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Archives of Dermatological Research

, Volume 308, Issue 1, pp 31–38 | Cite as

Immunoadsorber for specific apheresis of autoantibodies in the treatment of bullous pemphigoid

  • Michael MersmannEmail author
  • Jenny Dworschak
  • Kristin Ebermann
  • Lars Komorowski
  • Wolfgang Schlumberger
  • Winfried Stöcker
  • Detlef Zillikens
  • Christian Probst
  • Enno Schmidt
Original Paper

Abstract

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with autoantibodies against two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. As the pathogenic relevance of antibodies against the immunodominant NC16A domain of BP180 has been clearly demonstrated, specific removal of these antibodies should be a rational therapeutic approach. Here, we evaluated three recombinant forms of bacterially produced BP180 NC16A, a monomer, trimer, and tetramer, together with different matrices for their efficacy to specifically adsorb autoantibodies from BP plasma samples. An adsorber consisting of NC16A-trimer coupled to NHS-activated Sepharose 4 Fast Flow revealed satisfying adsorption rates and a high specificity. The NC16A-trimer adsorber was regenerable and autoclavable. It has the potential to be used for specific immunoadsorption to treat severe and refractory BP and other pemphigoid diseases associated with BP180 NC16A reactivity.

Keywords

BP180 Immunoadsorption Autoantibodies Bullous pemphigoid 

Notes

Acknowledgments

This work was supported by the European Regional Development Fund (project no. 122-09-017) and the Excellence Cluster Inflammation@Interfaces (DFG EXC306/1 and 2).

Compliance with ethical standards

Conflict of interest

MM, KE, LK, CP are employees, WS and WSch are board members of EUROIMMUN AG. ES and DZ have a scientific cooperation with EUROIMMUN.

