title: Neonatal Fc receptor promotes immune complex-mediated glomerular disease.
abstract: The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex-mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the α3 chain of type IV collagen (α3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with α3NC1 developed no albuminuria and had lower levels of serum IgG anti-α3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex-mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-α3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Florina
authors.initials: F
authors.lastname: Olaru
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Wentian
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Pathology and Immunology, and.
authors.forename: Hani
authors.initials: H
authors.lastname: Suleiman
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Patricia L
authors.initials: PL
authors.lastname: St John
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Linna
authors.initials: L
authors.lastname: Ge
authors.affiliation: Biogen Idec Hemophilia, Waltham, Massachusetts; and.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Mezo
authors.affiliation: Department of Pathology and Immunology, and.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Dale R
authors.initials: DR
authors.lastname: Abrahamson
authors.affiliation: Renal Division, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee dborza@mmc.edu dbborza@gmail.com.
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000378:metabolism; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000009:adverse effects / Q000502:physiology*; D001324:Autoantigens / Q000502:physiology; D024141:Collagen Type IV / Q000502:physiology; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011961:Receptors, Fc / Q000502:physiology*
chemical_list: D000936:Antigen-Antibody Complex; D001324:Autoantigens; D024141:Collagen Type IV; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C057112:type IV collagen alpha3 chain; C100688:Fc receptor, neonatal