scholarly journals Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

2021 ◽  
Vol 10 (19) ◽  
pp. 4501
Author(s):  
Barbora Knoppova ◽  
Colin Reily ◽  
R. Glenn King ◽  
Bruce A. Julian ◽  
Jan Novak ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Immune Complexes ◽  
Mesangial Cells ◽  
Specific Treatment ◽  
Kidney Injury ◽  
Pathogenic Potential ◽  
Clinical Observations ◽  
Circulating Levels ◽  
Disease Specific

IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

Collectin11 and Complement Activation in IgA Nephropathy

2021 ◽  
pp. CJN.04300321
Author(s):  
Min Wei ◽  
Wei-yi Guo ◽  
Bo-yang Xu ◽  
Su-fang Shi ◽  
Li-jun Liu ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Complement Activation ◽  
Immune Complexes ◽  
Mesangial Cells ◽  
Kidney Injury ◽  
Lectin Pathway ◽  
Independent Manner ◽  
Proximity Ligation ◽  
Injury Model

Background and objectives: IgA nephropathy is the most common primary glomerulonephritis worldwide. Previous research demonstrated that collectin11, an initiator of complement lectin pathway, was involved in both acute kidney injury and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy. Design, setting, participants, and measurements: The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. In vitro, human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by RT-qPCR and immunofluorescence. The codeposition of collctin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays. Results: 37% participants with IgA nephropathy (22/60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface via the interaction with deposited IgA1-immune complexes. In vitro, we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells. Conclusions: In situ-produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.

scholarly journals Cellular Signaling and Production of Galactose-Deficient IgA1 in IgA Nephropathy, an Autoimmune Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Colin Reily ◽  
Hiroyuki Ueda ◽  
Zhi-Qiang Huang ◽  
Jiri Mestecky ◽  
Bruce A. Julian ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Immune Complexes ◽  
Association Studies ◽  
Immunoglobulin A ◽  
Specific Treatment ◽  
Genome Wide Association Studies ◽  
Glomerular Injury ◽  
Stage Renal Disease ◽  
End Stage ◽  
Disease Specific

Immunoglobulin A (IgA) nephropathy (IgAN), the leading cause of primary glomerulonephritis, is characterized by IgA1-containing immunodeposits in the glomeruli. IgAN is a chronic disease, with up to 40% of patients progressing to end-stage renal disease, with no disease-specific treatment. Multiple studies of the origin of the glomerular immunodeposits have linked elevated circulating levels of aberrantly glycosylated IgA1 (galactose-deficient in someO-glycans; Gd-IgA1) with formation of nephritogenic Gd-IgA1-containing immune complexes. Gd-IgA1 is recognized as an autoantigen in susceptible individuals by anti-glycan autoantibodies, resulting in immune complexes that may ultimately deposit in the kidney and induce glomerular injury. Genetic studies have revealed that an elevated level of Gd-IgA1 in the circulation of IgAN patients is a hereditable trait. Moreover, recent genome-wide association studies have identified several immunity-related loci that associated with IgAN. Production of Gd-IgA1 by IgA1-secreting cells of IgAN patients has been attributed to abnormal expression and activity of several key glycosyltransferases. Substantial evidence is emerging that abnormal signaling in IgA1-producing cells is related to the production of Gd-IgA1. As Gd-IgA1 is the key autoantigen in IgAN, understanding the genetic, biochemical, and environmental aspects of the abnormal signaling in IgA1-producing cells will provide insight into possible targets for future disease-specific therapy.

