Pathogenesis Of IgA Nephropathy Research Articles

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives.

IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and renal failure. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the immunoproteasome probably plays an important role in IgAN. The immunoproteasome is a proteasome variant that is expressed when cells are stressed or receive inflammatory signals. While immunoproteasome is suggested to be mainly involved in major histocompatibility complex-I (MHC-I) antigen presentation, recent studies indicate that it may assert broad functions in trafficking events that activate both innate and adaptive immunity. In this review, we first summarize new insights into its functions in immunity, and discuss how it underlies its associations with IgAN. We also highlight its potential as a therapeutic target for the future.

Octreotide Delaying the Progression of Recurrent IgA Nephropathy After Kidney Transplantation.

IgA Nephropathy (IgAN) is a common cause of end-stage kidney disease worldwide. Unfortunately, the exact pathogenesis of IgAN remains uncertain without any targeted therapy. While kidney transplantation remains the gold standard treatment for those with end-stage kidney disease from IgAN, recurrence occurs frequently and may lead to early kidney transplant loss. Research has suggested that insulin-like growth factor-1 may play a role in mesangial cell proliferation in IgAN and Somatostatin may inhibit insulin-like growth factor-1. In this single case study, we report the use of octreotide, a somatostatin analogue, as a potential novel therapy for early recurrent IgAN post kidney transplant.

Matrix-assisted laser desorption/ionization mass spectrometry imaging to uncover protein alterations associated with the progression of IgA nephropathy.

IgA nephropathy (IgAN) is one of the most diffuse glomerulonephrites worldwide, and many issues still remain regarding our understanding of its pathogenesis. The disease is diagnosed by renal biopsy examination, but potential pitfalls still persist with regard to discriminating its primary origin and, as a result, determining patient outcome remains challenging. In this pilot study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was performed on renal biopsies obtained from patients with IgAN (n = 11) and other mesangioproliferative glomerulonephrites (MesPGN, n = 6) in order to enlighten proteomic alterations that may be associated with the progression of IgAN. Differences in the proteomic profiles of IgAN and MesPGN tissue could clearly be detected using this approach and, furthermore, 14 signals (AUC ≥ 0.8) were observed to have an altered intensity among the different CKD stages within the IgAN group. In particular, large increases in the intensity of these signals could be observed at CKD stages II and above. These signals primarily corresponded to proteins involved in either inflammatory and healing pathways and their increased intensity was localized within regions of tissue with large amounts of inflammatory cells or sclerosis. Despite much work in recent years, our molecular understanding of IgAN progression remains incomplete. This pilot study represents a promising starting point in the search for novel protein markers that can assist clinicians in better understanding the pathogenesis of IgAN and highlighting those patients who may progress to end-stage renal disease.

The Role of IgA in the Pathogenesis of IgA Nephropathy.

Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans, predominantly present in the mucosal areas where its main functions are the neutralization of toxins, prevention of microbial invasion across the mucosal epithelial barrier, and simultaneous maintenance of a physiologically indispensable symbiotic relationship with commensal bacteria. The process of IgA biosynthesis, interaction with receptors, and clearance can be disrupted in certain pathologies, like IgA nephropathy, which is the most common form of glomerulonephritis worldwide. This review summarizes the latest findings in the complex characteristics of the molecular structure and biological functions of IgA antibodies, offering an in-depth overview of recent advances in the understanding of biochemical, immunologic, and genetic factors important in the pathogenesis of IgA nephropathy.

BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF‑κB signaling pathway in glomerular mesangial cells.

