Glomerular IgA Deposition Research Articles

Glomerular IgA deposition through Th2-dominant mucosal immune responses

Glomerular IgA deposition through Th2-dominant mucosal immune responses

Prolonged membranous lupus nephritis with change of anti-ssDNA antibody titer and repeated renal relapse

We report a case of a 44-year-old woman with nephrotic syndrome who underwent renal biopsy three times. On each occasion, light microscopy showed membranous nephropathy with mild to moderate thickening of the glomerular capillary walls. Immunofluorescence microscopy showed predominant deposition of immunoglobulin (Ig) G, IgG1, IgG2, IgG3, and IgG4; C3; and C1q along the glomerular capillary walls and deposition of IgM and IgA in some parts of the walls. Electron microscopy revealed the accumulation of electron-dense deposits in the mesangium and the subepithelial area of the glomerular basement membrane. Virus-like particles were detected in the subendothelial cells in all three biopsy specimens. A definitive diagnosis of systemic lupus erythematosus (SLE) was made at the time of the second admission, when she was 31 years old. A diagnosis of membranous lupus nephritis was then made on the basis of the pathological and clinical findings. A change in anti-single-stranded (ss)DNA antibody titers was of particular interest in this patient. Occasional small increases in anti-double-stranded (ds)DNA antibody were found, but increased anti-ssDNA antibody titers occurred before there was any elevation of urinary protein during renal relapse, and a sustained increase in the titers was shown subsequently. Hypocomplementemia occurred in parallel with the increase of anti-ssDNA antibody. Immunosuppressive therapy with steroid promptly eliminated anti-dsDNA antibody, but anti-ssDNA antibody remained positive. The patient had normocomplementemia and proteinuria was absent. Later, anti-ssDNA antibody decreased. Renal function has remained in the normal range for 20 years.

The fate of glomerular mesangial IgA deposition in the donated kidney after allograft transplantation.

To investigate the fate of the mesangial IgA deposits in the donor kidney after allograft transplantation. Routine pre-transplant cadaveric donor kidney biopsy and repeated renal biopsies were performed at months 1, 3, and 6 after renal transplantation. The patients, 342 in number, were divided into IgA positive deposition kidney group (group A, n = 83) and non-IgA deposition kidney group (group B, n = 259). There were no significant differences between the two groups' sex, age, time of hemodialysis, warm ischemia time, cold ischemia time, complement-dependent cytotoxicity, level of panel-reactive assay, and the distribution of original disease. Recipients in group A received donor kidney with glomerular mesangial proliferation and marked diffuse granular IgA deposition. All of them showed edema, nephrotic range protienuria, microhematuria, hypoalbuminemia, hypertension, and delayed graft function. Borderline change was higher in group A than in group B, 37.3 and 16.2% (p < 0.001), respectively. Acute allograft rejection was higher in group A than in group B, 31.3 and 19.3% (p < 0.001), respectively. The glomerular mesangial IgA deposits gradually disappeared from the mesangial regions in grafts of acute rejection. Graft survival in both groups was not significant, being 93.8 and 95.6% in 1 yr, and 86.7 and 88.3% in 3 yr. Clinical features of the recipients which received from donor kidney with glomerular mesangial proliferation and marked diffuse granular IgA deposition: edema, proteinuria, microhematuria, hypoalbuminemia, hypertension, and delayed graft function. The presence of IgA deposits on donated kidney, by a possible increase of the immunogenicity of these kidneys, might be a cause of increased rejection. There were no significant differences between the two groups on long-term allograft survival.

Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy

IgA nephropathy is the most common form of glomerulonephritis worldwide. We previously reported a novel form of glomerulonephritis with glomerular IgA deposits following methicillin-resistant Staphylococcus aureus (S. aureus) infection. We investigated the role of S. aureus related antigens in the immunopathogenesis of IgA nephropathy by producing several monoclonal antibodies against S. aureus surface antigens and determining the epitopes of deposited antigens in patients with IgA nephropathy. Cell membrane proteins were isolated from cultured S. aureus. Mouse monoclonal antibodies against these proteins were generated, and their target epitopes were determined by antibody affinity chromatography and amino acid sequence analysis, and by monoclonal antibody screening of Escherichia coli clones transfected with plasmids from the Lambda S. aureus Genomic Library. Renal biopsy specimens from 116 patients with IgA nephropathy and 122 patients with other forms of renal disease were examined for glomerular antigen depositions by immunofluorescence microscopy. . The major antigen recognized by monoclonal antibodies against S. aureus cell membrane was identified as the S. aureus cell envelope antigen designated 'probable adhesin' (ACCESSION AP003131-77, Protein ID; BAB41819.1). In 68.1% (79/116) of renal biopsy specimens from patients with IgA nephropathy, S. aureus cell envelope antigen was localized in the glomeruli, and the data confirmed that S. aureus cell envelope antigen was co-localized with IgA antibody in the glomeruli. No deposition of this antigen was detected in the glomeruli of patients with non-immune complex deposit forms of glomerulonephritis. S. aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy.

Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy.

In human glomerulonephritis, including immunoglobulin-A nephropathy (IgAN), glomerular expression of macrophage migration inhibitory factor (MIF) is found to correlate with progressive renal injury. We have shown previously that polymeric IgA is capable of inducing MIF production in cultured human mesangial cells, suggesting a role in inducing inflammatory injury in IgAN. Herein, we examined whether IgA deposition and the subsequent renal injury can be ameliorated with anti-MIF treatment in an experimental murine model of IgAN. Glomerular IgA deposition was induced in 4-week-old BALB/c mice by intravenous injection of immune complexes consisting of dinitrophenyl-conjugated bovine serum albumin (DNP-BSA) and IgA MOPC-315 myeloma anti-DNP antibodies. To determine the therapeutic effect of anti-MIF, mice were given anti-MIF (5 mg/kg) or isotypic control antibody intravenously 2 h before the immune complexes administration. The mice were sacrificed 48 h after injection of DNP-IgA. Proteinuria and haematuria were determined and the kidneys were removed for histopathology, immunostaining and immunoblotting. The effect of exogenous MIF on production of TGF-beta 1 by cultured mesangial cells was also examined. IgA deposits were detected in glomeruli of all mice receiving the immune complexes while no glomerular deposit was detected in the control mice. Microscopic haematuria and mesangial hypercellularity were present in mice of the three experimental groups and were absent in the control group. Proteinuria was absent in all groups. Anti-MIF treatment also resulted in decreased renal expression of TGF-beta 1. Moreover, the reduction in TGF-beta 1 expression was confined mainly to glomerular mesangium. An in vitro culture experiment demonstrated that MIF increased TGF-beta 1 production in a time- and dose-dependent fashion. MIF-induced TGF-beta 1 synthesis was abolished by incubating cells with neutralizing antibody against MIF. Our finding shows that anti-MIF treatment can ameliorate kidney injury and reduce glomerular TGF-beta 1 expression in an experimental model of IgAN.

Lymphoid hyperplasia resulting in immune dysregulation is caused by porcine reproductive and respiratory syndrome virus infection in neonatal pigs.

