Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy

Moldoveanu, Zina; Suzuki, Hitoshi; Reily, Colin; Satake, Kenji; Novak, Lea; Xu, Nuo; Huang, Zhiqiang; Knoppová, Barbora; Khan, Atlas; Hall, Stacy; Yanagawa, Hiroyuki; Brown, Raymond Albert Joseph; Winstead, Colleen J.; O'Quinn, Darrell; Weinmann, Amy S.; Gharavi, Ali G.; Kiryluk, Krzysztof; Julian, Bruce A.; Weaver, Casey T.; Suzuki, Yusuke; Novák, Jan

doi:10.1016/j.jaut.2021.102593

Cited by 32 publications

(34 citation statements)

References 67 publications

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“…The IgA and IgG co-localized in the glomeruli, indicating that these immunoglobulins comprised immune complexes [ 46 ]. These findings strengthen the postulated multi-hit mechanism for the development of IgAN and the central role of IgG autoantibodies in the process, as confirmed recently in an experimental animal model [ 47 ].…”

Section: Introductionsupporting

confidence: 88%

“…As noted above, glomerular immune deposits in patients with IgAN are enriched for Gd-IgA1 glycoforms. A recent study provided experimental in vivo evidence to underscore the pathogenic role of IgG autoantibodies specific for Gd-IgA1 [ 47 ]. Specifically, Gd-IgA1-IgG immune complexes injected into immunodeficient mice deposited in the glomerular mesangium, together with murine complement C3, and produced glomerular injury with histological features mimicking IgAN, such as mesangioproliferative changes.…”

Section: Deposition Of Circulating Immune Complexes and Renal Injury (Hit #4)mentioning

confidence: 99%

“…Transcriptome profiling of kidney tissues from mice injected with Gd-IgA1-rIgG immune complexes revealed changes concordant with findings in kidney biopsy tissue from IgAN patients. Pathway-enrichment analysis showed that immune complexes formed by Gd-IgA1 and recombinant IgG (rIgG) dysregulated expression of genes in the MAPK signaling, phagosome, complement, and coagulation pathways, as well as in cell adhesion molecules, transcriptional misregulation, PPAR and Rap1 signaling, leukocyte migration, and osteocyte differentiation [ 47 ].…”

Section: Deposition Of Circulating Immune Complexes and Renal Injury (Hit #4)mentioning

confidence: 99%

“…It remains to be determined if small molecules can be designed that disrupt formation of pathogenic immune complexes, but discovery of the structures of each IgG autoantibody and Gd-IgA1 affords the opportunity to perform in silico screening of ligand libraries [ 208 , 209 ] in hopes of identifying, at least virtually, compounds that target critical areas of antibody-antibody binding. Compounds fitting this criterion could be validated by ELISA-based tests and further assessed in vitro (e.g., with cultured human mesangial cells) and in vivo in a small-animal model of IgAN [ 47 ]. It remains to be seen if these concepts for generating disease-specific treatments can be successfully implemented.…”

Section: Iga Nephropathy—disease-specific Treatment Approachesmentioning

confidence: 99%

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Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Knoppová

Reily

King

et al. 2021

JCM

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IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

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Section: Introductionsupporting

confidence: 88%

Section: Deposition Of Circulating Immune Complexes and Renal Injury (Hit #4)mentioning

confidence: 99%

Section: Deposition Of Circulating Immune Complexes and Renal Injury (Hit #4)mentioning

confidence: 99%

Section: Iga Nephropathy—disease-specific Treatment Approachesmentioning

confidence: 99%

See 2 more Smart Citations

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Knoppová

Reily

King

et al. 2021

JCM

Self Cite

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“…Recently, experimental evidence of the pathogenic potential of these IgG autoantibodies came from experiments based on injections of pre-formed immune complexes consisting of human Gal-deficient IgA1 and human IgG autoantibodies into immunodeficient mice. 35 These immune complexes, but not Gal-deficient IgA1 or IgG autoantibodies alone, induced glomerular injury with histologic features mimicking IgAN, confirming pathogenic role of IgG autoantibodies specific for Gal-deficient IgA1.…”

Section: Jan Novakmentioning

confidence: 66%

Proceedings of 16th International Symposium on IgA Nephropathy

2021

Kidney Dis

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

Xie

Liu

Gao

et al. 2021

The Journal of Pathology

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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. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy

Cited by 32 publications

References 67 publications

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Proceedings of 16th International Symposium on IgA Nephropathy

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

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