The aim of the present study was to investigate the involvement of B cell-activating factor (BAFF) in the pathogenesis of IgA nephropathy by activating the tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB signaling pathway in glomerular mesangial cells. For the clinical analysis, blood, urine and kidney tissue samples were collected from 58 patients diagnosed with primary IgA nephropathy by renal biopsy. For the in vitro study, glomerular mesangial cells were divided into five groups: Control (con)-short hairpin RNA (shRNA) (control group); con-shRNA + BAFF (20 ng/ml); con-shRNA + BAFF + BAFF-RFc chimera protein (500 µg/ml); TRAF6-shRNA; and TRAF6-shRNA + BAFF (20 ng/ml). For the in vivo experiments, 60 Sprague-Dawley rats were randomly divided into four groups: Con-small interfering RNA (siRNA) (control group); con-siRNA + IgA (IgA nephropathy group), BAFF-RFc chimera protein (2 µg/ml) + IgA, and TRAF6-siRNA (0.2 µM) + IgA. Reverse transcription-quantitative PCR was performed to evaluate the mRNA expression levels of TRAF6, connective tissue growth factor (CTGF), fibronectin (FN) and NF-κBP65. Western blot analysis was used to detect the protein expression levels of TRAF6, FN, CTGF and phosphorylated-NF-κBP65 in glomerular mesangial cells and kidney tissues. The results revealed that plasma BAFF levels were positively correlated with the severity of pathological damage in patients with IgA nephropathy. In vitro, BAFF induced the mRNA and protein expression of TRAF6, CTGF, FN and NF-κBP65 in glomerular mesangial cells. After the BAFF-RFc chimera protein was added to inhibit the binding of BAFF and BAFF-receptor (-R), this effect was reduced. In vivo, inhibition of the effects of BAFF via injection with the BAFF-R Fc chimera protein reduced kidney damage in rats suffering from IgA nephropathy. The effect on the expression of signaling pathway-associated proteins was also alleviated. In conclusion, BAFF enhanced the expression of fibroblast factors in the kidneys by activating the TRAF6/NF-κB signaling pathway.

IgA1 deposition may induce NLRP3 expression and macrophage transdifferentiation of podocyte in IgA nephropathy

BackgroundThe NLRP3 inflammasome plays an important role in mediating podocyte injury in various kidney diseases. The aim of this study was to investigate whether NLRP3 expression associated with podocyte injury was involved in the pathogenesis of IgA nephropathy (IgAN).MethodsNLRP3 inflammasomes and macrophage marker (F4/80) were detected in the renal tissues of IgAN patients. Association between kidney NLRP3 levels and the clinical feature of IgAN patients was analyzed. Podocytes were incubated with serum containing dys-glycosylated IgA1 protein isolated from IgAN patients. Expression of NLRP3 inflammasomes, F4/80, inflammatory cytokine and renal fibrosis marker were measured using RT-PCR and Western blotting.ResultsRenal NLRP3 inflammasome expression was significantly increased in IgAN patients compared to normal control tissues. Moreover, co-expression of NLRP3 and F4/80 could be observed in the podocytes of IgAN patients. Patients with eGFR < 60 ml/min/1.73 m2 had remarkably higher tubular NLRP3 expression (P < 0.05), while patients with gross proteinuria (≥ 3.5 g/day) had a significantly higher glomerular NLRP3 expression (P < 0.05). Further analysis indicated that dys-glycosylated IgA1 isolated from IgAN patient serum could induce podocyte expression of NLRP3 and the macrophage marker F4/80, which could lead to induction of an inflammatory reaction (increased expression of ICAM-1) and fibrosis (increased expression of α-SMA).ConclusionDys-glycosylated IgA1 isolated from IgAN patient serum could induce NLRP3 expression in podocytes and initiate podocyte macrophage transdifferentiation (PMT). After PMT, podocytes secrete proinflammatory cytokines that can contribute to the inflammation cascade and renal fibrosis changes associated with IgAN.

Secondary IgA Nephropathy Shares the Same Immune Features With Primary IgA Nephropathy

IntroductionGalactose-deficient IgA1 (Gd-IgA1) and related IgA/IgG immune complexes have been identified as the key drivers in the pathogenesis of IgA nephropathy (IgAN). However, their roles in the development of secondary IgAN are still unknown.MethodsIn this study, we measured the plasma Gd-IgA1 level, IgA/IgG complex, and Gd-IgA1 glomerular deposits in 100 patients with various kinds of secondary IgAN. Plasma Gd-IgA1 was measured using a lectin-based enzyme-linked immunosorbent assay, and Gd-IgA1 in glomerular deposits was examined by double immunofluorescent staining using its specific monoclonal antibody KM55.ResultsPatients with secondary IgAN presented with higher plasma Gd-IgA1 levels compared to healthy controls (median, 354.61 U/ml; interquartile range [IQR], 323.93, 395.57 U/ml vs. median, 303.17 U/ml; IQR, 282.24, 337.92 U/ml, P < 0.001) or patients with other kidney diseases (median, 314.61 U/ml; IQR, 278.97, 343.55 U/ml, P < 0.001). A similar trend was observed in plasma IgA/IgG immune complexes or IgA1. There were no differences between secondary and primary IgAN in plasma Gd-IgA1 levels (median, 378.54 U/ml; IQR, 315.96, 398.33 U/ml, P = 0.700) and IgA1-IgG complex levels (median, 18.76 U/ml; IQR, 14.51, 22.83 U/ml vs. median, 19.11 U/ml; IQR, 13.21, 22.37 U/ml, P = 0.888). Co-localized IgA1 and Gd-IgA1 of both secondary and primary IgAN indicated that they both share the feature of Gd-IgA1 deposits on the glomerular mesangium.ConclusionOur study strongly suggests that secondary IgAN shares a similar galactose-deficient IgA1-oriented pathogenesis with primary IgAN.