References

  1. 1.
    Bertram F, Brocker EB, Zillikens D, Schmidt E (2009) Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany. J Dtsch Dermatol Ges 7:434–440PubMedGoogle Scholar
  2. 2.
    Borradori L, Sonnenberg A (1999) Structure and function of hemidesmosomes: more than simple adhesion complexes. J Invest Dermatol 112:411–418PubMedCrossRefGoogle Scholar
  3. 3.
    Christophoridis S, Budinger L, Borradori L, Hunziker T, Merk HF, Hertl M (2000) IgG, IgA and IgE autoantibodies against the ectodomain of BP180 in patients with bullous and cicatricial pemphigoid and linear IgA bullous dermatosis. Br J Dermatol 143:349–355PubMedCrossRefGoogle Scholar
  4. 4.
    Di Zenzo G, Thoma-Uszynski S, Fontao L, Calabresi V, Hofmann SC, Hellmark T, Sebbag N, Pedicelli C, Sera F, Lacour JP, Wieslander J, Bruckner-Tuderman L, Borradori L, Zambruno G, Hertl M (2008) Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid. Clin Immunol 128:415–426PubMedCrossRefGoogle Scholar
  5. 5.
    Diaz LA, Ratrie H III, Saunders WS, Futamura S, Squiquera HL, Anhalt GJ, Giudice GJ (1990) Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome. J Clin Invest 86:1088–1094PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Dopp R, Schmidt E, Chimanovitch I, Leverkus M, Brocker EB, Zillikens D (2000) IgG4 and IgE are the major immunoglobulins targeting the NC16A domain of BP180 in Bullous pemphigoid: serum levels of these immunoglobulins reflect disease activity. J Am Acad Dermatol 42:577–583PubMedGoogle Scholar
  7. 7.
    Eming R, Sticherling M, Hofmann SC, Hunzelmann N, Kern JS, Kramer H, Pfeiffer C, Schuster V, Zillikens D, Goebeler M et al (2015) S2 k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid. J Dtsch Dermatol Ges 13:833–844PubMedGoogle Scholar
  8. 8.
    Fairley JA, Burnett CT, Fu CL, Larson DL, Fleming MG, Giudice GJ (2007) A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice. J Invest Dermatol 127:2605–2611PubMedCrossRefGoogle Scholar
  9. 9.
    Giudice GJ, Emery DJ, Zelickson BD, Anhalt GJ, Liu Z, Diaz LA (1993) Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain. J Immunol 151:5742–5750PubMedGoogle Scholar
  10. 10.
    Herrero-Gonzalez JE, Brauns O, Egner R, Ronspeck W, Mascaro JM Jr, Jonkman MF, Zillikens D, Sitaru C (2006) Immunoadsorption against two distinct epitopes on human type XVII collagen abolishes dermal-epidermal separation induced in vitro by autoantibodies from pemphigoid gestationis patients. Eur J Immunol 36:1039–1048PubMedCrossRefGoogle Scholar
  11. 11.
    Hiepe F, Pfuller B, Wolbart K, Bruns A, Leinenbach HP, Hepper M, Schossler W, Otto V (1999) C1q: a multifunctional ligand for a new immunoadsorption treatment. Ther Apher 3:246–251PubMedCrossRefGoogle Scholar
  12. 12.
    Hirose M, Recke A, Beckmann T, Shimizu A, Ishiko A, Bieber K, Westermann J, Zillikens D, Schmidt E, Ludwig RJ (2011) Repetitive immunization breaks tolerance to type XVII collagen and leads to bullous pemphigoid in mice. J Immunol 187:1176–1183PubMedCrossRefGoogle Scholar
  13. 13.
    Hofmann S, Thoma-Uszynski S, Hunziker T, Bernard P, Koebnick C, Stauber A, Schuler G, Borradori L, Hertl M (2002) Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 119:1065–1073PubMedCrossRefGoogle Scholar
  14. 14.
    Iwata H, Kamio N, Aoyama Y, Yamamoto Y, Hirako Y, Owaribe K, Kitajima Y (2009) IgG from patients with bullous pemphigoid depletes cultured keratinocytes of the 180-kDa bullous pemphigoid antigen (type XVII collagen) and weakens cell attachment. J Invest Dermatol 129:919–926PubMedCrossRefGoogle Scholar
  15. 15.
    Iwata Y, Komura K, Kodera M, Usuda T, Yokoyama Y, Hara T, Muroi E, Ogawa F, Takenaka M, Sato S (2008) Correlation of IgE autoantibody to BP180 with a severe form of bullous pemphigoid. Arch Dermatol 144:41–48PubMedCrossRefGoogle Scholar
  16. 16.
    Joly P, Baricault S, Sparsa A, Bernard P, Bedane C, Duvert-Lehembre S, Courville P, Bravard P, Remond B, Doffoel-Hantz V, Benichou J (2012) Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 132:1998–2004PubMedCrossRefGoogle Scholar
  17. 17.
    Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, Vaillant L, D’Incan M, Plantin P, Bedane C, Young P, Bernard P (2002) A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 346:321–327PubMedCrossRefGoogle Scholar
  18. 18.
    Kadar JG, Borberg H (1990) Biocompatibility of extracorporeal immunoadsorption systems. Transfus Sci 11:223–239PubMedCrossRefGoogle Scholar
  19. 19.
    Kasperkiewicz M, Schulze F, Meier M, van Beek N, Nitschke M, Zillikens D, Schmidt E (2014) Treatment of bullous pemphigoid with adjuvant immunoadsorption: a case series. J Am Acad Dermatol 71:1018–1020PubMedCrossRefGoogle Scholar
  20. 20.
    Kromminga A, Scheckenbach C, Georgi M, Hagel C, Arndt R, Christophers E, Brocker EB, Zillikens D (2000) Patients with bullous pemphigoid and linear IgA disease show a dual IgA and IgG autoimmune response to BP180. J Autoimmun 15:293–300PubMedCrossRefGoogle Scholar
  21. 21.
    Kumlien G, Ullstrom L, Losvall A, Persson LG, Tyden G (2006) Clinical experience with a new apheresis filter that specifically depletes ABO blood group antibodies. Transfusion 46:1568–1575PubMedCrossRefGoogle Scholar
  22. 22.
    Labib RS, Anhalt GJ, Patel HP, Mutasim DF, Diaz LA (1986) Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting. J Immunol 136:1231–1235PubMedGoogle Scholar
  23. 23.
    Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J (2008) Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study. BMJ 337:a180PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Langenhan J, Dworschak J, Saschenbrecker S, Komorowski L, Schlumberger W, Stocker W, Westermann J, Recke A, Zillikens D, Schmidt E, Probst C (2014) Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins. Exp Dermatol 23:253–259PubMedCrossRefGoogle Scholar
