Skip to main content

Advertisement

Springer Nature Link
Log in

Neonatal Fc receptor deficiency protects from tissue injury in experimental epidermolysis bullosa acquisita

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease caused by autoantibodies against type VII collagen. The neonatal Fc receptor (FcRn) regulates immunoglobulin G (IgG) homeostasis and thus controls serum levels of antibodies. In this study, we investigated the effects of FcRn deficiency on the levels of autoantibodies against type VII collagen and blistering in EBA. For this purpose, rabbit IgG against murine type VII collagen was injected into FcRn-deficient and wild-type (n = 10 per group) mice. Enzyme-linked immunosorbent assay levels of serum IgG against type VII collagen were significantly lower in mutant compared with wild-type mice. Analysis of serum levels of specific autoantibodies induced in FcRn-deficient and wild-type mice (n = 10 per group) by immunization with type VII collagen showed significantly lower serum levels of IgG against type VII collagen in FcRn-deficient mice compared with wild-type animals. Importantly, the extent of blistering disease after injection of IgG against type VII collagen was significantly reduced in FcRn-deficient mice compared to wild-type controls. Our data demonstrate that FcRn maintains levels of pathogenic autoantibodies and thereby promotes tissue injury in experimental EBA. Therefore, modulation of FcRn function using inhibitors may reduce pathogenic IgG levels, offering therapeutic benefit in patients with antibody-mediated diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

EBA:

epidermolysis bullosa acquisita

IF:

immunofluorescence

References

  1. Shlomchik MJ, Craft JE, Mamula MJ (2001) From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 1:147–153

    Article  PubMed  CAS  Google Scholar 

  2. Janeway CA, Travers P, Walport M, Shlomchik M (2001) Immunobiology, 5th edn. Garland, New York, pp 360–361

    Google Scholar 

  3. Morand EF (2007) Effects of glucocorticoids on inflammation and arthritis. Curr Opin Rheumatol 19:302–307

    Article  PubMed  CAS  Google Scholar 

  4. Ghetie V, Ward ES (2000) Multiple roles for the major histocompatibility complex class I- related receptor FcRn. Annu Rev Immunol 18:739–766

    Article  PubMed  CAS  Google Scholar 

  5. Ghetie V, Ward ES (2002) Transcytosis and catabolism of antibody. Immunol Res 25:97–113

    Article  PubMed  CAS  Google Scholar 

  6. Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES (1996) Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice. Eur J Immunol 26:690–696

    Article  PubMed  CAS  Google Scholar 

  7. Junghans RP, Anderson CL (1996) The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci USA 93:5512–5516

    Article  PubMed  CAS  Google Scholar 

  8. Sitaru C, Zillikens D (2005) Mechanisms of blister induction by autoantibodies. Exp Dermatol 14:861–875

    Article  PubMed  CAS  Google Scholar 

  9. Sitaru C (2007) Experimental models of epidermolysis bullosa acquisita. Exp Dermatol 16:520–531

    Article  PubMed  CAS  Google Scholar 

  10. Mihai S, Sitaru C (2007) Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol Med 11:462–481

    Article  PubMed  CAS  Google Scholar 

  11. Sitaru C, Kromminga A, Hashimoto T, Bröcker EB, Zillikens D (2002) Autoantibodies to type VII collagen mediate Fc gamma-dependent granulocyte activation and induce dermal-epidermal separation in cryosections of human skin. Am J Pathol 161:301–311

    PubMed  CAS  Google Scholar 

  12. Sitaru C, Mihai S, Otto C et al (2005) Induction of dermal–epidermal separation in mice by passive transfer of antibodies to type VII collagen. J Clin Invest 115:870–878

    PubMed  CAS  Google Scholar 

  13. Woodley DT, Ram R, Doostan A et al (2006) Induction of epidermolysis bullosa acquisita in mice by passive transfer of autoantibodies from patients. J Invest Dermatol 126:1323–1330

    Article  PubMed  CAS  Google Scholar 

  14. Sitaru C, Chiriac MT, Mihai S, Büning J, Gebert A, Ishiko A, Zillikens D (2006) Induction of complement-fixing autoantibodies against type VII collagen results in subepidermal blistering in mice. J Immunol 177:3461–3468

