Journal of Molecular Medicine

, Volume 86, Issue 8, pp 951–959 | Cite as

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

  • Alina Sesarman
  • Ana Gabriela Sitaru
  • Florina Olaru
  • Detlef Zillikens
  • Cassian Sitaru
Original Article

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.

Keywords

Autoantibodies Epidermolysis bullosa acquisita Extracellular matrix Inflammation 

Abbreviations

EBA

epidermolysis bullosa acquisita

IF

immunofluorescence

Supplementary material

109_2008_366_Fig1_ESM.jpg (247 kb)
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)

References

  1. 1.
    Shlomchik MJ, Craft JE, Mamula MJ (2001) From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 1:147–153PubMedCrossRefGoogle Scholar
  2. 2.
    Janeway CA, Travers P, Walport M, Shlomchik M (2001) Immunobiology, 5th edn. Garland, New York, pp 360–361Google Scholar
  3. 3.
    Morand EF (2007) Effects of glucocorticoids on inflammation and arthritis. Curr Opin Rheumatol 19:302–307PubMedCrossRefGoogle Scholar
  4. 4.
    Ghetie V, Ward ES (2000) Multiple roles for the major histocompatibility complex class I- related receptor FcRn. Annu Rev Immunol 18:739–766PubMedCrossRefGoogle Scholar
  5. 5.
    Ghetie V, Ward ES (2002) Transcytosis and catabolism of antibody. Immunol Res 25:97–113PubMedCrossRefGoogle Scholar
  6. 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 26:690–696PubMedCrossRefGoogle Scholar
  7. 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 93:5512–5516PubMedCrossRefGoogle Scholar
  8. 8.
    Sitaru C, Zillikens D (2005) Mechanisms of blister induction by autoantibodies. Exp Dermatol 14:861–875PubMedCrossRefGoogle Scholar
  9. 9.
    Sitaru C (2007) Experimental models of epidermolysis bullosa acquisita. Exp Dermatol 16:520–531PubMedCrossRefGoogle Scholar
  10. 10.
    Mihai S, Sitaru C (2007) Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol Med 11:462–481PubMedCrossRefGoogle Scholar
  11. 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 161:301–311PubMedGoogle Scholar
  12. 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 115:870–878PubMedGoogle Scholar
  13. 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 126:1323–1330PubMedCrossRefGoogle Scholar
  14. 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 177:3461–3468PubMedGoogle Scholar
  15. 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 118:664–671PubMedCrossRefGoogle Scholar
  16. 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 178:6514–6521PubMedGoogle Scholar
  17. 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 212:56–65PubMedCrossRefGoogle Scholar
  18. 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 113:1328–1333PubMedGoogle Scholar
  19. 19.
    Nandakumar KS, Holmdahl R (2006) Antibody-induced arthritis: disease mechanisms and genes involved at the effector phase of arthritis. Arthritis Res Ther 8:223PubMedCrossRefGoogle Scholar
  20. 20.
    Lundy SK, Sarkar S, Tesmer LA, Fox DA (2007) Cells of the synovium in rheumatoid arthritis. T lymphocytes. Arthritis Res Ther 9:202PubMedCrossRefGoogle Scholar
  21. 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 18:1759–1769PubMedCrossRefGoogle Scholar
  22. 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 115:3440–3450PubMedCrossRefGoogle Scholar
  23. 23.
    Nimmerjahn F, Ravetch JV (2007) The anti-inflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 204:11–15PubMedCrossRefGoogle Scholar
  24. 24.
    Kaneko Y, Nimmerjahn F, Ravetch JV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673PubMedCrossRefGoogle Scholar
  25. 25.
    Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Alina Sesarman
    • 1
  • Ana Gabriela Sitaru
    • 2
  • Florina Olaru
    • 1
  • Detlef Zillikens
    • 1
  • Cassian Sitaru
    • 1
    • 3
  1. 1.Department of DermatologyUniversity of LübeckLübeckGermany
  2. 2.Institute for Medical Microbiology and HygieneUniversity of LübeckLübeckGermany
  3. 3.Department of DermatologyUniversity of FreiburgFreiburgGermany

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