Mass spectrometry-based circulating IgA1 complexes screening driven identification of IgA-alpha-1-microglobulin complex in IgA nephropathy

2020 ◽  
Author(s):  
Boyang Xu ◽  
Li Zhu ◽  
Qingsong Wang ◽  
Yanfeng Zhao ◽  
Meng Jia ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Iga Nephropathy ◽  
Cell Injury ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Independent Population ◽  
Tubulointerstitial Lesions ◽  
Noninvasive Biomarker

Abstract Background IgA nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. Previous studies proved that renal-deposited IgA in IgAN came from circulating IgA1-containing complexes (CICs). Methods To explore the composition of CICs in IgAN, we isolated CICs from IgAN patients and healthy controls, and then quantitatively analyzed them by mass spectrometry. Meanwhile, the isolated CICs were used to treat human mesangial cells to monitor mesangial cell injury. Taken together the proteins content and injury effects, the key constituent in CICs was identified. Then, the circulating levels of identified key constituent-IgA complex were detected in an independent population by an in-house-developed ELISA. Results By comparing the proteins of CICs between IgAN patients and controls, we found that 14 proteins showed significantly different levels. Among them, alpha-1-microglobulin content in CICs was associated with not only in vitro mesangial cell proliferation and MCP-1 secretion but also in vivo eGFR levels and tubulointerstitial lesions in IgAN patients. Moreover, we found alpha-1-microglobulin was prone to bind aberrant glycosylated IgA1. Additionally, an elevated circulating IgA-alpha-1-microglobulin complex levels were detected in an independent IgAN population, and IgA-alpha-1-microglobulin complex levels were correlated with hypertension, eGFR levels and Oxford-T scores in these IgAN patients. Conclusions Our results suggest that the IgA-alpha-1-microglobulin complex is an important constituent in CICs, and that circulating IgA-alpha-1-microglobulin complex detection might serve as a potential noninvasive biomarker detection method for IgAN.

scholarly journals Microbial IgA Protease Removes IgA Immune Complexes from Mouse Glomeruli In Vivo: Potential Therapy for IgA Nephropathy

2008 ◽  
Vol 172 (1) ◽  
pp. 31-36 ◽  
Author(s):  
Michael E. Lamm ◽  
Steven N. Emancipator ◽  
Janet K. Robinson ◽  
Michifumi Yamashita ◽  
Hisashi Fujioka ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Immune Complexes ◽  
Iga Immune Complexes ◽  
Iga Protease

Interaction of immune complexes with Fc receptors in mesangial cells: A potential target for the treatment of IgA nephropathy

Nephrology ◽  
1997 ◽  
Vol 3 (1) ◽  
pp. 95-101 ◽  
Author(s):  
C. GÓMEZ-GUERRERO ◽  
N. DUQUE ◽  
MJ LÓPEZ-ARMADA ◽  
MT CASADO ◽  
F. VIVANCO ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Immune Complexes ◽  
Mesangial Cells ◽  
Fc Receptors ◽  
Potential Target

scholarly journals IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells

2011 ◽  
Vol 26 (11) ◽  
pp. 3451-3457 ◽  
Author(s):  
Jan Novak ◽  
Leona Raskova Kafkova ◽  
Hitoshi Suzuki ◽  
Milan Tomana ◽  
Karel Matousovic ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Immune Complexes ◽  
Pediatric Patients ◽  
Mesangial Cells ◽  
Human Mesangial Cells

scholarly journals Sialylation of IgG inhibits the formation of galactose-deficient IgA1-containing immune complexes and protects mesangial cells from injury in IgA nephropathy

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Youxia Liu ◽  
Hongfen Li ◽  
Huyan Yu ◽  
Fanghao Wang ◽  
Junya Jia ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
B Lymphocytes ◽  
Immune Complexes ◽  
Mononuclear Cells ◽  
Mesangial Cells ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Inflammatory State

