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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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Research Article Immunology Article has an altmetric score of 13

Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases

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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 6

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Relationship among pathogenic IgG doses, IgG clearance rate, and disease...
Relationship among pathogenic IgG doses, IgG clearance rate, and disease activity in FcRn-deficient mice. (A and B) FcRn–/– mice were pretreated with IgM (6.47 mg/g body weight) or HDIG (1 mg/g body weight) and 2 hours later injected i.p. with different doses of anti-mBP180 R530, anti-Dsg1 (PF1), or anti-Dsg3 (PV1). The mice were examined 48 hours after pathogenic IgG injection. Serum anti-mBP180 IgG levels in mice pretreated with IgM (black bars) or HDIG (white bars) were quantified by ELISA. Disease activities in mice pretreated with IgM (dark gray bars) or HDIG (light gray bars) were scored by clinical examination. As expected, higher doses of anti-mBP180 IgG (A), anti-Dsg1 IgG (B), and anti-Dsg3 IgG (data not shown) caused higher levels of pathogenic IgG in circulation and more severe clinical diseases. There was no difference in IgG levels and disease severity between IgM- and HDIG-treated mice at each dose of pathogenic IgG. (C–E) WT and FcRn–/– mice were injected i.p. with different doses of pathogenic IgG, and serum pathogenic IgG levels were assayed by ELISA 48 hours later. 59.1%, 50.6%, and 35.3% decreases (decr.) in anti-mBP180 IgG levels were seen in FcRn–/– compared with WT mice at 25, 50, and 100 doses, respectively (C). Similarly, higher doses of anti-Dsg1 and anti-Dsg3 IgG led to lower rates of IgG degradation (D and E). n = 6.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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