Pathogenesis Of IgA Nephropathy Research Articles

Exploring the mediating role of immune cells in the pathogenesis of IgA nephropathy through the inflammatory axis of gut microbiota from a genomic perspective.

IgA nephropathy (IgAN) is a chronic glomerular disease characterized by the deposition of IgA antibodies in the kidney's mesangium. Its pathogenesis involves genetic, immune, and environmental factors, particularly within the mucosal immune system and gut microbiota. Immune cells play a central role in mediating these processes, which this study investigates using Mendelian Randomization (MR) to explore causal relationships among gut microbiota, inflammatory markers, blood cells, and immune cells in IgAN pathogenesis. We conducted a two-sample MR analysis using Genome-Wide Association Study (GWAS) summary data to assess the causal effects of gut microbiota, inflammatory markers, and blood cell traits on IgAN. Data sources included the FinnGen dataset for IgAN and relevant GWAS datasets for immune traits, blood cells, and inflammatory markers. Inverse variance weighting (IVW) was the primary MR method, supported by sensitivity analyses. We particularly examined the mediation effect of immune cells on these exposures' influence on IgAN. Significant associations were found between several factors and IgAN. Gut microbiota traits, such as Firmicutes E and Sporomusales, increased IgAN risk, while Citrobacter A and Herbinix reduced it. Inflammatory markers, including Interleukin-10 and Fibroblast Growth Factor 23, promoted IgAN onset. Blood cell traits like red blood cell perturbation response increased risk, while monocyte perturbation response was protective. Immune traits played a key mediating role, with Transitional %B cells reducing IgAN risk and CD28- CD25 + + CD8br %T cells increasing it. This study highlights the pivotal mediating role of immune cells in the interactions between gut microbiota, inflammatory markers, and IgAN risk. These findings identify potential biomarkers and therapeutic targets, providing new insights into the immune mechanisms underlying IgAN and opportunities for intervention.

SBP1 contributes to mesangial proliferation and inflammation through mitochondrial respiration in glomerulus during IgA nephropathy.

Mesangial expansion and proliferation have been implicated in the pathogenesis of IgA nephropathy (IgAN). Mesangial cells in glomerulus are important contributors to commencement of IgAN. From minimal mesangial expansion to diffuse proliferation, the mesangial alteration is linked to clinical and pathological features of IgAN. Although selenium-binding protein 1 (SBP1) is associated with tissue injury, the roles of SBP1 in mesangial proliferation and inflammation in glomerulus during IgAN remains unclear. In the present study, we found that SBP1 gene levels were elevated in kidney tissues of patients with IgAN. Also, SBP1 protein levels were elevated in proliferative mesangial cells of glomerulus in kidney tissues from patients with IgAN. Urinary SBP1 protein levels were elevated in patients with IgAN. Elevated urinary SBP1 levels were positively correlated with segmental glomerulosclerosis of the Oxford classification related to mesangial proliferation in patients with IgAN. Over-expression of SBP1 induced cellular proliferation via mitochondrial respiration in human renal mesangial cells. Consistently, SBP1 knockdown and mitochondrial respiration inhibition suppressed cellular proliferation and induced mitochondrial oxidative stress in human renal mesangial cells. Furthermore, SBP1 induced pro-inflammatory phenotype by gene expression and production of pro-inflammatory cytokines and chemokines including IL-6, CXCL10, and CCL5 via NF-κB activation in human renal mesangial cells. These results suggest that SBP1 contributes to mesangial proliferation and inflammation via mitochondrial respiration during IgAN.

Long-Term Results from an Open-Label Extension Study of Atacicept for the Treatment of IgA Nephropathy.

