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

Barbora Knoppova,R Glenn King,Bruce A Julian,Jan Novak,Colin Reily,Todd J Green

doi:10.3390/jcm10194501

Barbora Knoppova, R Glenn King + Show 4 more

Open Access

https://doi.org/10.3390/jcm10194501

Copy DOI

Abstract

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.

Highlights

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in many countries [1]
These Gd-IgA1 molecules are recognized by IgG autoantibodies, leading to formation of immune complexes in the blood. Some of these circulating immune complexes accumulate in the glomerular mesangium and activate resident mesangial cells to induce kidney injury. This proposed sequence is in agreement with the observations that serum levels of Gd-IgA1 and the corresponding autoantibodies each correlate with disease severity and progression [30,32,33,34]
IgAN is characterized by glomerular immunodeposits enriched for Gd-IgA1 glycoforms and for IgG autoantibodies with specificity for the IgA1 with galactose-deficient

Summary

Introduction

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in many countries [1]. We have postulated that IgAN is an autoimmune disease with a multi-hit mechanism [31] (Figure 1): Gd-IgA1 is produced in greater quantities in IgAN patients compared with that in healthy individuals whereby circulating Gd-IgA1 levels are elevated (hit #1) These Gd-IgA1 molecules are recognized by IgG autoantibodies (hit #2), leading to formation of immune complexes in the blood (hit #3). Some of these circulating immune complexes accumulate in the glomerular mesangium and activate resident mesangial cells to induce kidney injury (hit #4) This proposed sequence is in agreement with the observations that serum levels of Gd-IgA1 (autoantigen) and the corresponding autoantibodies each correlate with disease severity and progression [30,32,33,34]. For patients with ESKD who undergo transplantation, recurrent disease in the allograft is predicted by elevated Gd-IgA1 levels, supporting the hypothesis on the extra-renal origin of IgAN [24,37]

Structure

Other Types of Autoantibodies Targeting Aberrantly Glycosylated Proteins

IgA Nephropathy—Disease-Specific Treatment Approaches

Findings

Conclusions