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 a3 chain of type IV collagen (a3NC1) 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 a3NC1 developed no albuminuria and had lower levels of serum IgG anti-a3NC1 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-a3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.

Membranous glomerulonephropathy in a patient with bullous pemphigoid

“…Sonia et al speculated that several immunological mechanisms lie behind the two diseases, for example, circulating immune complexes of antibodies to BP that mediate secondary MN, such as lupus nephritis, immunological cross reactions to common epitopes in both cutaneous and renal basement membranes, such as Goodpasture's syndrome, and multisystem autoimmune triggering events that are associated with kidney disease [3]. Neonatal Fc receptor (FcRn) promotes the formation of sub-epithelial immune complexes [18], and when combined with IgG, it allows the passage of IgG through the renal basement membrane; this is thought to play a key role in transcytosis within many organs and to maintain IgG homeostasis in the circulation [19]. Neonatal Fc receptor is associated with glomerulonephritis as well as BP [18,20,21], and it has high affinity for IgG4 [22].…”

“…Neonatal Fc receptor (FcRn) promotes the formation of sub-epithelial immune complexes [18], and when combined with IgG, it allows the passage of IgG through the renal basement membrane; this is thought to play a key role in transcytosis within many organs and to maintain IgG homeostasis in the circulation [19]. Neonatal Fc receptor is associated with glomerulonephritis as well as BP [18,20,21], and it has high affinity for IgG4 [22]. Thus, we speculated that the IgG4 of anti-BP180 antibody bound to FcRn was associated with immune reactions of podocytes in glomeruli during the course of autoimmune triggering events of BP in our patient.…”

New approaches in renal microscopy

“…The resolution of STORM could also reveal the orientation of molecules in the GBM. Lastly, using genetic models, the source of molecules in the two sides of the GBM appeared to be distinct, with the podocyte side contributing to the surface of the GBM on that side and presumably, endothelial cells contributing to molecules on the other side [45–47]. …”

“…For kidney tissues, deep-etch freeze-fracture (DEFF) was used successfully. For DEFF, a platinum replica of the surface of the tissue slice is made and imaged by TEM [45–47]. It provides superb resolution, but is technically challenging and more expensive than other EM techniques.…”

Podocyte-specific knockout of the neonatal Fc receptor (FcRn) results in differential protection depending on the model of immune-mediated kidney disease

“…FcRn is globally knocked out of mice, immune-mediated kidney disease is attenuated. (27) However, it remains unclear whether lack of FcRn in dendritic cells, endothelial cells, or podocytes provides this protective effect. Knowledge of precisely in which cells FcRn is required for induction of immune-mediated kidney disease would allow for the development of targeted therapies.…”