IgA nephropathy is associated with elevated urinary mitochondrial DNA copy numbers

Mitochondrial injury plays important roles in the pathogenesis of various kidney diseases. However, mitochondrial injury in IgA nephropathy (IgAN) remains largely unexplored. Here, we examined the associations among mitochondrial injury, IgAN, and treatment outcomes. We prospectively enrolled patients with IgAN and age-/sex-matched healthy volunteers (HVs) as controls (n = 31 each). Urinary copy numbers of the mitochondrial DNA (mtDNA) genes cytochrome-c oxidase-3 (COX3) and nicotinamide adenine dinucleotide dehydrogenase subunit-1 (ND1) were measured. Urinary mtDNA levels were elevated in the IgAN group compared with that in HVs (p < 0.001). Urinary ND1 levels were significantly higher in the low proteinuria group than in the high proteinuria group (p = 0.027). Changes in urinary levels of ND1 and COX3 were positively correlated with changes in proteinuria (p = 0.038 and 0.024, respectively) and inversely correlated with changes in the estimated glomerular filtration rate (p = 0.033 and 0.017, respectively) after medical treatment. Mitochondrial injury played important roles in IgAN pathogenesis and may be involved in early-stage glomerular inflammation, prior to pathological changes and increased proteinuria. The correlation between changes in urinary mtDNA and proteinuria suggest that these factors may be promising biomarkers for treatment outcomes in IgAN.

Increased Non-switched Memory B Cells are Associated with Plasmablasts, Serum IL-6 Levels and Renal Functional Impairments in IgAN Patients

ABSTRACTBackground: Circulating B cells are crucial for the pathogenesis of IgA nephropathy (IgAN). This study aimed at investigating the relationship between frequency of different subsets of circulating B cells and clinical measures in IgAN patients.Methods: The percentages of different subsets of circulating B cells in 23 IgAN patients and 14 healthy controls (HC) were determined by flow cytometry. Their serum IL-6 levels were measured by Cytometric Bead Array (CBA). Clinical parameters in five patients were measured before and after treatment for 8–12 weeks. The potential relationship between variants was analyzed.Results: In comparison with the HC, the frequency of CD3-CD19+ CD27+ IgD+IgM+ non-switched memory B cells (P = .0038) and CD3-CD19+ CD27hiCD38hi plasmablasts (P = .0467) and serum IL-6 (P = .0392) levels significantly increased in IgAN patients. The percentages of non-switched memory B cells were positively correlated with plasmablasts (R = 0.5781, P = .0039) and serum IL-6 levels (R = 0.6663, P = .0005) in the patients. The percentages of non-switched memory B cells (R = 0.8399, P < .0001), plasmablasts (R = 0.4486, P = .0318) and the levels of serum IL-6 (R = 0.5461, P = .0070) were positively correlated with the values of 24-h urine proteins in IgAN patients. The serum levels of IL-6 were negatively correlated with the eGFR values. Following standard treatment, the frequency of non-switched memory B cells and plasmablasts and the levels of 24-h urine proteins (P = .0317, P = .0079, P < .05) significantly decreased in IgAN patients.Conclusions: Abnormally higher frequency of non-switched memory B cells and plasmablasts may contribute to the pathogenesis of IgAN and be potential biomarkers for IgAN.

Elevated hsa-miR-590-3p expression down-regulates HMGB2 expression and contributes to the severity of IgA nephropathy.

