Immune abnormalities in IgA nephropathy

Abstract

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 (ESKD) within 20 years after disease onset. The pathogenesis of IgAN involves four sequential processes known as the “four-hit hypothesis” that 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.

Protocol for a systematic review of the application of the kidney failure risk equation and Oxford classification in estimating prognosis in IgA nephropathy

“…Identifying individuals at the highest risk for progression to ESRD is challenging and the 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines highlighted risk stratification as a high priority for research in IgAN [ 5 ]. The understanding of the pathophysiology of IgAN is constantly evolving and there are multiple therapeutic trials ongoing to find novel agents to stabilise patients at the highest risk of progression to ESRD [ 6 , 7 ]. Previous therapeutic trials in IgAN have been limited by the recruitment of individuals at lower risk of progression to ESRD.…”

Efficacy and safety of biologic agents for IgA nephropathy: A protocol for systematic review and meta-analysis

“…Subsequently, they generate IgG autoantibodies targeting terminal N-acetylgalactosamine (GalNAc) residues, leading to the formation of IgG-Gd-IgA1 immune complexes primarily deposited in the mesangial region of glomeruli. This triggers complement molecule activation and initiates inflammatory responses, ultimately resulting in disease development [16][17][18][19][20]. Biologic agents targeting immune pathogenesis offer a novel therapeutic approach for controlling IgAN progression by depleting or regulating B cells, plasma cells, alternate or lectin pathways involved in Gd-IgA1 production [21][22][23][24][25][26].…”

Exploring the crosstalk molecular mechanisms between IgA nephropathy and Sjögren’s syndrome based on comprehensive bioinformatics and immunohistochemical analyses

“…Abnormal activation and in ammatory in ltration of lymphocytes (T and B cells) is one of the prominent pathological features of IgAN [3]. Recently, multiple evidence suggests that intestinal mucosal hyperresponsiveness is related to the activation of B cell subsets through upregulating the expression of serum B-cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL), thereby increasing the production of gd-IgA1 [3].…”

“…Exploring the crosstalk molecular mechanisms between IgA nephropathy and Sjögren's syndrome based on comprehensive bioinformatics and immunohistochemical analyses Introduction Immunoglobulin A (IgA) nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide and caused by the deposition of antibodies (IgA) in the glomerular mesangial region [1,2]. Although the pathogenesis is still not fully understood, there is su cient evidence to support the IgAN as an autoimmune disease, and a "four-hit hypothesis" (Hit 1, increased production and circulation of galactose-de cient [gd]-IgA1; Hit 2, antiglycan antibodies target gd-IgA1; Hit 3 and Hit 4, formation of immune complexes and mesangial deposition) has been proposed to explain the immune-related mechanism of IgAN [3,4]. Abnormal activation and in ammatory in ltration of lymphocytes (T and B cells) is one of the prominent pathological features of IgAN [3].…”

“…Although the pathogenesis is still not fully understood, there is su cient evidence to support the IgAN as an autoimmune disease, and a "four-hit hypothesis" (Hit 1, increased production and circulation of galactose-de cient [gd]-IgA1; Hit 2, antiglycan antibodies target gd-IgA1; Hit 3 and Hit 4, formation of immune complexes and mesangial deposition) has been proposed to explain the immune-related mechanism of IgAN [3,4]. Abnormal activation and in ammatory in ltration of lymphocytes (T and B cells) is one of the prominent pathological features of IgAN [3]. Recently, multiple evidence suggests that intestinal mucosal hyperresponsiveness is related to the activation of B cell subsets through upregulating the expression of serum B-cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL), thereby increasing the production of gd-IgA1 [3].…”