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Comparison between groups B1 and B2 before and after the first steroid pulse therapy session. (A) An improvement in hematuria was observed in group B1, but not in group B2. The rate of change in hematuria in group B1 was significantly lower than that in group B2. (B) The rate of change in proteinuria before and after the first steroid pulse therapy session was not significantly different between groups B1 and B2. (C) The rate of change in serum creatinine before and after the first steroid pulse therapy session was not significantly different between groups B1 and B2.
Source publication
Recent studies have shown that galactose-deficient IgA1 (GdIgA1) has an important role in the pathogenesis of IgA nephropathy (IgAN). Although emerging data suggest that serum GdIgA1 can be a useful non-invasive IgAN biomarker, the localization of nephritogenic GdIgA1-producing B cells remains unclear. Recent clinical and experimental studies indic...
Similar publications
The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN).
Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid...
Objective . To investigate the influence of in vitro vibratory stimulation of human tonsillar mononuclear cells (TMCs). Methods . Fourteen IgA nephropathy (IgAN) patients with chronic tonsillitis (CT) and 12 CT patients with no renal pathology were enrolled. Group A TMCs were collected after 24 hours of culture and used to determine baseline levels...
The aim of this study is to investigate the distinctive clinicopathological characteristics of acute kidney injury (AKI) in immunoglobulin A (IgA) nephropathy and identify the possible risk factors for AKI in IgA nephropathy. This study was a hospital-based retrospective analysis of clinicopthological data of IgA nephropathy. The study was conducte...
Hematuria is the first manifestation of urinary abnormality in immunoglobulin A nephropathy (IgAN). Hematuria has recently been reported as a risk factor for deterioration of renal function; however, its cause remains unknown.
We analyzed the surface marker of peripheral blood mononuclear cells before and immediately after tonsillectomy in IgAN pat...
Citations
... Since Gd-IgA1 is central to the pathogenesis of IgAN, its association with therapy has been investigated in many studies. Nakata et al. 50 demonstrated a decline in serum Gd-IgA1 concentration and haematuria after tonsillectomy alone in 59% of a cohort of Japanese IgAN patients. When steroids were added to tonsillectomy, more patients improved in terms of haematuria and serum Gd-IgA1. ...
... The 'mishoming' of these cells to other lymphoid organs may explain, in part, the different responses observed to tonsillectomy alone. 50 The level of Gd-IgA1 was shown to be significantly reduced after 3 to 6 months of immunosuppression (including oral and/or systemic steroid or cycloserine) in a cohort of Taiwanese IgAN patients. 51 Prednisolone therapy showed a significant difference in serum levels of Gd-IgA1 from the baseline to 6 months posttransplant in a prospective study involving 36 posttransplant IgAN patients. ...
Introduction:
Immunoglobulin A (IgA) nephropathy (IgAN) results from abnormal accumulation of immune complexes containing galactose deficient IgA1 (Gd-IgA1) in the kidneys. About 40% of patients develop end-stage kidney disease within 20 years of renal biopsy. At present, the diagnosis and risk stratification of patients (using the international IgAN risk prediction tool) rely on renal biopsy, which is an invasive procedure. Also, treatment decisions are still dependent on proteinuria, which is not specific for IgA nephropathy. We discussed the role of serum and urine Gd- IgA1 in the diagnosis of IgAN, its association with disease progression and changes with treatment in patients with IgA nephropathy.
Materials and methods:
A systematic search of PubMed and Scopus databases was done to identify the articles that are relevant to the topic including systematic reviews and original articles.
Results:
Several studies showed that both serum and urine Gd-IgA1 differentiate IgA nephropathy patients from healthy people and other glomerulonephropathies. Thus, it is useful as a less invasive diagnostic biomarker, although detection methods varied between studies with different sensitivities. There are various reports of its use as a prognostic parameter. Evidence is emerging for its use as a monitoring parameter for treatment.
Conclusion:
Galactose deficient IgA1 is a promising biomarker in the management of IgA nephropathy, although a more robust and standardised means of estimation is required.
