Maiko Nakayama

Key Points: Serum IgM-free apoptosis inhibitor of macrophage reflects disease activity in human IgA nephropathy. Glomerular apoptosis inhibitor of macrophage deposition was colocalized with mesangial IgA and reflected the acute glomerular injuries by complement activation. Multivariate Cox regression analysis revealed serum IgM-free apoptosis inhibitor of macrophage as an independent predictor of hematuria remission in patients. Background: IgA nephropathy is characterized by mesangial deposits of IgA1-containing immune complex with complement 3. Our previous study demonstrated that apoptosis inhibitor of macrophage (AIM) plays a critical role in in situ IgA-containing immune complex formation and subsequent complement activation in murine IgA nephropathy. We further evaluated the clinicopathologic role of AIM in human IgA nephropathy. Methods: We enrolled 77 patients with IgA nephropathy, five patients with thin basement membrane disease as disease controls, and 40 age-matched healthy individuals as healthy controls. We analyzed the association between serum IgM-free AIM (sAIM)/glomerular AIM (gAIM) deposition area and clinicopathologic features. Results: sAIM level was higher in patients with IgA nephropathy at diagnosis than in disease and healthy controls (1.02±0.49 versus 0.56±0.19 versus 0.57±0.20 µ g/ml), significantly decreased to 0.67±0.44 µ g/ml after tonsillectomy and steroid pulse therapy, and was associated with serum IgA ( r ² =0.23) and IgA–IgG immune complex levels ( r ² =0.12). gAIM was colocalized with mesangial IgA and high intensity of gAIM was associated with the degree of hematuria (30–49 versus 10–19 per high-power field) and acute lesions, including those with Oxford classification scores of endocapillary hypercellularity (E1 3% versus E0 2%) and crescent formation (C1 3% versus C0 2%). Furthermore, gAIM deposition was positively correlated with glomerular complement 3 deposition ( r ² =0.54). Multivariate Cox regression analysis revealed sAIM as an independent predictor of hematuria remission (hazard ratio, 1.86; 95% confidence interval, 1.03 to 3.15). According to Kaplan–Meier analysis, patients with larger reduction of sAIM (≥0.45 µ g/ml) after tonsillectomy and steroid pulse therapy showed a significantly improved hematuria (6 versus 9 months). Conclusions: We suggest that IgA nephropathy patients with high sAIM levels have high disease activity and patients with high intensity of gAIM deposition have acute glomerular injuries leading to hematuria.

Aim: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, yet its pathogenesis remains incompletely understood. B cell activating factor (BAFF), a TNF family member involved in B cell activation and IgA class switching, has been proposed as a potential pathogenic factor in IgAN. However, its role in disease progression is unclear. This study aimed to investigate the pathological role of BAFF in IgAN using grouped ddY (gddY) mice, a spontaneous murine model of IgAN. Methods: gddY mice were treated with anti‐BAFF monoclonal antibody (anti‐BAFF Ab) or PBS via intraperitoneal injection twice a week for 4 weeks. Urinary albumin, serum immunoglobulins, and IgA‐IgG immune complex were measured pre‐ and post‐treatment. Serum levels of aberrantly glycosylated IgA were quantified using specific lectin‐based assays. Glomerular IgA and C3 depositions were evaluated by immunofluorescence, and B cell populations in spleen and bone marrow were analysed by flowcytometry. Results: Anti‐BAFF Ab treatment significantly reduced serum IgA, IgG, and IgM levels as compared with PBS treatment ( p < 0.001, p = 0.003, and p = 0.002, respectively). However, it did not affect serum aberrantly glycosylated IgA, IgA‐IgG immune complex, and urinary albumin excretion. Glomerular depositions of IgA and C3 as well as B cell population in the spleen and bone marrow were also not affected by anti‐BAFF Ab treatment. Conclusion: BAFF inhibition reduces general immunoglobulin levels but does not impact nephritogenic IgA production or disease progression in murine IgAN. These findings suggest that BAFF‐dependent IgA production may not be involved in the pathogenesis of IgAN.

Aim: Minimal change disease (MCD) is one of the causes of idiopathic nephrotic syndrome, and 40% of patients have allergic diseases. About 30% of MCD patients become resistant to steroid after a long period of steroid therapy; however, the mechanism of steroid resistance is unclear. Thymic stromal lymphopoietin (TSLP), an epithelial cytokine, is known to be associated with steroid‐resistant allergic disease. Experiments using mouse models of asthma suggest that TSLP‐mediated phosphorylation of signal transducer and activator of transcription 5 (STAT5) binds to corticosteroid receptors, resulting in steroid resistance. In the present study, we aim to investigate whether TSLP is involved in steroid resistance in patients with MCD. Methods: We compared serum TSLP levels in patients with MCD ( n = 26) and healthy controls ( n = 13). The cultured podocytes were used to investigate whether TSLP attenuates the podocyte‐protective effect of dexamethasone (DEX) and whether the administration of a TSLP‐neutralising antibody abolishes TSLP‐induced steroid resistance. Results: The level of serum TSLP in patients with MCD was significantly higher than that in healthy controls ( p < 0.05). Of note, in patients with MCD, serum TSLP levels significantly elevated at recurrence ( p < 0.05). In vitro, DEX protected podocytes from Adriamycin‐induced injury. The protective effect of DEX on podocytes was attenuated by co‐culture with TSLP ( p < 0.01). However, treatment with TSLP neutralising antibody improved TSLP‐induced steroid resistance ( p < 0.001). We also found that TSLP induces STAT5 activation in podocytes, which is blocked by TSLP‐neutralising antibodies. Conclusion: TSLP may be involved in steroid resistance via the STAT5 pathway in podocytes.

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.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including βII-spectrin. Most patients with IgAN also have serum anti–βII-spectrin IgA. As in patients with IgAN, IgA ⁺ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to βII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous βII-spectrin exposed on the surface of embryonic kidney–derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.

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.