Peripheral blood mononuclear cells (PBMCs) play important roles in the pathogenesis of IgA nephropathy (IgAN). Our study aimed to provide a deep understanding of IgAN and focused on the dysregulation of hsa‐miR‐590‐3p and its target gene HMGB2 in PBMCs. Three gene expression profile datasets (GSE14795, GSE73953 and GSE25590) were downloaded from the GEO database. The DEGs (differentially expressed genes)‐miRNA network that was associated with IgAN was constructed by Cytoscape, and HMGB2 and hsa‐miR‐590‐3p were selected for further exploration. The dual‐luciferase reporter system was utilized to verify their interaction. Then, the expression levels of HMGB2 and hsa‐miR‐590‐3p in PBMCs were detected by qPCR in another cohort, and the correlation of their expression levels with the clinical pathological manifestations and serum Gd‐IgA1(galactose‐deficient IgA1) levels was also investigated. HMGB2 was identified as the target gene of hsa‐miR‐590‐3p. Furtherly, the elderly patients had higher HMGB2 expression levels than the expression levels of the younger patients. As the serum creatinine, serum BUN levels increased, the expression of HMGB2 decreased; Besides, the HMGB2 expression was positively correlated with serum complement 3(C3) levels, and it also had a negative correlation with the diastolic blood pressure, but not reach statistical significance. What is more, both hsa‐miR‐590‐3p and HMGB2 expression had a slight correlation tendency with serum Gd‐IgA1 levels in the whole population. In conclusion, HMGB2, the target gene of hsa‐miR‐590‐3p, was identified to correlate with the severity of IgAN, and this provides more clues for the pathogenesis of IgAN.

The TLR4-MyD88-NF-κB Pathway Is Involved in sIgA-Mediated IgA Nephropathy

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Previous studies have shown that secretory IgA (sIgA; an important antibody in mucosal immunity) was critically involved in IgAN immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. However, it remains unclear whether sIgA and TLRs interact to mediate the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. Methods: IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (NsIgA). Immunohistochemistry was used to assess expression of TLR4, MyD88, NF-κB, tumour necrosis factor (TNF)-α, interleukin (IL-6), and monocyte chemoattractant protein (MCP)-1 in renal tissues of IgAN patients. Human renal mesangial cells (HRMCs) were cultured in vitro and binding of sIgA to HRMCs was assessed by flow cytometry. HRMCs were cultured in the presence of sIgA (400 μg/mL) for 24 h. Transcript and protein levels of TLR4, MyD88, NF-κB and cytokines in HRMCs were determined by qPCR, western blotting and ELISA, respectively. Finally, shRNA lentiviral particles were used to silence TLR4 expression and a small-molecule inhibitor (BAY 11-7082) was used to block NF-κB signalling in HRMCs and changes in cytokine production were observed. Results: Flow cytometry showed that P-sIgA bound HRMCs (85% positive) significantly better than N-sIgA (P< 0.05). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients. Expression levels in renal tissue in patients with positive sIgA deposition were higher than that in patients with negative sIgA deposition. Compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB (P<0.05). TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Conclusions: Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No. 81570645/H0509), the Innovation Scientists and Technicians Troop Construction Projects of Henan Province (2018JR0014), the Sponsored by Program for Science & Technology Innovation Talents in Universities of Henan Province (18HASTIT043), and the Major Project of Henan Medical Science and Technology Research Program (201501018). Declaration of Interests: The authors have no conflicts or financial interests to declare. Ethics Approval Statement: The study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University, and was carried out according to the principles laid out in the World Medical Association’s Declaration of Helsinki.

Use of gas chromatography mass spectrometry to elucidate metabolites predicting the phenotypes of IgA nephropathy in hyper IgA mice.

