IgA Nephropathy: Significance of IgA1-Containing Immune Complexes in Clinical Settings

Abstract

IgA nephropathy (IgAN) is considered to be an autoimmune disease characterized by the formation of IgA1-containing immune complexes in the circulation and glomerular immunodeposits. Extensive research has identified multiple genetic, immunological, and environmental factors contributing to disease development and progression. The pathogenesis of IgAN is considered a multifactorial process involving the formation of immune complexes wherein aberrantly O-glycosylated IgA1 is recognized as an autoantigen. Consequently, the clinical presentation of IgAN is highly variable, with a wide spectrum of manifestations ranging from isolated microscopic hematuria or episodic macroscopic hematuria to nephrotic-range proteinuria. Whereas some patients may exhibit a slowly progressive form of IgAN, others may present with a rapidly progressive glomerulonephritis leading to kidney failure. Development of the treatment for IgAN requires an understanding of the characteristics of the pathogenic IgA1-containing immune complexes that enter the glomerular mesangium and induce kidney injury. However, not all details of the mechanisms involved in the production of galactose-deficient IgA1 and immune-complex formation are fully understood. Here, we review what we have learned about the characteristics of nephritogenic IgA1 in the half-century since the first description of IgAN in 1968.

Keywords: IgA nephropathy; biomarker; galactose-deficient IgA1; immune complexes.

Figure 1

Mechanisms contributing to the production of Gd-IgA1 and the formation of pathogenic immune complexes. Mucosal immune dysregulation in NALT and/or GALT is thought to be involved in the production of Gd-IgA1. TLR9 and TLR7 play a crucial role in the overproduction of Gd-IgA1 via plasma-cell differentiation that results in secretion of Gd-IgA1 or autoantibodies specific for Gd-IgA1 that drive the formation of Gd-IgA1-containing immune complexes. Some of these complexes deposit in the glomeruli, activate mesangial cells, and induce kidney injury through complement activation. The Gd-IgA1-driven multi-hit process is considered the most likely mechanism for the pathogenesis of IgAN. LIF; leukemia inhibitory factor, OSM; oncostatin, AIM; apoptosis inhibitor of macrophages. CBX; chromobox homolog.