Bacterial IgA protease-mediated degradation of agIgA1 and agIgA1 immune complexes as a potential therapy for IgA Nephropathy

Li Wang; Xueying Li; Hongchun Shen; Nan Mao; Honglian Wang; Luke Cui; Yuan Cheng; Junming Fan

doi:10.1038/srep30964

Bacterial IgA protease-mediated degradation of agIgA1 and agIgA1 immune complexes as a potential therapy for IgA Nephropathy

Sci Rep. 2016 Aug 3:6:30964. doi: 10.1038/srep30964.

Authors

Li Wang^{1

2}, Xueying Li³, Hongchun Shen⁴, Nan Mao⁵, Honglian Wang¹, Luke Cui⁶, Yuan Cheng⁷, Junming Fan^{2

3

8}

Affiliations

¹ 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.
² State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
³ Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
⁴ College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, 646000, China.
⁵ Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610041, China.
⁶ Department of Nephrology, The Third People's Hospital of Chengdu, Chengdu, Sichuan, 610041, China.
⁷ Department of Nephrology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518000, China.
⁸ Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Bacterial / metabolism*
Antigen-Antibody Complex / metabolism*
Bacterial Proteins / pharmacology*
Glomerulonephritis, IGA / drug therapy*
Glomerulonephritis, IGA / metabolism
Gram-Negative Aerobic Rods and Cocci / enzymology*
Humans
Immunoglobulin A / metabolism*
Male
Mice, Inbred BALB C
Peptide Hydrolases / pharmacology*

Substances

Antibodies, Bacterial
Antigen-Antibody Complex
Bacterial Proteins
Immunoglobulin A
Peptide Hydrolases