The mucosal immune system, via a dynamic immune network, serves as the first line of defense against exogenous antigens. Mucosal immune system dysregulation is closely associated with the pathogenesis of immunoglobulin A nephropathy (IgAN), as illustrated by IgAN having the clinical feature of gross hematuria, often concurrent with mucosal infections. Notably, previous studies have demonstrated the efficacy of tonsillectomy and found that a targeted-release formulation of budesonide reduced proteinuria in patients with IgAN. However, it remains unclear how exogenous antigens interact with the mucosal immune system to induce or exacerbate IgAN. Thus, in this review, we focus on the dysregulation of mucosal immune response in the pathogenesis of IgAN.

In patients with IgA nephropathy (IgAN), circulatory IgA1 and IgA1 in the mesangial deposits contain galactose-deficient IgA1 (Gd-IgA1). Some of the Gd-IgA1 from the glomerular deposits is excreted in the urine and thus urinary Gd-IgA1 may represent a disease-specific marker. We recruited 338 Japanese biopsy-proven IgAN patients and 120 patients with other renal diseases (disease controls). Urine samples collected at the time of renal biopsy were used to measure Gd-IgA1 levels using a specific monoclonal antibody (KM55 mAb). Urinary Gd-IgA1 levels were significantly higher in patients with IgAN than in disease controls. Moreover, urinary Gd-IgA1 was significantly correlated with the severity of the histopathological parameters in IgAN patients. Next, we validated the use of urinary Gd-IgA1 levels in the other Asian cohorts. In the Korean cohort, urinary Gd-IgA1 levels were also higher in patients with IgAN than in disease controls. Even in Japanese patients with IgAN and trace proteinuria (less than 0.3 g/gCr), urinary Gd-IgA1 was detected. Thus, urinary Gd-IgA1 may be an early disease-specific biomarker useful for determining the disease activity of IgAN.

Glomerulonephritis (GN) is a group of heterogeneous immune-mediated kidney diseases that causes inflammation within the glomerulus. Autoantibodies (auto-Abs) are considered to be central effectors in the pathogenesis of several types of GN. Immunoglobulin A nephropathy (IgAN) is the most common GN worldwide and is characterized by the deposition of IgA in the glomerular mesangium of the kidneys, which is thought to be mediated by immune complexes containing non-specific IgA. However, we recently reported that IgA auto-Abs specific to mesangial cells (anti-mesangium IgA) were found in the sera of gddY mice, a spontaneous IgAN model, and patients with IgAN. We identified two autoantigens (β2-spectrin and CBX3) that are selectively expressed on the mesangial cell surface and targeted by anti-mesangial IgA. Our findings redefined IgAN as a tissue-specific autoimmune disease. Regarding the mechanisms of production of anti-mesangium IgA, studies using gddY mice have revealed that the production of anti-CBX3 IgA is induced by particular strains of commensal bacteria in the oral cavity, possibly through their molecular mimicry to CBX3. Here, we discuss a new concept of IgAN pathogenesis from the perspective of this disease as autoimmune GN caused by tissue-specific auto-Abs.

In IgA nephropathy (IgAN), the mechanism of IgA-containing immune complexes deposition in the glomerular mesangium had been unclear. We recently reported the presence of IgA antibodies with specificity for mesangial cells (antimesangium IgA antibodies) in sera from patients with IgAN, and identified β2-spectrin (SPTBN1) and CBX3 as target antigens. However, the role of antimesangium IgA antibodies in human IgAN is unclear. We measured serum anti-SPTBN1 and anti-CBX3 IgA levels in patients with IgAN (n = 119) and other kidney diseases (disease control [DC], n = 51) using 2 independent cohorts, 1 from Japan and 1 from the UK. The study also assessed the surface expression of the autoantigens on human mesangial cells and the pattern of O-glycosylation of serum anti-SPTBN1 and anti-CBX3 IgA antibodies. Overall, 30 and 3 patients with IgAN and DC, respectively, had detectable anti-SPTBN1 IgA antibodies (sensitivity, 25%; specificity, 94%); whereas 48 and 3 patients with IgAN and DC, respectively, had detectable anti-CBX3 IgA antibodies (sensitivity, 40%; specificity, 94%). In total, 62 patients (52%) with IgAN had detectable anti-SPTBN1 and/or anti-CBX3 IgA antibodies. The expression of SPTBN1 and CBX3 on the surface of human mesangial cells was confirmed by immunofluorescence (IF) microscopy. Serum anti-SPTBN1 and anti-CBX3 IgA antibodies from patients with IgAN were recognized by an antigalactose-deficient IgA1 antibody (KM55) by Western blotting. We show that anti-SPTBN1 and anti-CBX3 IgA antibodies are detected with high specificity in patients with IgAN from Japan and the UK, and are enriched for IgA1 with poorly galactosylated O-glycoforms.

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide; however, the underlying mechanisms of this disease are not fully understood. This review explores several animal models that provide insights into IgAN pathogenesis, emphasizing the roles of aberrant IgA1 glycosylation and immune complex formation. It discusses spontaneous, immunization, and transgenic models illustrating unique aspects of IgAN development and progression. The animal models, represented by the grouped ddY (gddY) mouse, have provided guidance concerning the multi-hit pathogenesis of IgAN. In this paradigm, genetic and environmental factors, including the dysregulation of the mucosal immune system, lead to increased levels of aberrantly glycosylated IgA, nephritogenic immune complex formation, and subsequent glomerular deposition, followed by mesangial cell activation and injury. Additionally, this review considers the implications of clinical trials targeting molecular pathways influenced by IgAN (e.g., a proliferation-inducing ligand [APRIL]). Collectively, these animal models have expanded the understanding of IgAN pathogenesis while facilitating the development of therapeutic strategies that are currently under clinical investigation. Animal-model-based studies have the potential to facilitate the development of targeted therapies with reduced side effects for IgAN patients.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, and galactose-deficient IgA1 (Gd-IgA1) is widely recognized as the central pathogenic molecule in the current multi-hit model of IgAN. Over the past few decades, advances in our understanding of IgAN pathogenesis have driven the development of mechanism-based therapies targeting Gd-IgA1-producing cells and the pathways that regulate their differentiation and survival. Recent clinical trials have demonstrated marked reductions in circulating Gd-IgA1, accompanied by significant improvements in proteinuria and preservation of kidney function, highlighting the transition from non-specific disease-modifying therapies toward mechanism-based therapies in IgAN. However, optimizing the use of these emerging therapies requires a deeper understanding of the immune mechanisms responsible for pathogenic Gd-IgA1 production. In this review, we summarize current knowledge regarding the cellular sources and molecular pathways responsible for the production of Gd-IgA1, review recent advances in therapies targeting these cells, and discuss the emerging concept that specific Gd-IgA1 fractions, including IgA-type anti-mesangial cell autoantibodies (IgA-MESCA), may contribute to the disease pathogenesis.