title: Bacterial IgA protease-mediated degradation of agIgA1 and agIgA1 immune complexes as a potential therapy for IgA Nephropathy.
abstract: Mesangial deposition of aberrantly glycosylated IgA1 (agIgA1) and its immune complexes is a key pathogenic mechanism of IgA nephropathy (IgAN). However, treatment of IgAN remains ineffective. We report here that bacteria-derived IgA proteases are capable of degrading these pathogenic agIgA1 and derived immune complexes in vitro and in vivo. By screening 14 different bacterial strains (6 species), we found that 4 bacterial IgA proteases from H. influenzae, N. gonorrhoeae and N. meningitidis exhibited high cleaving activities on serum agIgA1 and artificial galactose-depleted IgA1 in vitro and the deposited agIgA1-containing immune complexes in the mesangium of renal biopsy from IgAN patients and in a passive mouse model of IgAN in vitro. In the modified mouse model of passive IgAN with abundant in situ mesangial deposition of the agIgA-IgG immune complexes, a single intravenous delivery of IgA protease from H. influenzae was able to effectively degrade the deposited agIgA-IgG immune complexes within the glomerulus, demonstrating a therapeutic potential for IgAN. In conclusion, the bacteria-derived IgA proteases are biologically active enzymes capable of cleaving the circulating agIgA and the deposited agIgA-IgG immune complexes within the kidney of IgAN. Thus, the use of such IgA proteases may represent a novel therapy for IgAN.
authors.affiliation: Laboratory of Organ Fibrosis Prophylaxis and Treatment by Combine Traditional Chinese and Western Medicine, Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.|State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Hongchun
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610041, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Mao
authors.affiliation: Laboratory of Organ Fibrosis Prophylaxis and Treatment by Combine Traditional Chinese and Western Medicine, Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Honglian
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nephrology, The Third People's Hospital of Chengdu, Chengdu, Sichuan, 610041, China.
authors.forename: Luke
authors.initials: L
authors.lastname: Cui
authors.affiliation: Department of Nephrology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518000, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.|Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.|Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
authors.forename: Junming
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000378:metabolism*; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D001426:Bacterial Proteins / Q000494:pharmacology*; D005922:Glomerulonephritis, IGA / Q000188:drug therapy* / Q000378:metabolism; D016946:Gram-Negative Aerobic Rods and Cocci / Q000201:enzymology*; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D010447:Peptide Hydrolases / Q000494:pharmacology*
chemical_list: D000907:Antibodies, Bacterial; D000936:Antigen-Antibody Complex; D001426:Bacterial Proteins; D007070:Immunoglobulin A; D010447:Peptide Hydrolases