Amid growing evidence that numerous viral infections can produce immunopathology, including nonspecific polyclonal lymphocyte activation, the need to test the direct impact of an infecting virus on the immune system of the host is crucial. This can best be tested in the isolator piglet model in which maternal and other extrinsic influences can be excluded. Therefore, neonatal isolator piglets were colonized with a benign Escherichia coli, or kept germfree, and then inoculated with wild-type porcine reproductive and respiratory syndrome virus (PRRSV) or sham medium. Two weeks after inoculation, serum IgM, IgG, and IgA levels were 30- to 50-, 20- to 80-, and 10- to 20-fold higher, respectively, in animals receiving virus vs sham controls, although <1% was virus specific. PRRSV-infected piglets also had bronchial tree-associated lymph nodes and submandibular lymph nodes that were 5-10 times larger than colonized, sham-inoculated animals. Size-exclusion fast performance liquid chromatography revealed that PRRSV-infected sera contained high-molecular-mass fractions that contained IgG, suggesting the presence of immune complexes. Lesions, inflammatory cell infiltration, glomerular deposits of IgG, IgM, and IgA, and Abs of all three isotypes to basement membrane and vascular endothelium were observed in the kidneys of PRRSV-infected piglets. Furthermore, autoantibodies specific for Golgi Ags and dsDNA could be detected 3-4 wk after viral inoculation. These data demonstrate that PRRSV induces B cell hyperplasia in isolator piglets that leads to immunologic injury and suggests that the isolator piglet model could serve as a useful model to determine the mechanisms of virus-induced immunopathology in this species.

TP002 Detection of a staphylococcal enterotoxin I gene (sei) variant in Staphylococcus aureus strains isolated from clinical samples and food products

Glomerulonephritis associated with MRSA infection: A possible role of bacterial superantigen. We report 10 cases of glomerulonephritis following methicillin-resistant Staphylococcus aureus (MRSA) infection. The clinical features of this syndrome were an abrupt or insidious onset of rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome and occasionally purpura, following MRSA infection. The renal histologic findings showed a variety of types of proliferative glomerulonephritis with varying degrees of crescent formation; immunofluorescence revealed of glomerular deposition of IgA, IgG, and C3. Laboratory findings showed polyclonal increases of serum IgA and IgG, with high levels of circulating immune complexes (ICs). Increased numbers of DR+CD4+, and DR+CD8+ T cells were observed in the peripheral circulation, with a high frequency of T cell receptor (TCR) Vβ+ cells. MRSA produced enterotoxins C and A and toxic shock syndrome toxin (TSST)-1, all of which are known to act as superantigens. From the above observations, we speculate that post-MRSA glomerulonephritis may be induced by superantigens causing production of high levels of cytokines, and polyclonal activation of IgG and IgA. The formation of ICs containing IgA and IgG in the circulation result in development of glomerulonephritis and vasculitis. Accordingly, microbial superantigens may play an important role in the pathogenesis of this unique syndrome of nephritis and vasculitis.

Roles of bone marrow cells in glomerular diseases

Bone marrow transplantation (BMT) has been used as a tool to investigate various roles of bone marrow cells in glomerular diseases. BMT from IgA nephropathy-prone mice caused glomerular IgA deposition associated with increased circulating macromolecular IgA in normal recipients. Conversely, glomerular mesangial lesions of IgA nephropathy-prone mice were markedly diminished by BMT from normal donors, and the circulating levels of macromolecular IgA were also decreased in the recipients. These data suggest that IgA nephropathy may be a stem-cell disease. BMT clearly decreased the glomerular injuries in glomerular diseases other than murine IgA nephropathy. Theoretically, one mechanism underlying the therapeutic effect of BMT is the replacement of the recipient's destructive immune cells with the donor's bone marrow cells. Interestingly, when BMT was performed by using bone marrow cells of green fluorescent protein (GFP) transgenic mice to investigate the differentiation of bone marrow stem cells in recipients, it was revealed that bone marrow-derived cells differentiated into glomerular cells in mice receiving BMT. This result suggests an alternative mechanism, in that bone marrow cells not only replace harmful immune cells but that they also replenish injured glomerular cells in BMT recipients, which results in the repair of glomerular lesions after BMT. In addition, the glomerular remodeling could participate in maintaining glomerular homeostasis. If the mechanisms of glomerular remodeling are investigated, this could offer a new therapeutic strategy for the repair of glomerular injuries.

Clinicopathological correlation of intrarenal cytokines and chemokines in IgA nephropathy.