    PubMed  CAS  Google Scholar 

  15. Sitaru C, Schmidt E, Petermann S, Munteanu SL, Bröcker EB, Zillikens D (2002) Autoantibodies to bullous pemphigoid antigen 180 induce dermal-epidermal separation in cryosections of human skin. J Invest Dermatol 118:664–671

    Article  PubMed  CAS  Google Scholar 

  16. Mihai S, Chiriac MT, Takahashi K, Thurman JM, Holers VM, Zillikens D, Botto M, Sitaru C (2007) The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita. J Immunol 178:6514–6521

    PubMed  CAS  Google Scholar 

  17. Chiriac MT, Roesler J, Sindrilaru A, Scharffetter-Kochanek K, Zillikens D, Sitaru C (2007) NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage. J Pathol 212:56–65

    Article  PubMed  CAS  Google Scholar 

  18. Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D (2004) The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest 113:1328–1333

    PubMed  CAS  Google Scholar 

  19. Nandakumar KS, Holmdahl R (2006) Antibody-induced arthritis: disease mechanisms and genes involved at the effector phase of arthritis. Arthritis Res Ther 8:223

    Article  PubMed  Google Scholar 

  20. Lundy SK, Sarkar S, Tesmer LA, Fox DA (2007) Cells of the synovium in rheumatoid arthritis. T lymphocytes. Arthritis Res Ther 9:202

    Article  PubMed  Google Scholar 

  21. Petkova SB, Akilesh S, Sproule TJ, Christianson GJ, Al Khabbaz H, Brown AC, Presta LG, Meng YG, Roopenian DC (2006) Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 18:1759–1769

    Article  PubMed  CAS  Google Scholar 

  22. Li N, Zhao M, Hilario-Vargas J, Prisayanh P, Warren S, Diaz LA, Roopenian DC, Liu Z (2005) Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest 115:3440–3450

    Article  PubMed  CAS  Google Scholar 

  23. Nimmerjahn F, Ravetch JV (2007) The anti-inflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 204:11–15

    Article  PubMed  CAS  Google Scholar 

  24. Kaneko Y, Nimmerjahn F, Ravetch JV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673

    Article  PubMed  CAS  Google Scholar 

  25. Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the focus program “Autoimmunity” of the Medical Faculty of the University of Lübeck (project B1, to CS).

Conflict of interest statement

No conflict of interest has been declared.

Author information

Authors and Affiliations

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

    Alina Sesarman, Florina Olaru, Detlef Zillikens & Cassian Sitaru

  2. Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany

    Ana Gabriela Sitaru

  3. Department of Dermatology, University of Freiburg, Hauptstrasse 7, 79104, Freiburg, Germany

    Cassian Sitaru

Authors
  1. Alina Sesarman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Gabriela Sitaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florina Olaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Detlef Zillikens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cassian Sitaru
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cassian Sitaru.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1

Recombinant His-mCVII. Equimolar amounts of GST (lane 1), GST-mCVIIc (lane 2), DHFR-His-BP180 (lane 3), and His-mCVIIc (lane 4) were separated by 15% SDS-PAGE and stained with Coomassie blue. Immunoblot analysis with an antibody raised against murine type VII collagen, preadsorbed against GST, does not reveal reactivity against GST (lane 5) or DHFR-His-BP180 (lane 7) but detects binding to GST-mCVIIc (lane 6) and His-mCVIIc (lane 8). An RGS-His antibody (Qiagen) does not bind to GST (lane 9) and GST-mCVIIc (lane 10) but recognizes DHFR-His-BP180 (lane 11) and His-mCVIIc (lane 12) by immunoblot analysis (JPG 252 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sesarman, A., Sitaru, A.G., Olaru, F. et al. Neonatal Fc receptor deficiency protects from tissue injury in experimental epidermolysis bullosa acquisita. J Mol Med 86, 951–959 (2008). https://doi.org/10.1007/s00109-008-0366-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-008-0366-7

Keywords

Search

Navigation