IgA nephropathy, a common chronic kidney disease, has various possible outcomes. Therefore, the identification of novel prognostic biomarkers is needed. To this purpose, we used gas chromatography mass spectrometry to search for metabolites capable of predicting the phenotypes of IgA nephropathy in hyper IgA (HIGA) mice, an established model mice for IgA nephropathy. We measured the plasma metabolite levels in 12- and 22-week-old mice, prior to the manifestation of IgA nephropathy phenotypes, and statistically investigated the associations between these metabolites and the phenotypes of IgA nephropathy, such as the urine protein levels and histological phenotypes of the kidney at 32 weeks. We observed that in plasma samples collected from 12- and 22-week-old HIGA mice, the urinary protein levels were significantly associated with 8 and 10 metabolites, the glomerular cellular component levels were significantly associated with 8 and 7 metabolites, and the mesangial substrate levels were significantly associated with 8 and 8 metabolites, respectively. Among the candidate metabolites associated with the phenotypes of IgA nephropathy, coniferyl alcohol levels were significantly higher in HIGA mice at all of the 12, 22, and 32 weeks of age. Since this study was an observational study, we could not elucidate the underlying mechanisms; however, we were able to identify new candidate metabolites, such as coniferyl alcohol, as being potentially involved in the pathogenesis of IgA nephropathy. These results might help to develop novel laboratory tests and therapeutic reagents for IgA nephropathy in the future.

SUN-036 SPLEEN TYROSINE KINASE (SYK) INHIBITION IN IGA NEPHROPATHY: A GLOBAL, PHASE II, RANDOMISED PLACEBO-CONTROLLED TRIAL OF FOSTAMATINIB

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, causing chronic kidney disease and end-stage renal disease. Pre-clinical data implicates SYK in the pathogenesis of IgAN (Kim MJ et al J Immunol 2012, McAdoo et al JASN 2014). We hypothesize that SYK inhibition with fostamatinib may represent a novel therapeutic opportunity. This ascending-dose study (NCT02112838) enrolled patients from 20 renal centers in Asia, Europe and USA with a recent diagnostic biopsy showing IgAN with mesangial and/or endocapillary hypercellularity at diagnosis. All patients previously received a maximum tolerated dose of renin-angiotensin-aldosterone system (RAAS) blockade for ≥12 weeks during the run-in period. At screening, the inclusion criteria were intended to be sPCR >442mg/g (50 mg/mmol) and >884 mg/g for USA only, and eGFR >30 ml/min/1.73 sqm were randomised to 3 groups: placebo BID (n=25), fostamatinib 100mg BID (n=26) or fostamatinib 150mg BID (n=25) orally for 24 weeks. Because of rate of recruitment, some patients with lower sPCR and eGFR were recruited following assessment with medical monitor. At end of study, patients were offered an optional repeat kidney biopsy. Of the 76 patients enrolled, the median age was 40.5 years; 67%, 30%, and 2% were white, Asian, and African-American, respectively; mean (range) disease duration was 3.0 yrs (0.1 to 25 yr). Baseline sPCR and eGFR are shown in Table 1; baseline median mesangial cellularity score, % glomeruli showing endocapillary hypercellularity and segmental sclerosis, and % tubular atrophy/interstitial fibrosis [continuous data for Oxford Classification criteria] were 0.6 (0–2), 0 (0-37%), 15.6 (0-54%), and 30 (0-60), respectively. Both doses of fostamatinib reduced proteinuria (sPCR) compared to baseline, although the differences were not significant (Table 1). In a pre-specified subgroup analysis of patients with baseline sPCR ≥1000mg/g, there was a dose dependent reduction in sPCR, which did not reach significance (Figure 1). There were no significant changes in eGFR during the study. Serial renal biopsies samples were available from a limited number of patients. Analysis of serial renal biopsies showed no significant changes in median Oxford classification scores. There was no increase in infectious episodes in either treatment group. Eight serious adverse events occurred in 6 patients. Six patients discontinued due to an AE. There were 7 fostamatinib-treated patients who had >50% higher sPCR at week 24 compared to baseline. Immunohistochemical analysis of macrophages and SYK in the renal biopsies is in progress. Table 1Kidney function and proteinuria Median (range)GroupsPlacebo (n=25)100 mg (n=26)150 mg (n=25)eGFR (ml/min/1.73 sq m) baseline51 (25,104)50 (20,109)35 (18,103)eGFR (ml/min/1.73 sq m) 24 weeks51 (21, 115)51 (25,120)37 (13, 93)sPCR (mg/g) baseline1272 (525, 9938)1828 (387, 16259)1878 (664, 4076)sPCR (mg/g) 24 weeks1034 (78, 13819)842 (97, 9803)1299 (309, 4661) Open table in a new tab This is the first clinical trial of a new class of medication (SYK inhibitor) in patients with kidney disease. The results suggest that further investigation of fostamatinib as a novel therapy for IgAN is warranted in patients with >1g proteinuria/day (presented on behalf of SIGN clinical trial collaboration group).