Key Points Participants who completed a 36-week double-blind study of atacicept were eligible for a 60-week, open-label extension study.Atacicept 96-week treatment resulted in sustained reductions in galactose-deficient IgA1, hematuria, and urine protein-creatinine ratio.The slope of the eGFR was similar to that observed in the general population without kidney disease. Background B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) play key roles in the pathogenesis of IgA nephropathy. Atacicept is a novel fully humanized fusion protein, self-administered at home by subcutaneous injection, that binds and inhibits BAFF and APRIL. By inhibiting BAFF and APRIL, atacicept targets the underlying B-cell–mediated pathogenesis driving disease progression. This study evaluated the long-term efficacy and safety of atacicept in patients with IgA nephropathy over 96 weeks. Methods Participants with IgA nephropathy who received atacicept (25, 75, or 150 mg) or placebo in a 36-week phase 2b, randomized, blinded trial were enrolled in an open-label extension study and received atacicept 150 mg for an additional 60 weeks. Key efficacy outcomes were changes in galactose-deficient IgA1 (Gd-IgA1), percentage of participants with hematuria, urine protein-creatinine ratio (UPCR), and eGFR over 96 weeks. Long-term safety data were also evaluated. Results There were 113 participants (67 [59%] male; 46 [41%] female) who ranged in age from 18 to 67 years who received ≥1 atacicept dose. Over 96 weeks, safety data demonstrated that atacicept was generally well tolerated. There were also sustained reductions (mean±SEM) in Gd-IgA1 (−66%±2%), percentage of participants with hematuria (−75%; 95% confidence intervals, −87 to −59; in participants with baseline hematuria), and UPCR (−52%±5%). The mean annualized slope of eGFR was −0.6±0.5 ml/min per 1.73 m2 through 96 weeks. Conclusions Atacicept was also well tolerated over the duration of the study. Atacicept treatment reduced Gd-IgA1, hematuria, and UPCR with stabilization of eGFR through 96 weeks. Clinical Trial registry name and registration number: Atacicept in Subjects with IgA Nephropathy (ORIGIN 3), NCT04716231.

Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial.

Key Points This phase 2, double-blind, randomized controlled trial evaluated the complement C5 inhibitor, ravulizumab, in adults with IgA nephropathy.A 30.1% (90% confidence interval, 13.7% to 43.5%) relative reduction in proteinuria for ravulizumab versus placebo was observed at approximately 6 months.Treatment with ravulizumab was well tolerated. Background The complement system plays a central role in the pathogenesis of IgA nephropathy. We present findings from a phase 2 trial of ravulizumab, a complement C5 inhibitor. Methods The Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy (NCT04564339) was a randomized, double-blind, placebo-controlled trial of ravulizumab in addition to standard of care. Adults with IgA nephropathy, proteinuria ≥1 g/d, and eGFR ≥30 ml/min per 1.73 m2, and on stable renin-angiotensin blockade were randomized 2:1 to ravulizumab (intravenous every 8 weeks) or placebo for 26 weeks. From week 26–50, all participants received open-label ravulizumab. The primary end point was percentage change in proteinuria from baseline (BL) to week 26. Secondary end points included change in proteinuria at week 50 and eGFR. Safety, pharmacokinetics, and pharmacodynamics were evaluated. Results Forty-three patients were randomized to ravulizumab and 23 to placebo. At week 26, a statistically significant reduction in proteinuria was observed with ravulizumab versus placebo: −41.9% (95% confidence interval [CI], −50.2% to −32.0%) change in urine protein with ravulizumab and −16.8% (95% CI, −31.8% to 1.6%) change with placebo (30.1% treatment effect; P = 0.005). At week 50, there was a −44.8% (95% CI, −55.1% to −32.1%) change from BL in urine protein with ravulizumab, and in patients who crossed over from placebo to ravulizumab at week 26, the change from BL (week 0) to week 50 was −45.1% (−58.0% to −28.4%). The least squares mean change in eGFR from BL to week 26 with ravulizumab was 0.2 (95% CI, −2.3 to 2.7) ml/min per 1.73 m2 and with placebo was −4.5 (−7.9 to −1.1) ml/min per 1.73 m2. From BL to week 50, the least squares mean change in eGFR with ravulizumab was −3.9 (95% CI, −6.4 to−1.3) ml/min per 1.73 m2, and in patients who crossed over from placebo to ravulizumab at week 26, it was −6.3 (−9.7 to −2.9) ml/min per 1.73 m2. Ravulizumab was well tolerated, with an adverse event profile similar to that for placebo. Conclusions An early, sustained, and clinically meaningful reduction in proteinuria and trend toward stabilization of eGFR were observed with ravulizumab versus placebo. A phase 3 trial (NCT06291376) is enrolling. Clinical Trial registry name and registration number: Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy, NCT04564339.

Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy.

The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway. In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria (defined as a 24-hour urinary protein-to-creatinine ratio of ≥1 [with protein and creatinine both measured in grams]) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period. The main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed. Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

Lessons from IgA Nephropathy Models.

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.

Integrated temporal transcriptional and epigenetic single-cell analysis reveals the intrarenal immune characteristics in an early-stage model of IgA nephropathy during its acute injury.

