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

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

doi:10.1038/srep30964

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.

Highlights

(C) Quantification of catalytic activities of different bacterial IgA protease by ELISA-based assay
We studied the functional role of bacterial IgA proteases in a pathological condition with a passive mouse model of IgAN in which a massive glomerular deposition of IgA1-IgG immune complexes has been described by Lamm[9]
We examined the therapeutic potential of the purified bacterial IgA protease from H. influnzae 49247 in the IgAN mouse model which was induced by intravenously administration of the agIgA1-IgG immune complexs as described above. 6 hours after the immune complexs injection, mice were further intravenously delivered various dosages of the IgA protease from H. influenzae 49247. 2 hours later, mice were sacrificed and frozen kidney sections were examined for immune complexs by immunofluorescence

Summary

Introduction

In a patient with severe HSPN (Henoch-Schonlein purpura nephritis), an autoimmune disorder that mimics IgAN, renal injury unexpectedly relieved after acquiring a IgA-deficiency secondary disease[6]. This observation suggests that the removal of IgA-containing immune complexes from the kidney may represent a novel therapy for IgAN. A pioneer work by Lamm and colleagues has shown that the bacteria-derived IgA protease can efficiently degrade the deposited IgA1-IgG immune complexes in a passive mouse model of IgAN9. We examined the therapeutic potential of a bacterial IgA protease from H. influenzae in a passive mouse model of IgAN

Methods

Results

Conclusion