A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis

Abstract

BackgroundIn Goodpasture disease, the noncollagenous domain 1 of the α3 chain (α3NC1) of type IV collagen is the main target antigen of antibodies against glomerular basement membrane (GBM). We previously identified a nephritogenic epitope, P14 (α3127–148), that could induce crescentic nephritis in WKY rats, and defined its core motif. Designing a modified peptide, replacing critical pathogenic residues with nonpathogenic ones (on the basis of homologous regions in α1NC1 chain of type IV collagen, known to be nonpathogenic), might provide a therapeutic option for anti-GBM GN.MethodsWe synthesized a modified peptide, replacing a single amino acid, and injected it into α3-P14–immunized rats from day 0 (the early-treatment group) or a later-treatment group (from days 17 to 21). A scrambled peptide administrated with the same protocol served as a control.ResultsThe modified peptide, but not the scrambled peptide, attenuated anti-GBM GN in both treatment groups, and halted further crescent formation even after disease onset. Kidneys from the modified peptide–treated rats exhibited reductions in IgG deposits, complement activation, and infiltration by T cells and macrophages. Treatment also resulted in an anti-inflammatory cytokine profile versus a proinflammatory profile for animals not receiving the modified peptide; it also reduced α3-P14–specific T cell activation, modulated T cell differentiation by decreasing Th17 cells and enhancing the ratio of Treg/Th17 cells, and inhibited binding of α3-P14 to antibodies and MHC II molecules.ConclusionsA modified peptide involving alteration of a critical motif in a nephritogenic T cell epitope alleviated anti-GBM GN in a rat model. Our findings may provide insights into an immunotherapeutic approach for autoimmune kidney disorders such as Goodpasture disease.

Regulatory role and mechanisms of myeloid TLR4 in anti-GBM glomerulonephritis

“…Anti-glomerular basement membrane glomerulonephritis (anti-GBM GN) is a severe form of kidney disease characterized by rapidly progressive renal insufficiency with widespread glomerular crescent formation. It is a stereotypic autoimmune glomerular disease with the pathogenic autoantibodies targeting the epitopes on the α3 chain of type IV collagen [1][2][3]. Immune cells including lymphocytes, macrophages and neutrophils, intrinsic renal cells and a complex cytokine network, as well as autoantibody deposition and complement activation are involved in the pathogenesis of anti-GBM GN [4][5][6].…”

Macrophage-derived macrophage migration inhibitory factor mediates renal injury in anti-glomerular basement membrane glomerulonephritis

“…A n t i -g l o m e r u l a r b a s e m e n t m e m b r a n e c r e s c e n t i c glomerulonephritis (anti-GBM CGN) is an autoimmune glomerular disease that progresses rapidly. It is characterized by glomerular crescentic formation and the presence of autoantibodies that target specific epitopes on the a3 chain of type IV collagen (1)(2)(3). The development of anti-GBM CGN involves different cellular components, such as macrophages, lymphocytes, intrinsic renal cells, and a complex network of cytokines (4,5).…”

B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-β-catenin pathway

“…Like other APC cells such as dendritic cells or macrophages, podocytes express MHC class II molecules [ 13 , 14 ] and importantly, the co-stimulatory molecule B7-1 [ 15 , 16 ], also known as CD80, to initiate T cell activation and inflammation [ 17 ]. Commonly, APC cells present antigens to T lymphocytes to trigger inflammation [ 18 – 20 ]. B7-1 plays an important role in this process [ 21 ].…”