Kidney inflammation plays a crucial role in the pathogenesis of IgA nephropathy (IgAN), yet the specific phenotypes of immune cells involved in disease progression remain incompletely understood. Utilizing joint profiling through longitudinal single-cell RNA-sequencing (scRNAseq) and single-cell assay for transposase-accessible chromatin sequencing (scATACseq) can provide a comprehensive framework for elucidating the development of cell subset diversity and how chromatin accessibility regulates transcription. We aimed to characterize the dynamic immune cellular landscape at a high resolution in an early IgAN mouse model with acute kidney injury (AKI). A murine model was utilized to mimic 3 immunological states -"immune stability (IS), immune activation (IA) and immune remission (IR)" in early human IgAN-associated glomerulopathy during AKI, achieved through lipopolysaccharide (LPS) injection. Urinary albumin to creatinine ratio (UACR) was measured to further validate the exacerbation and resolution of kidney inflammation during this course. Paired scRNAseq and scATACseq analysis was performed on CD45+ immune cells isolated from kidney tissues obtained from CTRL (healthy vehicle), IS, IA and IR (4 or 5 mice each). The analyses revealed 7 major cell types and 24 clusters based on 72304 single-cell transcriptomes, allowing for the identification and characterization of various immune cell types within each cluster. Our data offer an impartial depiction of the immunological characteristics, as the proportions of immune cell types fluctuated throughout different stages of the disease. Specifically, these analyses also revealed novel subpopulations, such as a macrophage subset (Nlrp1b Mac) with distinct epigenetic features and a unique transcription factor motif profile, potentially exerting immunoregulatory effects, as well as an early subset of Tex distinguished by their effector and cytolytic potential (CX3CR1-transTeff). Furthermore, in order to investigate the potential interaction between immune cells and renal resident cells, we conducted single-cell RNA sequencing on kidney cells obtained from a separate cohort of IS and IA mice without isolating immune cells. These findings underscored the diverse roles played by macrophages and CD8+ T cells in maintaining homeostasis of endothelial cells (ECs) under stress. This study presents a comprehensive analysis of the dynamic changes in immune cell profiles in a model of IgAN, identifying key cell types and their roles and interactions. These findings significantly contribute to the understanding of the pathogenesis of IgAN and may provide potential targets for therapeutic intervention.

Establishment of a Human Hybridoma Cell Line That Produces IgG Autoantibody Involved in the Pathogenesis of IgA Nephropathy

Establishment of a Human Hybridoma Cell Line That Produces IgG Autoantibody Involved in the Pathogenesis of IgA Nephropathy

Identification of susceptibility loci and relevant cell type for IgA nephropathy in Han Chinese by integrative genome-wide analysis.

Although many susceptibility loci for IgA nephropathy (IgAN) have been identified, they only account for 11.0% of the overall IgAN variance. We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10 417 controls to identify additional genetic loci of IgAN. Considering that inflammatory bowel disease (IBD) and asthma might share an etiology of dysregulated mucosal immunity with IgAN, we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma. Among 8 669 456 imputed variants, we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498. Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4+CD25-IL17+ Th17 cell was the most relevant cell type for IgAN, which highlights the essential role of Th17 pathway in the pathogenesis of IgAN. Furthermore, we identified six more novel loci associated with IgAN, which included three loci showing pleiotropic effects with IBD or asthma (2q35/PNKD, 6q25.2/SCAF8, and 22q11.21/UBE2L3) and three loci specific to IgAN (14q32.32/TRAF3, 16q22.2/TXNL4B, and 21q21.3/LINC00113) in the pleiotropic analysis. Our findings support the involvement of mucosal immunity, especially T cell immune response and IL-17 signal pathway, in the development of IgAN and shed light on further investigation of IgAN.

New Insights and Future Perspectives of APRIL in IgA Nephropathy.

