Wei-Yi Guo1,2,3,4, Di Song1,2,3,4, Xiao-Rong Liu5, Zhi Chen6, Hui-Jie Xiao7, Jie Ding7, Shu-Zhen Sun8, Hong-Yan Liu9, Su-Xia Wang1,2,3,4, Feng Yu10,11,12,13,14, Ming-Hui Zhao1,2,3,4,15. 1. Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China. 2. Peking University Institute of Nephrology, Beijing, People's Republic of China. 3. Key laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China. 4. Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, 100034, People's Republic of China. 5. Department of Nephrology, Beijing Children's Hospital affiliated to Capital Medical University, Beijing, 100045, People's Republic of China. desin2000@sina.com. 6. Department of Nephrology, Beijing Children's Hospital affiliated to Capital Medical University, Beijing, 100045, People's Republic of China. 7. Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China. 8. Department of Pediatrics, Shandong Provincial Hospital affiliated with Shandong University, Jinan, People's Republic of China. 9. Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China. 10. Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China. yufengevert1@sina.com. 11. Peking University Institute of Nephrology, Beijing, People's Republic of China. yufengevert1@sina.com. 12. Key laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China. yufengevert1@sina.com. 13. Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, 100034, People's Republic of China. yufengevert1@sina.com. 14. Department of Nephrology, Peking University International Hospital, Beijing, 102206, People's Republic of China. yufengevert1@sina.com. 15. Peking-Tsinghua Center for Life Sciences, Beijing, People's Republic of China.
Abstract
OBJECTIVE: Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Anti-complement factor H (CFH) antibodies were thought to participate in the pathogenesis of aHUS. The aim of this study was to address the functions and properties of CFH autoantibodies in a Chinese Han cohort of aHUS patients. METHODS: Thirty-six anti-CFH antibody-positive aHUS patients at the acute phase of the disease were involved in this study. Clinical data of the patients were collected. Anti-CFH immunoglobulin G (IgG) subclasses and antibody isotypes were detected by ELISA. Epitope mapping was performed using recombinant CFH fragments (SCRs 1-4, SCR 7, SCRs 11-14, and SCRs 19-20). Purified IgG from plasma from seven patients were used for functional analyses. RESULTS: All patients presented with the classic triad of HUS. The anti-CFH autoantibodies mostly bound to the SCRs 19-20 domains of CFH but not the SCRs 1-4 domains. CFI cofactor activity was not disturbed by the anti-CFH antibody in any of the seven patients. Purified IgG interfered with the binding of CFH to C3b and CFH-mediated sheep erythrocyte protection in all seven patients. IgG from 4/5 (80%) patients tested inhibited the binding of CFH to glomerular endothelial cells. CONCLUSIONS: Our study suggests that the properties of CFH antibodies from patients with aHUS, including the recognition of SCRs and IgG subclasses, can influence and impair the biological role of CFH and therefore contribute to aHUS susceptibility.
OBJECTIVE:Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Anti-complement factor H (CFH) antibodies were thought to participate in the pathogenesis of aHUS. The aim of this study was to address the functions and properties of CFH autoantibodies in a Chinese Han cohort of aHUS patients. METHODS: Thirty-six anti-CFH antibody-positive aHUS patients at the acute phase of the disease were involved in this study. Clinical data of the patients were collected. Anti-CFH immunoglobulin G (IgG) subclasses and antibody isotypes were detected by ELISA. Epitope mapping was performed using recombinant CFH fragments (SCRs 1-4, SCR 7, SCRs 11-14, and SCRs 19-20). Purified IgG from plasma from seven patients were used for functional analyses. RESULTS: All patients presented with the classic triad of HUS. The anti-CFH autoantibodies mostly bound to the SCRs 19-20 domains of CFH but not the SCRs 1-4 domains. CFI cofactor activity was not disturbed by the anti-CFH antibody in any of the seven patients. Purified IgG interfered with the binding of CFH to C3b and CFH-mediated sheep erythrocyte protection in all seven patients. IgG from 4/5 (80%) patients tested inhibited the binding of CFH to glomerular endothelial cells. CONCLUSIONS: Our study suggests that the properties of CFH antibodies from patients with aHUS, including the recognition of SCRs and IgG subclasses, can influence and impair the biological role of CFH and therefore contribute to aHUS susceptibility.
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