  25. 25.
    Liu Z, Diaz LA, Troy JL, Taylor AF, Emery DJ, Fairley JA, Giudice GJ (1993) A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest 92:2480–2488PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Marazza G, Pham HC, Scharer L, Pedrazzetti PP, Hunziker T, Trueb RM, Hohl D, Itin P, Lautenschlager S, Naldi L, Borradori L (2009) Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study. Br J Dermatol 161:861–868PubMedCrossRefGoogle Scholar
  27. 27.
    Messingham KA, Noe MH, Chapman MA, Giudice GJ, Fairley JA (2009) A novel ELISA reveals high frequencies of BP180-specific IgE production in bullous pemphigoid. J Immunol Methods 346:18–25PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Messingham KN, Srikantha R, DeGueme AM, Fairley JA (2011) FcR-independent effects of IgE and IgG autoantibodies in bullous pemphigoid. J Immunol 187:553–560PubMedCrossRefGoogle Scholar
  29. 29.
    Meyersburg D, Schmidt E, Kasperkiewicz M, Zillikens D (2012) Immunoadsorption in dermatology. Ther Apher Dial 16:311–320PubMedCrossRefGoogle Scholar
  30. 30.
    Nishie W, Sawamura D, Goto M, Ito K, Shibaki A, McMillan JR, Sakai K, Nakamura H, Olasz E, Yancey KB, Akiyama M, Shimizu H (2007) Humanization of autoantigen. Nat Med 13:378–383PubMedCrossRefGoogle Scholar
  31. 31.
    Perriard J, Jaunin F, Favre B, Budinger L, Hertl M, Saurat JH, Borradori L (1999) IgG autoantibodies from bullous pemphigoid (BP) patients bind antigenic sites on both the extracellular and the intracellular domains of the BP antigen 180. J Invest Dermatol 112:141–147PubMedCrossRefGoogle Scholar
  32. 32.
    Ronspeck W, Brinckmann R, Egner R, Gebauer F, Winkler D, Jekow P, Wallukat G, Muller J, Kunze R (2003) Peptide based adsorbers for therapeutic immunoadsorption. Ther Apher Dial 7:91–97PubMedCrossRefGoogle Scholar
  33. 33.
    Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima B, Prudlo C, Pawelczyk B, Messmer EM, Schuhmann M, Sinkgraven R, Buchner L, Budinger L, Pfeiffer C, Sticherling M, Hertl M, Kaiser HW, Meurer M, Zillikens D, Messer G (2002) Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol 138:903–908PubMedCrossRefGoogle Scholar
  34. 34.
    Schmidt E, Obe K, Brocker EB, Zillikens D (2000) Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid. Arch Dermatol 136:174–178PubMedCrossRefGoogle Scholar
  35. 35.
    Schmidt E, Reimer S, Kruse N, Jainta S, Brocker EB, Marinkovich MP, Giudice GJ, Zillikens D (2000) Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes. J Invest Dermatol 115:842–848PubMedCrossRefGoogle Scholar
  36. 36.
    Schmidt E, Zillikens D (2010) Immunoadsorption in dermatology. Arch Dermatol Res 302:241–253PubMedCrossRefGoogle Scholar
  37. 37.
    Schmidt E, Zillikens D (2013) Pemphigoid diseases. Lancet 381:320–332PubMedCrossRefGoogle Scholar
  38. 38.
    Schmidt E, Zillikens D (2013) Immunoadsorption for autoimmune bullous disease. In: Braun N (Ed) Fundamentals and applications of immunoadsorption. Uni-Med, Bremen, 2nd edn, pp 46–56Google Scholar
  39. 39.
    Schulze FS, Beckmann T, Nimmerjahn F, Ishiko A, Collin M, Kohl J, Goletz S, Zillikens D, Ludwig R, Schmidt E (2014) Fcgamma receptors III and IV mediate tissue destruction in a novel adult mouse model of bullous pemphigoid. Am J Pathol 184:2185–2196PubMedCrossRefGoogle Scholar
  40. 40.
    Sitaru C, Dahnrich C, Probst C, Komorowski L, Blocker I, Schmidt E, Schlumberger W, Rose C, Stocker W, Zillikens D (2007) Enzyme-linked immunosorbent assay using multimers of the 16th non-collagenous domain of the BP180 antigen for sensitive and specific detection of pemphigoid autoantibodies. Exp Dermatol 16:770–777PubMedCrossRefGoogle Scholar
  41. 41.
    Sitaru C, Schmidt E, Petermann S, Munteanu LS, Brocker EB, Zillikens D (2002) Autoantibodies to bullous pemphigoid antigen 180 induce dermal-epidermal separation in cryosections of human skin. J Invest Dermatol 118:664–671PubMedCrossRefGoogle Scholar
  42. 42.
    Stanley JR, Hawley-Nelson P, Yuspa SH, Shevach EM, Katz SI (1981) Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell 24:897–903PubMedCrossRefGoogle Scholar
  43. 43.
    Ujiie H, Shibaki A, Nishie W, Sawamura D, Wang G, Tateishi Y, Li Q, Moriuchi R, Qiao H, Nakamura H, Akiyama M, Shimizu H (2010) A novel active mouse model for bullous pemphigoid targeting humanized pathogenic antigen. J Immunol 184:2166–2174PubMedCrossRefGoogle Scholar
  44. 44.
    Wallukat G, Muller J, Hetzer R (2002) Specific removal of beta1-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy. N Engl J Med 347:1806PubMedCrossRefGoogle Scholar
  45. 45.
    Zone JJ, Taylor T, Hull C, Schmidt L, Meyer L (2007) IgE basement membrane zone antibodies induce eosinophil infiltration and histological blisters in engrafted human skin on SCID mice. J Invest Dermatol 127:1167–1174PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Michael Mersmann
    • 1
    Email author
  • Jenny Dworschak
    • 2
  • Kristin Ebermann
    • 1
  • Lars Komorowski
    • 1
  • Wolfgang Schlumberger
    • 1
  • Winfried Stöcker
    • 1
  • Detlef Zillikens
    • 3
  • Christian Probst
    • 1
  • Enno Schmidt
    • 2
    • 3
  1. 1.Institute of Experimental ImmunologyLübeckGermany
  2. 2.Lübeck Institute of Experimental DermatologyUniversity of LübeckLübeckGermany
  3. 3.Department of DermatologyUniversity of LübeckLübeckGermany

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