... 9, 10 It has also been suggested that Gd-IgA1 in the circulating blood may be produced, in part, by palatine-tonsil B cells. 11 Previous studies showed that a tumor-necrosis-factor family member, a proliferation-inducing ligand was overexpressed in B cells located in germinal centers of tonsils from patients with IgAN, and its expression levels correlated with the severity of proteinuria. Serum level of Gd-IgA1 in many patients with IgAN decreased after tonsillectomy. ...
Introduction
Galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy has been beneficial to some patients with IgAN, possibly due to the removal of tonsillar cytokine-activated cells producing Gd-IgA1. To test this hypothesis, we used immortalized IgA1-producing cell lines derived from tonsils of patients with IgAN or obstructive sleep apnea (OSA) and assessed the effect of leukemia inhibitory factor (LIF) or oncostatin M (OSM) on Gd-IgA1 production.
Methods
Gd-IgA1 production was measured by lectin enzyme-linked immunosorbent assay; JAK-STAT signaling in cultured cells was assessed by immunoblotting of cell lysates; and validated by using small interfering RNA (siRNA) knock-down and small-molecule inhibitors.
Results
IgAN-derived cells produced more Gd-IgA1 than the cells from patients with OSA, and exhibited elevated Gd-IgA1 production in response to LIF, but not OSM. This effect was associated with dysregulated STAT1 phosphorylation, as confirmed by STAT1 siRNA knock-down. JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction. Unexpectedly, high concentrations of AZD1480, but only in the presence of LIF, reduced Gd-IgA1 production in the cells derived from patients with IgAN to that of the control cells from patients with OSA. Based on modeling LIF-LIFR-gp130-JAK2 receptor complex, we postulate that LIF binding to LIFR may sequester gp130 and/or JAK2 from other pathways; and when combined with JAK2 inhibition, enables full blockade of the aberrant O-glycosylation pathways in IgAN.
Conclusion
In summary, IgAN cells exhibit LIF-mediated overproduction of Gd-IgA1 due to abnormal signaling. JAK2 inhibitors can counter these LIF-induced effects and block Gd-IgA1 synthesis in IgAN.
... In addition, a meta-analysis reported that tonsillectomy may induce clinical remission and reduce the likelihood of ESKD in patients with IgAN (36). Patients with higher TLR9 expression in the tonsils had a lower serum Gd-IgA1 level, and hematuria improved immediately after tonsillectomy (37). Similarly, for IgAN patients undergoing kidney transplantation, tonsillectomy has also been reported to decrease proteinuria and induce clinical remission in recurrent IgAN or IgA vasculitis (38)(39)(40)(41). ...
IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. IgAN progresses to end-stage kidney disease in 20-40% of patients within 20 years of diagnosis. Kidney transplantation is the most effective option for patients with end-stage kidney disease caused by IgAN, but recurrence can occur in the transplanted kidney. The IgAN recurrence rate varies from 1% to 10% per year, and varies according to the follow-up period, diagnostic modality, and biopsy criteria. Of note, studies based on protocol biopsies have reported a higher incidence of recurrence, which also occurred earlier after transplantation. In addition, recent data show that recurrence of IgAN is a more significant cause of allograft failure than previously believed. Little is known about the pathophysiology of IgAN recurrence, but several potential biomarkers have been investigated. Among them, galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, and soluble CD89 could play a pivotal role in disease activity. This review aims to describe the current status of recurrent IgAN, including the incidence, clinical characteristics, risk factors, and future perspectives, with a focus on the available therapeutic approaches.
... Modulation of NALT Evidence suggested that NALT or palatine tonsils may also be responsible for the synthesis of Gd-IgA1 in patients with IgAN [23,33,124]. Although several studies show that tonsillectomy could reduce the serum levels of Gd-IgA1 [125,126], data from European and Asian studies revealed that tonsillectomy is associated with an increased likelihood of developing IBD and irritable bowel syndrome [127,128]. ...
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with varied clinical and histopathological features between individuals, particularly across races. As an autoimmune disease, IgAN arises from consequences of increased circulating levels of galactose-deficient IgA1 and mesangial deposition of IgA-containing immune complexes, which are recognized as key events in the widely accepted “multi-hit” pathogenesis of IgAN. The emerging evidence further provides insights into the role of genes, environment, mucosal immunity and complement system. These developments are paralleled by the increasing availability of diagnostic tools, potential biomarkers and therapeutic agents. In this review, we summarize current evidence and outline novel findings in the prognosis, clinical trials and translational research from the updated perspectives of IgAN pathogenesis.
