Antibodies to Pathogenic Epitopes or Type XVII Collagen Cause Skin Fragility in a Complement-Dependent and -Independent Manner

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
The Journal of Immunology (Impact Factor: 4.92). 04/2012; 188(11):5792-9. DOI: 10.4049/jimmunol.1003402
Source: PubMed


In bullous pemphigoid (BP), the most prevalent autoimmune blistering disease, type XVII collagen (COL17) is targeted by circulating autoantibodies. BP is thought to be an autoantibody-mediated complement-fixing blistering disease, and a juxtamembranous noncollagenous 16A (NC16A) domain spanning Glu(490) to Arg(566) was proved to be the main pathogenic region on COL17, although precise pathogenic epitopes within NC16A have not been elucidated. In this study, we showed that injection of rabbit IgG Abs targeting Asp(522) to Gln(545) induced skin fragility associated with in vivo deposition of IgG and complement in neonatal COL17-humanized mice. Notably, immunoadsorption of rabbit anti-NC16A IgG Ab with this epitope (Asp(522) to Gln(545)) or the anti-NC16A IgG administered together with the peptides of this epitope as a decoy ameliorated skin fragility in the injected neonatal COL17-humanized mice compared with the anti-NC16A IgG alone even though all of the mice showed both IgG and complement deposition. These results led us to investigate an additional, complement-independent mechanism of skin fragility in the mice injected with anti-COL17 Abs. The rabbit anti-NC16A IgG depleted the expression of COL17 in cultured normal human keratinocytes, whereas immunoadsorption of the same IgG with this epitope significantly suppressed the depletion effect. Moreover, passive transfer of F(ab')(2) fragments of the human BP or rabbit IgG Abs against COL17 demonstrated skin fragility in neonatal COL17-humanized mice. In summary, this study reveals the importance of Abs directed against distinct epitopes on COL17, which induce skin fragility in complement-dependent as well as complement-independent ways.

Download full-text


Available from: Hideyuki Ujiie
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering skin disease characterized by autoantibodies to type VII collagen. Clinically, a noninflammatory and an inflammatory variant of EBA can be distinguished. Despite major achievements in the understanding of EBA, current therapeutic options are far from optimal. However, with an emerging and more detailed understanding of the events ultimately leading to blister formation in EBA, novel therapeutic options may become available for patients with EBA. Therefore, this article reviews the current understanding of the pathogenesis of EBA and may indicate possible avenues towards a more targeted therapy for EBA and possibly other antibody-mediated autoimmune diseases.
    No preview · Article · Jul 2011 · Dermatologic clinics
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jul 2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bullous pemphigoid (BP), an autoimmune subepidermal blistering skin disease, demonstrates tense blisters with or without widespread erythema, blistering along the lamina lucida, immunoglobulin G and/or complement deposits at the basement membrane zone, and the presence of circulating autoantibodies against hemidesmosomal molecules. These autoantibodies usually react against 180-kDa and/or 230-kDa proteins, designated as BP180 and BP230, respectively. The precise blistering mechanisms after autoantibodies bind to antigens are not fully understood. Immune complexes are thought to initially activate the complement cascade, which may induce activation of proteases and/or cytokines and cause dermal-epidermal separation. However, why does separation run specifically within the lamina lucida in a space as narrow as 500 nm wide? This review mainly focuses on the possible mechanisms of BP-specific blistering and how separation occurs along the lamina lucida, based on existing evidence.
    Full-text · Article · Apr 2013 · Experimental Dermatology
Show more