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Pathogenesis of Epidermolysis Bullosa Acquisita

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Blistering Diseases

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Abstract

Epidermolysis bullosa acquisita is a chronic mucocutaneous autoimmune bullous dermatosis (AIBD), characterized by autoantibodies directed to type VII collagen (COL7). Over the last decades, clinical research and experimental systems modeling the disease have unraveled many steps in EBA pathogenesis. Loss of tolerance to COL7, which ultimately leads to autoantibody production, is associated with specific major histocompatibility (MHC) and non-MHC genes and requires autoreactive T cells. After binding of the autoantibodies to COL7 located at the dermal-epidermal junction, a multistep process is initiated leading to subepidermal blistering. This cascade includes the generation of a proinflammatory milieu in the skin as well as extravasation and Fc gamma receptor-dependent activation of effector leukocytes. Inflammatory mediators, released by these cells, including reactive oxygen species and proteolytic enzymes, finally induce dermal-epidermal separation.

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References

  1. Elliott GT. Two cases of epidermolysis bullosa. J Cutan Genitourin Dis. 1895;13:10.

    Google Scholar 

  2. Buijsrogge JJ, Diercks GF, Pas HH, et al. The many faces of epidermolysis bullosa acquisita after serration pattern analysis by direct immunofluorescence microscopy. Br J Dermatol. 2011;165:92–8.

    Article  CAS  PubMed  Google Scholar 

  3. Woodley DT, Briggaman RA, O’Keefe EJ, et al. Identification of the skin basement-membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med. 1984;310:1007–13.

    Article  CAS  PubMed  Google Scholar 

  4. Woodley DT, Burgeson RE, Lunstrum G, et al. Epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen. J Clin Invest. 1988;81:683–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Gammon WR, Inman AO, Wheeler CEJ. Differences in complement-dependent chemotactic activity generated by bullous pemphigoid and epidermolysis bullosa acquisita immune complexes: demonstration by leukocytic attachment and organ culture methods. J Invest Dermatol. 1984;83:57–61.

    Article  CAS  PubMed  Google Scholar 

  6. Sitaru C, Kromminga A, Hashimoto T, et al. Autoantibodies to type VII collagen mediate Fcgamma-dependent neutrophil activation and induce dermal-epidermal separation in cryosections of human skin. Am J Pathol. 2002;161:301–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Recke A, Sitaru C, Vidarsson G, et al. Pathogenicity of IgG subclass autoantibodies to type VII collagen: induction of dermal-epidermal separation. J Autoimmun. 2010;34:435–44.

    Article  CAS  PubMed  Google Scholar 

  8. Kulkarni S, Sitaru C, Andersson KE, et al. Essential role for PI3Kβ[beta] in neutrophil activation by immune complexes. Sci Signal. 2011;4:ra23.

    Article  PubMed  Google Scholar 

  9. Sitaru C, Mihai S, Otto C, et al. Induction of dermal-epidermal separation in mice by passive transfer of antibodies specific to type VII collagen. J Clin Invest. 2005;115:870–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Woodley DT, Chang C, Saadat P, et al. Evidence that anti-type VII collagen antibodies are pathogenic and responsible for the clinical, histological, and immunological features of epidermolysis bullosa acquisita. J Invest Dermatol. 2005;124:958–64.

    Article  CAS  PubMed  Google Scholar 

  11. Sitaru C, Chiriac MT, Mihai S, et al. Induction of complement-fixing autoantibodies against type VII collagen results in subepidermal blistering in mice. J Immunol. 2006;177:3461–8.

    Article  CAS  PubMed  Google Scholar 

  12. Ludwig RJ, Recke A, Bieber K, et al. Generation of antibodies of distinct subclasses and specificity is linked to H2s in an active mouse model of epidermolysis bullosa acquisita. J Invest Dermatol. 2011;131:167–76.

    Article  CAS  PubMed  Google Scholar 

  13. Chen M, O’Toole EA, Sanghavi J, et al. The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with Crohn’s disease have autoantibodies to type VII collagen. J Invest Dermatol. 2002;118:1059–64.

    Article  CAS  PubMed  Google Scholar 

  14. Oostingh GJ, Sitaru C, Zillikens D, et al. Subclass distribution of type VII collagen-specific autoantibodies in patients with inflammatory bowel disease. J Dermatol Sci. 2005;37:182–4.

