Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.
Antibodies, Autoantibodies, Autoantigens, Autoimmune-Diseases, Desmoglein-1, Desmoglein-3, Dose-Response-Relationship-Drug, Enzyme-Linked-Immunosorbent-Assay, Histocompatibility-Antigens-Class-I, Humans, Immunoglobulin-G, Immunoglobulins-Intravenous, Immunotherapy, Mice-Inbred-C57BL, Neutrophils, Pemphigoid-Bullous, Pemphigus, Phenotype, Receptors-Fc, Research-Support-N, I, H, -Extramural, Research-Support-Non-U, S, -Gov't
J Clin Invest 2005 Dec; 115(12):3440-50.
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.
Li, N; Zhao, M; Hilario, Vargas J.; Prisayanh, P; Warren, S; Diaz, L A.; Roopenian, D C.; and Liu, Z, "Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases." (2005). Faculty Research 2000 - 2009. 1159.