Abstract Background The addition of sialic acid alters IgG from a pro-inflammatory state to an anti-inflammatory state. However, there is a lack of research on the changes of IgG sialylation in IgA nephropathy (IgAN). Methods This study included a total of 184 IgAN patients. The sialylated IgG (SA-IgG), IgG-galactose-deficient IgA1 complex (IgG-Gd-IgA1-IC), IL-6, TNF-α, and TGF-β were detected using commercial ELISA kits. SA-IgG, non-sialylated IgG (NSA-IgG), sialylated IgG-IgA1 complex (SA-IgG-IgA1), and non-sialylated IgG-IgA1 complex (NSA-IgG-IgA1) were purified from IgAN patients and healthy controls (HCs). Results The mean SA-IgG levels in plasma and B lymphocytes in IgAN patients were significantly higher than those of healthy controls. A positive correlation was found between SA-IgG levels in plasma and B lymphocytes. In vitro, the results showed that the release of IgG-Gd-IgA1-IC was significantly decreased in peripheral blood mononuclear cells (PBMCs) cultured with SA-IgG from both IgAN patients and healthy controls. The proliferation ability and the release of IL-6, TNF-α, and TGF-β in human mesangial cells (HMCs) were measured after stimulating with SA-IgG-IgA1-IC and NSA-IgG-IgA1-IC. The mesangial cell proliferation levels induced by NSA-IgG-IgA1-IC derived from IgAN patients were significantly higher than those caused by SA-IgG-IgA1-IC derived from IgAN patients and healthy controls. Compared with NSA-IgG-IgA1 from healthy controls, IgAN-NSA-IgG-IgA1 could significantly upregulate the expression of IL-6 and TNF-α in mesangial cells. The data showed that there weren’t any significant differences in the levels of IL-6, TNF-α, and TGF-β when treated with IgAN-SA-IgG-IgA1 and HC-NSA-IgG-IgA1. Conclusions The present study demonstrated that the sialylation of IgG increased in patients with IgA nephropathy. It exerted an inhibitory effect on the formation of Gd-IgA1-containing immune complexes in PBMCs and the proliferation and inflammation activation in mesangial cells.

scholarly journals IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells

2005 ◽  
Vol 67 (2) ◽  
pp. 504-513 ◽  
Author(s):  
Jan Novak ◽  
Milan Tomana ◽  
Rhubell Brown ◽  
Stacy Hall ◽  
Lea Novak ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Immune Complexes ◽  
Mesangial Cells

scholarly journals Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction via ROS Damage and Upregulation of HIF-1

2020 ◽  
Vol 21 (9) ◽  
pp. 3400
Author(s):  
Kuan-Chou Chen ◽  
Chang-Rong Chen ◽  
Chang-Yu Chen ◽  
Kai-Yi Tzou ◽  
Chiung-Chi Peng ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Renal Damage ◽  
Mesangial Cells ◽  
Cell Model ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Mitochondrial Potential ◽  
Interacting Protein ◽  
Atp Production

Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1 transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1 protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 M) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1 pathway and clinically, some protective agents like antioxidants are recommended for co-treatment.

scholarly journals New Insights into the Pathogenesis of IgA Nephropathy

2015 ◽  
Vol 1 (1) ◽  
pp. 8-18 ◽  
Author(s):  
Jan Novak ◽  
Dana Rizk ◽  
Kazuo Takahashi ◽  
XianWen Zhang ◽  
Qi Bian ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Iga Nephropathy ◽  
Immune Complexes ◽  
Molecular Mechanisms ◽  
Disease Risk ◽  
Disease Process ◽  
Contributing Factors ◽  
Specific Therapy ◽  
Risk Alleles ◽  
Disease Specific

Background: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically: it is the highest in eastern Asia and northern Europe, lower in other parts of Europe and North America, and the lowest in Africa. IgA nephropathy is diagnosed by the pathological assessment of a renal biopsy specimen. Currently, therapy is not disease targeted but rather focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for the diagnosis, prognosis, and assessment of responses to therapy are needed. Summary: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schönlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in the formation of pathogenic IgA1-containing immune complexes will enable the development of disease-specific therapies as well as diagnostic and prognostic biomarkers. Key Messages: IgA nephropathy is an autoimmune disease caused by the glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of the pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to the development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy.

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