    Article  CAS  PubMed  Google Scholar 

  15. Licarete E, Ganz S, Recknagel M, et al. Prevalence of collagen VII-specific autoantibodies in patients with autoimmune and inflammatory diseases. BMC Immunol. 2012;13:16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649–53.

    Article  CAS  PubMed  Google Scholar 

  17. Komorowski L, Muller R, Vorobyev A, et al. Sensitive and specific assays for routine serological diagnosis of epidermolysis bullosa acquisita. J Am Acad Dermatol. 2012;68(3):e89–95.

    Article  PubMed  Google Scholar 

  18. Kim JH, Kim YH, Kim SC. Epidermolysis bullosa acquisita: a retrospective clinical analysis of 30 cases. Acta Derm Venereol. 2011;91:307–12.

    Article  CAS  PubMed  Google Scholar 

  19. Gammon WR, Heise ER, Burke WA, et al. Increased frequency of HLA-DR2 in patients with autoantibodies to epidermolysis bullosa acquisita antigen: evidence that the expression of autoimmunity to type VII collagen is HLA class II allele associated. J Invest Dermatol. 1988;91:228–32.

    Article  CAS  PubMed  Google Scholar 

  20. Zumelzu C, Le Roux-Villet C, Loiseau P, et al. Black patients of African descent and HLA-DRB1*15:03 frequency overrepresented in epidermolysis bullosa acquisita. J Invest Dermatol. 2011. doi:10.1038/jid.2011.231.

    PubMed  Google Scholar 

  21. Asghari F, Fitzner B, Holzhuter SA, et al. Identification of quantitative trait loci for murine autoimmune pancreatitis. J Med Genet. 2011;48:557–62.

    Article  PubMed  Google Scholar 

  22. Ludwig RJ, Muller S, Marques A, et al. Identification of quantitative trait loci in experimental epidermolysis bullosa acquisita. J Invest Dermatol. 2012;132:1409–15.

    Article  CAS  PubMed  Google Scholar 

  23. Muller R, Dahler C, Mobs C, et al. T and B cells target identical regions of the non-collagenous domain 1 of type VII collagen in epidermolysis bullosa acquisita. Clin Immunol. 2010;135:99–107.

    Article  PubMed  Google Scholar 

  24. Sitaru AG, Sesarman A, Mihai S, et al. T cells are required for the production of blister-inducing autoantibodies in experimental epidermolysis bullosa acquisita. J Immunol. 2010;184:1596–603.

    Article  CAS  PubMed  Google Scholar 

  25. Hammers CM, Bieber K, Kalies K, et al. Complement-fixing anti-type VII collagen antibodies are induced in Th1-polarized lymph nodes of epidermolysis bullosa acquisita-susceptible mice. J Immunol. 2011. doi:10.4049/jimmunol.1100796.

    PubMed  Google Scholar 

  26. Kasperkiewicz M, Müller R, Manz R, et al. Heat shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that non-malignant plasma cells are not therapeutic targets. Blood. 2011;117:6135–42.

    Article  CAS  PubMed  Google Scholar 

  27. Gandhi K, Chen M, Aasi S, et al. Autoantibodies to type VII collagen have heterogeneous subclass and light chain compositions and their complement-activating capacities do not correlate with the inflammatory clinical phenotype. J Clin Immunol. 2000;20:416–23.

    Article  CAS  PubMed  Google Scholar 

  28. Ishii N, Recke A, Mihai S, et al. Autoantibody-induced intestinal inflammation and weight loss in experimental epidermolysis bullosa acquisita. J Pathol. 2011;224:234–44.

    Article  CAS  PubMed  Google Scholar 

  29. Lohi J, Leivo I, Tani T, et al. Laminins, tenascin and type VII collagen in colorectal mucosa. Histochem J. 1996;28:431–40.

    Article  CAS  PubMed  Google Scholar 

  30. Leivo I, Tani T, Laitinen L, et al. Anchoring complex components laminin-5 and type VII collagen in intestine: association with migrating and differentiating enterocytes. J Histochem Cytochem. 1996;44:1267–77.