... Furthermore, the group in which serum Gd-IgA1 levels decreased after tonsillectomy alone exhibited significantly higher levels of tonsillar TLR9 expression and increased improvements in hematuria immediately after tonsillectomy compared with the group in which Gd-IgA1 levels only decreased after the addition of steroid pulse therapy after tonsillectomy. The results of these studies indicate that the Gd-IgA1-producing cells are present in palatine tonsils [78]. Recently, a genome-wide association study revealed that a TNFSF13 (APRIL) variant is involved in IgAN susceptibility [79]. ...
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.
... We have previously reported that the changes in the serum level of IgA before and after tonsillectomy correlated with the remission rates of proteinuria [13]. Moreover, patients whose serum Gd-IgA1 levels decreased after tonsillectomy alone showed better improvement in haematuria after tonsillectomy [14]. These ndings suggested that the changes in serum IgA and Gd-IgA1 levels before and after treatment are useful biomarkers to predict treatment response. ...
Background
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Approximately 30–40% of patients progress to end-stage renal disease over 20 years. Mucosal immune dysregulation in nasal-associated lymphoid tissue (NALT) may be involved in the pathogenesis of IgAN. In Japan, the efficacy of tonsillectomy combined with steroid pulse therapy (TSP) has been reported. Meanwhile, the risk of surgery i.e., tonsillectomy and the adverse effects related to systemic steroid administration are major concerns for TSP. To overcome these problems, we propose a topical steroid therapy targeting NALT. This therapeutic concept is a novel approach to regulate the mucosal immunity of NALT. In this study, we aim to evaluate the safety and efficacy of dexamethasone-based elixir gargling in patients with IgAN.
Methods
This will be a single-centre, open-label, historical controlled study. We plan to enroll 20 patients diagnosed with IgAN who were scheduled to undergo tonsillectomy. All participants are required to sign a written consent form. The study protocol has been reviewed and approved by Juntendo University Hospital Certified Review Board (CRB3180012). Patients will receive steroid gargling therapy with 10 ml of 0.01% undiluted solution of dexamethasone elixir four times per day for 4 weeks. The primary endpoint is the safety of steroid gargling, including the incidence of adverse events (oral/pharyngeal discomfort and taste disorders), presence of elevated inflammatory markers and presence of glucose intolerance. The secondary endpoint is the efficacy of steroid gargling, including serum IgA and galactose-deficient IgA1 (Gd-IgA1) level, renal function, proteinuria and haematuria. All statistical analyses will be conducted using the SAS statistical software (version 9.4, SAS Institute, Cary, NC, USA).
Discussion
There are few reports of intra-oral, topical steroids in renal disease. Once the steroid gargle is evaluated as safe in this study, extending the gargling period for longer term—for example 3 to 6 months—would be considered in the subsequent large-scale study. This pilot trial would also help in assessing the financial, technical, administrative, or logistic feasibility of a larger study.
Trial registration number
Japan Registry of Clinical Trials (jRCTs031200127). https://jrct.niph.go.jp/latest-detail/jRCTs031200127. Protocol version: October 15, 2021 Ver. 1.3. The date of registration 09/23/2020
... Gut-associated lymphoid tissue (GALT), including Peyer's Patches, which are thought to contain a high concentration of conventional surface IgA1-expressing primed mucosal B cells and plasma cells, may be responsible for the production of Gd-IgA1 in IgAN [69,70]. Although other studies suggest the nasopharynx-associated lymphoid tissue (NALT) or palatine tonsils may also play an important role in Gd-IgA1 production in patients with IgAN [71,72]. Undoubtedly, reducing Gd-IgA1 levels is a promising approach for disease modification [36]. ...
