Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases
Ning Li, … , Derry C. Roopenian, Zhi Liu
Ning Li, … , Derry C. Roopenian, Zhi Liu
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3440-3450. https://doi.org/10.1172/JCI24394.
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Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases

Abstract

Numerous mechanisms of action have been proposed for intravenous Ig (IVIG). In this study, we used IgG passive transfer murine models of bullous pemphigoid (BP), pemphigus foliaceus (PF), and pemphigus vulgaris (PV) to test the hypothesis that the effect of IVIG in autoantibody-mediated cutaneous bullous diseases is to accelerate the degradation of pathogenic IgG by saturation of the MHC-like Fc receptor neonatal Fc receptor (FcRn). BP, PF, and PV are organ-specific antibody-mediated diseases in which autoantibodies target the hemidesmosomal antigen BP180 and desmosomal antigens Dsg1 and Dsg3, respectively. Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce the BP, PF, and PV disease phenotypes, respectively. We found that FcRn-deficient mice were resistant to experimental BP, PF, and PV. Circulating levels of pathogenic IgG in FcRn-deficient mice were significantly reduced compared with those in WT mice. Administration of high-dose human IgG (HDIG) to WT mice also drastically reduced circulating pathogenic IgG levels and prevented blistering. In FcRn-deficient mice, no additional protective effect with HDIG was realized. These data demonstrate that the therapeutic efficacy of HDIG treatment in the pemphigus and pemphigoid models is dependent on FcRn. Thus, FcRn is a promising therapeutic target for treating such IgG-mediated autoimmune diseases.

Authors

Ning Li, Minglang Zhao, Julio Hilario-Vargas, Phillip Prisayanh, Simon Warren, Luis A. Diaz, Derry C. Roopenian, Zhi Liu

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Figure 5

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No further degradation of pathogenic IgG by HDIG in FcRn-deficient mice....
No further degradation of pathogenic IgG by HDIG in FcRn-deficient mice. WT and FcRn–/– mice were pretreated with buffer control, IgM control (6.47 mg/g body weight), or HDIG (1 mg/g body weight) and then injected i.p. with pathogenic anti-BP180 IgG (25 μg/g body weight), anti-Dsg1 IgG (PF1, 40 μg/g body weight), or anti-Dsg3 IgG (50 μg/g body weight). Pathogenic IgG levels in circulation at different time points after pathogenic IgG injection were quantified by ELISA. (A) BP model. Significantly higher levels of circulating anti-BP180 IgG were present in WT mice without HDIG treatment than WT mice with HDIG treatment at 12, 24, and 48 hours. In contrast to WT mice, FcRn-deficient mice with and without HDIG treatment showed similar levels of circulating anti-BP180 IgG. IgM pretreatment had no effect on the serum anti-mBP180 IgG levels at all time points examined (1.04 ± 0.11, 2.47 ± 0.34, 2.09 ± 0.32, and 2.16 ± 0.29 OD492nm reading units at 6, 12, 24, and 48 hours, respectively). (B) PF model. HDIG treatment resulted in significantly reduced levels of anti-Dsg1 IgG in WT mice but not in FcRn–/– mice 48 hours after injection as compared with control IgM-treated WT mice. (C) PV model. As in the PF model, HDIG caused a significant reduction in circulating anti-Dsg3 IgG levels in WT but not in FcRn–/– mice 48 hours after injection. These data show that increased degradation of pathogenic IgG is mainly dependent upon the FcRn-mediated pathway. n = 6. *P < 0.05; **P < 0.001.