Renal deposition and clearance of recombinant poly-IgA complexes in a model of IgA nephropathy

Xinfang Xie, Pan Liu, Li Gao, Xue Zhang, Ping Lan, Vanesa Bijol, Jicheng Lv, Hong Zhang, Jing Jin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly-IgA mimic. Both uninduced rIgA (mono-rIgA) and polymeric SA-rIgA (poly-rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono-rIgA, this synthetic poly-rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long-lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly-rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer-lasting IgA deposition to cause renal damage.

Original languageEnglish (US)
Pages (from-to)159-172
Number of pages14
JournalJournal of Pathology
Volume254
Issue number2
DOIs
StatePublished - Jun 2021

Keywords

  • IgA Fc
  • IgA nephropathy
  • biotin-mediated oligomerization
  • glomerular mesangial deposition
  • recombinant probe

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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