Immune abnormalities in IgA nephropathy

Abstract

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and it is characterized by mesangial IgA deposition. Asymptomatic hematuria with various degrees of proteinuria is the most common clinical presentation and up to 20%-40% of patients develop end-stage kidney disease within 20 years after disease onset. The pathogenesis of IgAN involves four sequential processes known as the "four-hit hypothesis" which starts with the production of a galactose-deficient IgA1 (gd-IgA1), followed by the formation of anti-gd-IgA1 IgG or IgA1 autoantibodies and immune complexes that ultimately deposit in the glomerular mesangium, leading to inflammation and injury. Although several key questions about the production of gd-IgA1 and the formation of anti-gd-IgA1 antibodies remain unanswered, a growing body of evidence is shedding light on the innate and adaptive immune mechanisms involved in this complex pathogenic process. Herein, we will focus on these mechanisms that, along with genetic and environmental factors, are thought to play a key role in disease pathogenesis.

Keywords: IgA nephropathy; adaptive immunity; galactose-deficient IgA1; innate immunity.

Graphical Abstract

Figure 1:

Representation of four hit hypothesis involved in the pathogenesis of IgA nephropathy.

Figure 2:

IgA forms and subclasses (A and B, modified from ‘Perše M, Večerić-Haler Ž. The role of IgA in the pathogenesis of IgA nephropathy. Int J Mol Sci 2019;20:6199’). Schematic representation of the nine serine and threonine residues in the hinge region that serve as potential O-glycosylations (up to six are O-glycosylated). Six different type of O-glycans can be found in the IgA1 HR. The residues highlighted in yellow are the frequent sites with galactose-deficient O-glycan (C).