IgA nephropathy (IgAN) is characterized by immune-mediated glomerulonephritis, with the accumulation of galactose-deficient IgA1 (Gd-IgA1) in the glomeruli and increased levels of circulating Gd-IgA1 and Gd-IgA1-containing immune complexes. An incomplete understanding of the underlying mechanisms and differences in clinical and pathological features between individuals and ethnicities has contributed to the lack of established treatments for IgAN. A tumor necrosis factor (TNF) family member, a proliferation-inducing ligand (APRIL), is a crucial cytokine essential for the generation and survival of plasma cells. Recent studies demonstrated that APRIL is a pivotal mediator in the production of Gd-IgA1 in IgAN. As our understanding of the autoimmune pathogenesis underlying IgAN has improved, various pharmacological therapeutic targets, including APRIL antagonists, have emerged. Preliminary results showed that APRIL-targeting agents effectively reduced proteinuria and Gd-IgA1 levels without significantly increasing adverse events, indicating their potential as novel therapeutic agents for IgAN. In the present review, we discuss the current understanding of the role of APRIL in the pathogenesis of IgAN and novel therapeutic strategies focusing on APRIL-targeting agents for IgAN. APRIL inhibitors may offer new hope to patients with IgAN.

Utilizing complement inhibition in IgA nephropathy.

The role of complement in the pathogenesis of IgA nephropathy has been heavily explored over the past 50 years. This has led to the general acceptance that complement plays an important role in the clinical presentation and risk for progression of disease in patients with IgA nephropathy. Herein, we review the evidence for complement activation in IgA nephropathy, focusing on evidence that the lectin and alternate pathways are the main actors. We are entering an era of intense investigation of various inhibitors of complement, which should ultimately be the best indicator of contributions of the lectin, alternate and common complement pathways to disease burden. More importantly, we will see if these efforts result in the discovery of clinically relevant options in managing this important disease.

C4d, rather than C3d and C5b-9, is associated with graft loss in recurrent IgA deposition after kidney transplantation.

Recurrent IgA deposition is common after kidney transplantation. However, it is difficult to define whether IgA deposition is innocuous or contributes to organ damage. Next, although complement is known to be involved in the pathogenesis of IgA nephropathy (IgAN), its involvement has not been studied systematically in kidney transplant recipients (KTR). KTR with biopsy-proven native IgAN who underwent kidney biopsy after transplantation between 1995 and 2020 were included. Recurrent IgA deposition was defined as IgA deposit in the glomerulus. Staining of complement factors C4d, C3d, and C5b-9 were quantitatively evaluated using ImageScope. Sixty-seven KTR (85% male, 46±13 years old, 12 [6-24] months after transplantation, 58% with indication biopsy) were included in the analyses. Of them, 25 (37%) had recurrent IgA deposition. There were no clinical differences between KTR with and without recurrent IgA deposition. C3d and C5b-9 were always present in biopsies with IgA deposition, while C4d was present in 48% of the biopsies. During a median follow-up of 9.6 [4.8-14] years, 18 (27%) KTR developed death-censored graft failure. Recurrent IgA deposition was not associated with graft failure. Of the evaluated complement factors, only C4d staining was associated with graft failure in KTR with recurrent IgA deposition (Hazard ratio = 2.55, 95% confidence interval = 1.07-6.03, p = 0.034). Recurrent IgA deposition was not associated with graft failure in itself. C4d, when present, is strongly associated with graft loss in KTR with recurrent IgA deposition, suggesting a pathogenic role for the lectin pathway in recurrent IgAN.

B-Cell Epigenetic Modulation of IgA Response by 5-Azacytidine and IgA Nephropathy.

IgA nephropathy is an important global cause of kidney failure. Dysregulation of IgA production is thought to play a key role in IgA nephropathy pathogenesis, however, little is known about the epigenetic mechanisms such as RNA 5- methylcytosine (5mC) modification in regulating IgA synthesis. To decipher the role of RNA 5mC in regulation of IgA class switch, the miR-23b-/- and LCWE induced Kawasaki disease mice were treated with 5-azacytidine. Trdmt1-/- and double Trdmt1-/-/ miR-23b-/- mice, Aid-/- mice or Aid-/-/ miR-23b-/- mice were also employed. We showed that miR-23b down regulated expression of Transfer RNA Aspartic Acid Methyltransferase 1 (Trdmt1) and consequently reduced 5-methylcytosine (m5C) RNA modification and IgA synthesis in B cells. Inhibition of m5C RNA modification normalised serum IgA levels and ameliorated progression of the IgA nephropathy-like kidney disease in miR-23b-/- and Kawasaki disease mice while mesangial IgA and C3 deposition failed to develop in Trdmt1-/-miR-23b-/- mice. By contrast, increased m5C RNA modification resulted in an exaggerated IgA nephropathy phenotype. miR-23b regulation of serum IgA levels and the development of an IgA nephropathy-like kidney disease in miR-23b-/- and Kawasaki disease mice is likely mediated through TRDMT1 driven 5-methylcytosine RNA modification in B cells, resulting in impaired activation-induced cytidine deaminase activity and IgA class switch recombination. This study revealed TRDMT1 induced RNA 5mC methylation regulate IgA class switch and inhibition of RNA 5mC by 5-Azacytidine could ameliorate progression of IgA nephropathy.