    Article  CAS  PubMed  Google Scholar 

  31. Wetzels RH, Robben HC, Leigh IM, et al. Distribution patterns of type VII collagen in normal and malignant human tissues. Am J Pathol. 1991;139:451–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Sesarman A, Sitaru AG, Olaru F, et al. Neonatal Fc receptor deficiency protects from tissue injury in experimental epidermolysis bullosa acquisita. J Mol Med (Berl). 2008;86:951–9.

    Article  CAS  Google Scholar 

  33. Kasperkiewicz M, Hirose M, Recke A, et al. Clearance rates of circulating and tissue-bound autoantibodies to type VII collagen in experimental epidermolysis bullosa acquisita. Br J Dermatol. 2010;162:1064–70.

    Article  CAS  PubMed  Google Scholar 

  34. Abrams ML, Smidt A, Benjamin L, et al. Congenital epidermolysis bullosa acquisita: vertical transfer of maternal autoantibody from mother to infant. Arch Dermatol. 2010;147(3):337–41.

    Article  PubMed  Google Scholar 

  35. Gammon WR, Murrell DF, Jenison MW, et al. Autoantibodies to type VII collagen recognize epitopes in a fibronectin-like region of the noncollagenous (NC1) domain. J Invest Dermatol. 1993;100:618–22.

    Article  CAS  PubMed  Google Scholar 

  36. Tanaka T, Furukawa F, Imamura S. Epitope mapping for epidermolysis bullosa acquisita autoantibody by molecularly cloned cDNA for type VII collagen. J Invest Dermatol. 1994;102:706–9.

    Article  CAS  PubMed  Google Scholar 

  37. Jones DA, Hunt SW, Prisayanh PS, et al. Immunodominant autoepitopes of type VII collagen are short, paired peptide sequences within the fibronectin type III homology region of the noncollagenous (NC1) domain. J Invest Dermatol. 1995;104:231–5.

    Article  CAS  PubMed  Google Scholar 

  38. Lapiere JC, Woodley DT, Parente MG, et al. Epitope mapping of type VII collagen. Identification of discrete peptide sequences recognized by sera from patients with acquired epidermolysis bullosa. J Clin Invest. 1993;92:1831–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Ishii N, Yoshida M, Hisamatsu Y, et al. Epidermolysis bullosa acquisita sera react with distinct epitopes on the NC1 and NC2 domains of type VII collagen: study using immunoblotting of domain-specific recombinant proteins and postembedding immunoelectron microscopy. Br J Dermatol. 2004;150:843–51.

    Article  CAS  PubMed  Google Scholar 

  40. Ishii N, Yoshida M, Ishida-Yamamoto A, et al. Some epidermolysis bullosa acquisita sera react with epitopes within the triple-helical collagenous domain as indicated by immunoelectron microscopy. Br J Dermatol. 2009;160:1090–3.

    Article  CAS  PubMed  Google Scholar 

  41. Schmidt E, Hopfner B, Chen M, et al. Childhood epidermolysis bullosa acquisita: a novel variant with reactivity to all three structural domains of type VII collagen. Br J Dermatol. 2002;147:592–7.

    Article  CAS  PubMed  Google Scholar 

  42. Ishii N, Hamada T, Dainichi T, et al. Epidermolysis bullosa acquisita: what’s new? J Dermatol. 2010;37:220–30.

    Article  PubMed  Google Scholar 

  43. Chen M, Doostan A, Bandyopadhyay P, et al. The cartilage matrix protein subdomain of type VII collagen is pathogenic for epidermolysis bullosa acquisita. Am J Pathol. 2007;170:2009–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Mihai S, Chiriac MT, Takahashi K, et al. The alternative pathway in complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita. J Immunol. 2007;178:6514–21.

    Article  CAS  PubMed  Google Scholar 

  45. Natsuga K, Nishie W, Shinkuma S, et al. Antibodies to pathogenic epitopes on type XVII collagen cause skin fragility in a complement-dependent and -independent manner. J Immunol. 2012;188(11):5792–9.

    Article  CAS  PubMed  Google Scholar 

  46. Liu Z, Sui W, Zhao M, et al. Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. J Autoimmun. 2008;31:331–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Ludwig RJ, Schmidt E. Cytokines in autoimmune bullous skin diseases. Epiphenomena or contribution to pathogenesis? G Ital Dermatol Venereol. 2009;144:339–49.

