A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis
| Autor: | Miao Wang, Zhao Cui, Xiao-yu Jia, Ming-Hui Zhao, Yue Shi, Qiu-hua Gu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Anti-Glomerular Basement Membrane Disease T cell 030232 urology & nephrology Peptide Autoantigens Rats Inbred WKY Epitope 03 medical and health sciences Type IV collagen 0302 clinical medicine Glomerulonephritis medicine Animals Autoantibodies chemistry.chemical_classification biology Chemistry Glomerular basement membrane General Medicine Molecular biology Complement system Rats Disease Models Animal 030104 developmental biology medicine.anatomical_structure Basic Research Nephrology biology.protein Female Kidney Diseases Kidney disorder Antibody Peptides |
| Zdroj: | J Am Soc Nephrol |
| Popis: | Background In 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. Methods We 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. Results The 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. Conclusions A 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. |
| Databáze: | OpenAIRE |
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