SUN-016 CHARACTERISTICS OF NAÏVE AND GERMINAL CENTER B CELLS IN MURINE IGA NEPHROPATHY

The pathogenesis of IgA nephropathy (IgAN) is associated with dysregulation of immune system, however the characteristics of B cells that are responsible for production of nephritogenic IgA have been obscure. The majority of plasma cells residing in bone marrow are long-lived plasma cells, which are mainly generated via germinal center (GC) of peripheral lymphoid tissues. On the other hand, we have reported the abnormality in mucosal GC in human IgAN (JASN 28; 1227, 2017). To evaluate the abnormality in GC reaction, we used IgAN model mice.

SUN-028 PROGNOSTIC VALUE OF MESANGIAL C3 AND C4d DEPOSITION IN IgA NEPHROPATHY

Activation of complement system can play an important role in the pathogenesis of IgA nephropathy (IgAN). C3 and C4d can be representative markers of alternative and lectin pathway, respectively. We studied whether mesangial C3 or C4d deposits can predict adverse renal outcome better than conventional risk factors and determined relative contribution of each pathway to disease progression.

Expressions of CD3 and CD4 T Cells in Peripheral Blood of Patients with Immunoglobulin A Nephropathy and Their Clinical Significance

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis characterized by abnormal immune response-mediated deposition of polymeric IgA (pIgA) in mesangium. As a type of important immune cells, the relationship of CD3 or CD4 with the pathogenesis of IgAN remains poorly understood. In this study, 38 patients with IgAN, 7 patients with idiopathic membranous nephropathy (MN) and 46 healthy adults without history of kidney disease were enrolled. Peripheral blood was collected for further evaluation of the expressions of CD3 and CD4 and IgA by flow cytometry, quantitative polymerase chain reaction (qPCR) and Western blot. Meanwhile, the expression of IgA was detected by ELISA. The result showed that expression of CD3 T cells was down-regulated in patients with IgAN, while amounts of CD4 T cells and IgA level were significantly increased compared to normal control (P &lt; 0.05). However, no signficant changes in CD3, CD4 T cells were found in patients with MN. Our study demonstrates that CD3 and CD4 T cells as well as IgA are involved in the pathogenesis of IgAN and these targets might be beneficial for the treatment of IgAN.

Recent advances in risk prediction, therapeutics and pathogenesis of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the world's commonest primary glomerular disease with variable clinical presentation and progression rates that are dependent on clinical-pathologic phenotype and duration of follow-up. Overall 4-40% of patients progress to end-stage kidney disease (ESKD) by 10 years. Treatment decisions remain a challenge due to these variations. The ultimate goal of management is to prevent progression to ESKD and of vital importance is the potential reversible early detection of active glomerular inflammation prior to scarring. IgAN is globally, is the most common biopsy proven glomerulonephritis and a leading cause of ESKD. The Oxford pathological classification was devised by a collaborative pathology and nephrology network to provide an evidence-based scoring system with reproducible independent pathology features of predictive value. Clinical variables that alter prognosis include male sex, increasing age, increased body weight, smoking, Pacific Asian ethnicity, hypertension, proteinuria, and complement deficiency. Excellent conservative therapy is the cornerstone of therapy with tight blood control, renin-angiotensin system inhibition, and statin therapy. The role of immunosuppressive therapy including corticosteroids in IgAN remains open with ongoing clinical trials of low dose oral corticosteroids and enteric coated budesonide. Complement activation contributes to the pathogenic process of IgAN with evidence from genetic, serological, histological and in-vitro studies. This knowledge has translated to clinical trials of investigational agents directly targeting the alternative pathway.