    CAS  PubMed  Google Scholar 

  48. Chiriac MT, Roesler J, Sindrilaru A, et al. NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage. J Pathol. 2007;212:56–65.

    Article  CAS  PubMed  Google Scholar 

  49. Liu Z, Zhao M, Li N, et al. Differential roles for beta2 integrins in experimental autoimmune bullous pemphigoid. Blood. 2006;107:1063–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Schon MP, Ludwig RJ. Lymphocyte trafficking to inflamed skin—molecular mechanisms and implications for therapeutic target molecules. Expert Opin Ther Targets. 2005;9:225–43.

    Article  PubMed  Google Scholar 

  51. Dahlman-Ghozlan K, Ortonne JP, Heilborn JD, et al. Altered tissue expression pattern of cell adhesion molecules, ICAM-1, E-selectin and VCAM-1, in bullous pemphigoid during methotrexate therapy. Exp Dermatol. 2004;13:65–9.

    Article  CAS  PubMed  Google Scholar 

  52. Zebrowska A, Sysa-Jedrzejowska A, Wagrowska-Danilewicz M, et al. Expression of selected integrins and selectins in bullous pemphigoid. Mediators Inflamm. 2007;2007:31051.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Woodley DT, Ram R, Doostan A, et al. Induction of epidermolysis bullosa acquisita in mice by passive transfer of autoantibodies from patients. J Invest Dermatol. 2006;126:1323–30.

    Article  CAS  PubMed  Google Scholar 

  54. Sesarman A, Mihai S, Chiriac MT, et al. Binding of avian IgY to type VII collagen does not activate complement and leukocytes fail to induce subepidermal blistering in mice. Br J Dermatol. 2008;158:463–71.

    Article  CAS  PubMed  Google Scholar 

  55. Kasperkiewicz M, Nimmerjahn F, Wende S, et al. Genetic identification and functional validation of FcγRIV as key molecule in autoantibody-induced tissue injury. J Pathol. 2012;228:8–19. PMID: 22430937.

    CAS  PubMed  Google Scholar 

  56. Zhao M, Trimbeger ME, Li N, et al. Role of FcRs in animal model of autoimmune bullous pemphigoid. J Immunol. 2006;177:3398–405.

    Article  CAS  PubMed  Google Scholar 

  57. Hellberg L, Samavedam UK, Holdorf K, et al. Methylprednisolone blocks autoantibody-induced tissue damage in experimental models of bullous pemphigoid and epidermolysis bullosa acquisita through inhibition of neutrophil activation. J Invest Dermatol. 2013;133(10):2390–9. doi: 10.1038/jid.2013.91.

  58. Shimanovich I, Mihai S, Oostingh GJ, et al. Granulocyte-derived elastase and gelatinase B are required for dermal-epidermal separation induced by autoantibodies from patients with epidermolysis bullosa acquisita and bullous pemphigoid. J Pathol. 2004;204:519–27.

    Article  CAS  PubMed  Google Scholar 

  59. Cowin AJ, Adams DH, Strudwick XL, et al. Flightless I deficiency enhances wound repair by increasing cell migration and proliferation. J Pathol. 2007;211:572–81.

    Article  CAS  PubMed  Google Scholar 

  60. Kopecki Z, Arkell RM, Strudwick XL, et al. Overexpression of the Flii gene increases dermal-epidermal blistering in an autoimmune ColVII mouse model of epidermolysis bullosa acquisita. J Pathol. 2011;225:401–13.

    Article  CAS  PubMed  Google Scholar 

  61. Leineweber S, Schonig S, Seeger K. Insight into interactions of the von-Willebrand-factor-A-like domain 2 with the FNIII-like domain 9 of collagen VII by NMR and SPR. FEBS Lett. 2011;585:1748–52.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, University of Lübeck, Lübeck, Germany

    Ralf J. Ludwig MD & Detlef Zillikens MD

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  1. Ralf J. Ludwig MD
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  2. Detlef Zillikens MD
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Correspondence to Ralf J. Ludwig MD .

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  1. Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia

    Dédée F. Murrell

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Ludwig, R.J., Zillikens, D. (2015). Pathogenesis of Epidermolysis Bullosa Acquisita. In: Murrell, D. (eds) Blistering Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-45698-9_12

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  • DOI: https://doi.org/10.1007/978-3-662-45698-9_12

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