular (shown as a blue elliptical bar) and transmembrane domains (shown as a black curved bar). The asterisks indicate the approximate location of the mutations alongside intervals of 50 amino acids within the collagen XVII polypeptide chain. The size of the asterisk corresponds to the number of mutations detected within the specified interval. The second half of this image depicts the combined results of studies measuring the reactivity of sera from patients with bullous pemphigoid to epitopes alongside collagen XVII. The intensity of the color relates to the percent reactivity identified within the individual domains. The NC16a region of collagen XVII (AA 490–566) was identified as having the highest immunogenicity in the majority of patients but reactivity to various subdomains within the intracellular region must be considered. As such, gene therapy must target the greatest number of mutations, while avoiding highly immunogenic areas of epitope binding [9,10,11,12,13].