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

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 1

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High-dose Ig inhibits experimental BP by accelerating degradation of pat...
High-dose Ig inhibits experimental BP by accelerating degradation of pathogenic anti-mBP180 IgG. Neonatal C57BL/6J mice were pretreated with buffer, IgM (12.93 mg/g body weight), or different doses of HDIG (0–2 mg/g body weight) and injected i.p. with pathogenic IgG (25 μg/g body weight) 2 hours later. The animals were examined 48 hours after pathogenic IgG injection. Control mice showed typical BP clinically (A) and histologically (B). In contrast, mice pretreated with HDIG were protected from BP, and the protective effect was dose dependent (C–F). (G) HDIG treatment resulted in significant reduction in clinical skin disease (bars 3–5) as compared with IgM (bar 1) and buffer controls (bar 2). (H) MPO assays revealed a significant reduction in neutrophil infiltration in mice treated with HDIG (bars 3–5) as compared with control mice (bars 1 and 2). (I) ELISA showed a similar pattern of reduction in circulating pathogenic IgG in mice treated with HDIG (bars 3–5) relative to controls (bars 1 and 2). n = 8 in each group. *P < 0.05; **P < 0.001. e, epidermis; d, dermis; v, vesicle. Arrow indicates site of pathogenic antibody binding.