M2a and M2b macrophages predominate in kidney tissues and M2 subpopulations were associated with the severity of disease of IgAN patients

M2 macrophages play important roles during the injury and repair phases in kidney. Our aims are to investigate the distribution of M2 subpopulations and the correlation with clinicopathological features of IgA nephropathy (IgAN) patients. In this study, renal samples from 49 IgAN patients were detected by immunofluorescence. The markers of M2 macrophages, including M2a (CD206+/CD68+), M2b (CD86+/CD68+) and M2c (CD163+/CD68+) were identified. We found M2a and M2b macrophages were the predominant subpopulations in kidney tissues of IgAN. M2a macrophages were mainly distributed in tubulointerstitium with renal lesions like segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis. However, there were larger numbers of M2c in glomeruli with minor lesions. Moreover, M2a and M2c macrophages were inversely correlated with the clinical and pathologic features, respectively. These results suggest M2 subpopulations were involved in the progression of IgAN, and M2a and M2c macrophages might show different properties to participate in the pathogenesis of IgAN.

D-amino acid oxidase contributes IgA nephropathy through regulation of IgA production in intestinal mucosa

Abstract Gut mucosa protects our body against threats of bacteria using antimicrobial proteins such as defensins, cathelicidins or lysozyme. D-amino acid oxidase (DAO) is one of the antimicrobial protein that is released from goblet cells into lumen and catabolize D-amino acids, which is essential for almost all bacteria, into antibacterial agent; H2O2. IgA is major immunoglobulin in gut. Maturation of B cells into IgA-secreting plasma cells are lead through two pathways; T cell dependent or independent mechanism. A number of reports indicated the accumulation of systemic IgA in the animals lacking antimicrobial proteins. However, the mechanism how loss of innate immunity affects acquired immunity is yet to be clarified. We found that mouse lacking DAO activity showed accumulation of systemic IgA. Analysis of intestinal microbiota in DAO null mice revealed increased amount of specific bacteria that stimulated IgA production. Crossbreeding experiment between DAO null mice and T cell receptor double knockout (Tcrb−/−, Tcrd−/−) mice showed that the hyper production of IgA is caused by T cell dependent B cell activation. IgA nephropathy (IgAN) occasionally causes chronic kidney impairment. Recent genome wide association analysis indicated the linkage between IgAN and genes associated with mucosal immunity. We found that high IgA (HIGA) mouse, an animal model of IgAN, lacked DAO activity, and that high plasma IgA in HIGA mice is dependent on intestinal microbiota. These results indicated that loss of DAO activity involves in pathogenesis of IgAN through disturbance of mucosal immunity.

Loss of the Golgi Matrix Protein 130 Cause Aberrant IgA1 Glycosylation in IgA Nephropathy

Background: Aberrant O-glycosylation IgA1 production is a major factor in the pathogenesis of IgA nephropathy, but the underlying mechanism is still unclear. IgA1 glycosylation modification is in Golgi, and downregulation of the Golgi peripheral membrane protein Golgi matrix protein 130 (GM130) could lead to glycosylation deficiency. In this study, we aimed to explore the role of GM130 in glycosylate deficiency IgA1 (Gd-IgA1) production. Methods: We enrolled 27 IgA nephropathy patients, 12 patients with chronic tonsillitis, 15 non-IgAN chronic kidney disease patients, and 15 healthy volunteers as healthy control. We explored GM130 expression in Tonsillar tissue by immunofluorescence staining and Western blotting and expression in peripheral blood mononuclear cells (PBMCs) by flow cytometry. The concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia Villosa lectin-binding assay. Real-time PCR and Western blot were used to analyze the levels of β1,3-Gal transferase (C1GALT1) and ST6GalNAC2, respectively. To explore the contribution of GM130 in IgA1 O-glycosylation modification, cells were subjected to experiments for evaluation of GM130 silencing by GM130-siRNA transfection. Results: GM130 expression was significantly decreased in tonsil tissues and PBMC of IgAN patients; the expression of C1GALT1 decreased and Gd-IgA1 level increased significantly in patients with IgAN patients. The expression of GM130 was negatively related to Gd-IgA1 production. By siRNA transfection, our results clearly indicated that the downregulation of GM130 can increase IgA1 O-glycosylation deficiency, which is thought to reduce C1GALT1 expression but not affect the expression of ST6GalNAC2. Conclusion: We identified and demonstrated that GM130 plays an important role in IgA1 O-glycans deficiency in IgAN patients, by negatively regulating C1GALT1 expression. We believe that this finding will provide theoretical foundations for a new mechanism of Gd-IgA1 production in IgAN patients.