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

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.

IgA Nephropathy – Current and Future Perspectives in Treatment

Abstract Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy in our adult population and is associated with a high lifetime risk of kidney failure. Recent years have succeeded in describing the pathogenesis of IgAN at the molecular level, where immune complexes containing specific galactose deficient IgA1 play an essential role. The gold standard in the diagnosis of IgAN remains renal biopsy followed by determination of a prognostic score using the Oxford classification. A fundamental goal in the management of patients with IgAN is to optimize supportive therapy involving active lifestyle modification and renoprotective medications. The reno-protective drug menu has recently been expanded to include effective sodium-glucose cotransporter 2 inhibitors (SGLT2i), and additional agents are on the way. However, despite maximal supportive therapy, a wide range of patients remain at high risk of disease progression and require the deployment of immunomodulatory drugs. To date, however, we do not have high potency agents that are well tolerated and safe. This has led to the initiation of many studies to target the inflammatory process at different pathogenetic levels. In this article, we summarize the current standards in the treatment of IgAN and present new promising options in the management of this disease.

Galectin-3 contributes to pathogenesis of IgA nephropathy

IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous “grouped” ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.

Pathogenesis of IgA nephropathy as a tissue-specific autoimmune disease.

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. IgA nephropathy (IgAN) is the most common GN worldwide and is characterized by 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 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.

Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice

Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA-IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

IgA class-switched CD27-CD21+ B cells in IgA nephropathy.

IgA nephropathy (IgAN) is characterised by the production of galactose-deficient IgA1 (GdIgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA-secretion remain unknown. We carried out flow cytometry analysis of peripheral blood B cells in patients with IgA nephropathy and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies. In addition to global changes in the B cell landscape - expansion of naive and reduction in memory B cells - IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21pos. IgAN patients further have an expanded population of IgApos antibody-secreting cells, which correlate with serum IgA levels. Both IgApos plasmabalsts and CD27neg B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide (LPS) in the serum and IgAposCD27neg B cell frequency. We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgAposCD27neg B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow to further investigate this pathway to uncover biomarkers and develop therapeutic interventions.

Analysis of IgG subclass staining for IgG immunofluorescence-positive IgAnephropathy.

The clinicopathological significance of IgG subclass staining is unclear in IgG immunofluorescence (IF)-positive IgA nephropathy (IgAN). This study investigated IgG subclass distribution in IgG IF-positive IgAN by IF staining and examined their clinicopathological significance. From January 2015 to December 2020, 27 biopsies from 26 patients with IgG IF-positive IgAN who were IF-positive for any IgG subclass staining were collected. We compared the clinicopathological findings between cases with and without IF positivity for each IgG subclass. Of the 27 biopsies with IgG IF-positive IgAN, 20 (74.1%) were IF-positive for IgG1, 10 (37.0%) were positive for IgG2, 7 (25.9%) were positive for IgG3, and none were positive for IgG4. Oxford E and C scores were significantly higher in cases of IgG IF-positive IgAN than IgG IF-negative IgAN. The age at biopsy had a negative correlation with IgG1 IF intensity (γ=-0.604, p=0.001). The levels of proteinuria and microscopic hematuria as well as Oxford classification score were not significantly different between cases with or without positive staining for each IgG subclass. IgG IF intensity had a positive correlation with IgG1 IF intensity (γ=0.741, p<0.001). IgG1-positive IF staining intensity was highest among each IgG subclass in IgG IF-positive IgAN biopsies. A negative correlation was revealed between the age at biopsy and IgG1 IF intensity. Oxford E and C scores were higher in patients with IgG IF-positive IgAN than in those with IgG IF-negative IgAN. The Oxford score was not significantly different between the IgG subclasses, but the IF intensity of IgG had a positive correlation with the IF intensity of IgG1 in IgG IF-positive IgAN biopsies. Further studies should assess relationships between IgG subclass IF deposition and examine the pathogenesis of IgAN.