Immunoglobulin A nephropathy (IgAN) is a rare autoimmune disorder and the leading cause of biopsy-reported glomerulonephritis (GN) worldwide. Disease progression is driven by the formation and deposition of immune complexes composed of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 autoantibodies (anti-Gd-IgA1 antibodies) in the glomeruli, where they trigger complement-mediated inflammation that can result in loss of kidney function and end-stage kidney disease (ESKD). With the risk of progression and limited treatment options, there is an unmet need for therapies that address the formation of pathogenic Gd-IgA1 antibody and anti-Gd-IgA1 antibody-containing immune complexes. New therapeutic approaches target immunological aspects of IgAN, including complement-mediated inflammation and pathogenic antibody production by inhibiting activation or promoting depletion of B cells and CD38-positive plasma cells. This article will review therapies, both approved and in development, that support the depletion of Gd-IgA1-producing cells in IgAN and have the potential to modify the course of this disease. Ultimately, we propose here a novel therapeutic approach by depleting CD38-positive plasma cells, as the source of the autoimmunity, to treat patients with IgAN.
... В этиологии IgAN значительное внимание отводится вирусным и бактериальным инфекциям. Существенное место в патогенезе IgAN принадлежит и СГА-инфекциям [84,89]. Каждая из этих причин накладывает свой отпечаток на генез IgAN. ...
M and M-like proteins represent the main pathogenicity factors of Streptococcus pyogenes, a widely spread and potentially lethal bacterial pathogen. These proteins provide resistance of the microbe to innate and adaptive immune response, due to attraction of specific human proteins to the streptococcal surface. Nonimmune binding of immunoglobulins G (IgG) and A (IgA) via their Fc domains to M and M-like proteins was described over 40 years ago, but its role for the pathogenicity of Streptococcus pyogenes is far from definite resolution. The discovery of this phenomenon should be considered among quite significant achievements of modern microbiology, since it had a huge impact upon development of innovative approaches, technologies and tools for microbiological, immunological and molecular diagnostics. It also promoted fundamental studies in pathogenesis of distinct infectious states and their complications caused by S. pyogenes. The non-immune binding of host immunoglobulins was previously suggested to be important mainly in immune conditions on the surface of mucous membranes and their secretions, but not in blood plasma, whereas other studies have pointed to significance of this phenomenon in protecting microbes from phagocytosis in non-immune blood of the host. It was also shown that the effect of Fc-binding causes increased pathogenicity of streptococci both in primary focus of infection, and during chronical course of the process, thus contributing to development of autoimmune diseases caused by S. pyogenes infection and leading to tissue damage in experimental animals. The experimental autoimmune process can be prevented by administering purified Fc fragments of immunoglobulins to the animals, blocking this process at the early stages of its development. A significant place in pathogenesis of IgA nephropathy (IgAN) belongs to streptococcal diseases. IgAN has been described as a mesangial proliferative process, due to initial IgA-Fcα deposition in renal mesangium cells. The data from literature describe successful modeling of individual IgAN traits, and expand our understanding of pathogenic properties and functions of Fcα binding receptor M proteins of S. pyogenes. The data reviewed in the article also presume the relevance of recently proposed ideas about an important role of non-immune Ig binding in streptococcal diseases, even in cases that differ in their development mechanism. These studies, including possible search for tools and techniques of preventive and potentially therapeutic applications, require additional efforts to study the binding of Fc fragments of IgG and IgA to M and M-like proteins of Streptococcus pyogenes.
... Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney. is considered standard-of-care for patients with IgAN in Japan (4)(5)(6). Our previous studies of a murine IgAN model suggest that commensal microbial colonization is essential for the development of IgAN in mice overexpressing the TNF-family member BAFF (7,8). This model shares many features with human IgAN, including underglycosylated IgA; clinical and histological measures of kidney injury, such as proteinuria; and IgA-dominant glomerulonephritis (7,8). ...
IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production is not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries of high disease prevalence tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses we characterized the tonsil microbiota in patients with IgAN versus non-related household-matched control subjects and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN cases. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice, rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B x hC-Tg). Colonization of B x hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria-specific IgA-secreting cells within in the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts such as Neisseria in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.
... This finding suggests that the main source of IgA in patients with IgAN is the tonsils, which are part of the NALT. Furthermore, when Gd-IgA1 levels were measured before and after tonsillectomy, it was confirmed that hematuria was significantly improved early after tonsillectomy in patients whose Gd-IgA1 levels decreased after tonsillectomy alone [55]. These results suggest that the palatine tonsils may be the major site of Gd-IgA1 production. ...
A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.
