Qiu-Hua Gu1,2,3,4, Megan Huynh5, Yue Shi1,2,3,4, Xiao-Yu Jia1,2,3,4, Jie-Jian Luo6, Tai-Jiao Jiang6,7, Zhao Cui8,2,3,4, Joshua D Ooi5, A Richard Kitching5,9,10, Ming-Hui Zhao1,2,3,4,11. 1. Renal Division, Peking University First Hospital, Beijing, PR China. 2. Institute of Nephrology, Peking University, Beijing, PR China. 3. Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China. 4. Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China. 5. Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia. 6. Key Laboratory of Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, PR China. 7. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, PR China. 8. Renal Division, Peking University First Hospital, Beijing, PR China cuizhao@bjmu.edu.cn. 9. Department of Nephrology, Monash Health, Clayton, Victoria, Australia. 10. Department of Paediatric Nephrology, Monash Health, Clayton, Victoria, Australia. 11. Peking-Tsinghua Center for Life Sciences, Beijing, PR China.
Abstract
BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3127-148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. METHODS: To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. RESULTS: On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3127-148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3127-148. B7 induced T cell activation from human α3127-148-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3135-145-immunized mice. CONCLUSIONS: Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.
BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3127-148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. METHODS: To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. RESULTS: On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3127-148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3127-148. B7 induced T cell activation from human α3127-148-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3135-145-immunized mice. CONCLUSIONS: Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.
Authors: Lindsay S Cairns; Richard G Phelps; Laura Bowie; Andrew M Hall; Walaa W M Saweirs; Andrew J Rees; Robert N Barker Journal: J Am Soc Nephrol Date: 2003-11 Impact factor: 10.121
Authors: Heather L E Lang; Helle Jacobsen; Shinji Ikemizu; Christina Andersson; Karl Harlos; Lars Madsen; Peter Hjorth; Leif Sondergaard; Arne Svejgaard; Kai Wucherpfennig; David I Stuart; John I Bell; E Yvonne Jones; Lars Fugger Journal: Nat Immunol Date: 2002-09-03 Impact factor: 25.606