The pathogenetic mechanisms of IgA nephropathy are diverse and are not yet clearly elucidated. We believe pro-inflammatory cytokines, Th1/Th2, and chemokines would be involved in the pathogenetic pathways and would affect the functional and histological consequences of IgA nephropathy. By using semiquantitative reverse transcriptase-polymerase chain reactions (RT-PCR), we measured the level of intrarenal gene expression of various cytokines and chemokines in 61 renal core biopsy specimens confirmed as IgA nephropathy. And, by using immunohistochemistry (IHC), the degree of expression and the location of various cytokines and chemokines in renal tissues in 29 of the above patients were attempted to be determined. In RT-PCR, the gamma-interferon (IFN-gamma)/interleukin-10 (IL-10) ratio was higher in patients with renal dysfunction than in those with normal renal function. The levels of pro-inflammatory cytokine gene transcripts (tumor necrosis factor-alpha (TNF-alpha), IL-1beta) were high in patients with significant proteinuria. In patients with severe glomerular sclerosis, the ratio of IFN-gamma/IL-10 gene transcripts was high. The level of IL-10 gene transcript was related to the severity of tubular atrophy and interstitial fibrosis. The extent of intrarenal arteriolar lesions correlated with the expression of the IL-8 gene transcript. The degree of IgA deposition in glomeruli was related to the expression of IL-15 and IL-6. In IHC, TNF-alpha, IFN-gamma and IL-2 were immunostained dominantly in the mesangial region, but not in the tubulointerstitial region. In contrast, positive reactions for IL-10 were observed primarily in tubules. Significant reactions for IL-8 were noted in the periarteriolar and arteriolar areas. The results of RT-PCR and IHC showed positive relationships, but these were not statistically significant. This study suggests that pro-inflammatory, Th1/Th2 cytokines and chemokines are involved in the specific processes of inflammation and immunological injury in IgA nephropathy.

Interleukin-12 alters the physicochemical characteristics of serum and glomerular IgA and modifies glycosylation in a ddY mouse strain having high IgA levels.

We recently developed a ddY mouse strain having high IgA levels (HIGA) that provided a murine model of IgA nephropathy. We additionally showed that administration of interleukin (IL)-12, a potent helper T (Th)1-inducing cytokine, induced an apparent reduction in serum IgA levels. In the present study, we assessed the influence of IL-12 administration on several physicochemical characteristics of nephritogenic IgA molecules in HIGA mice. HIGA mice received daily intraperitoneal injections of IL-12 or control injections of phosphate-buffered saline for 3 weeks. Crescent formation and levels of circulating and glomerular IgA were analysed. Moreover, potential changes in charge, size, and glycosylation of serum and glomerular IgA were investigated. In the IL-12 group, glomerular IgA deposition was faint, although crescent formation was more marked than in the control group. Serum IgA levels in IL-12 mice were significantly lower than in controls. IL-12-treated mice also showed markedly decreased acidic and polymeric IgA both in sera and in glomerular eluate. A lectin-binding study revealed a markedly reduced ratio of sialylated and galactosylated IgA in the sera and in glomerular eluate from HIGA mice kidneys. IL-12 treatment significantly increased sialylation and galactosylation of circulating IgA, although glycosylation of IgA in glomerular eluate remained low. In HIGA mice showing under-glycosylation, IL-12 administration may lead to changes in the physicochemical characteristics of IgA, and this may occur through a shift to Th1. These results suggest that the Th1 and Th2 balance might play a role in the development of immunopathologic lesions in this model of IgA nephropathy.

Production of interferon‐γ by tonsillar lymphocytes from patients with IgA nephropathy induced by stimulation with Haemophilus parainfluenzae antigens

IgA nephropathy (IgAN) is characterized by the presence of IgA deposits, predominantly in the glomerular mesangium, and by mesangial proliferative glomerulonephritis (GN). Concerning its pathogenesis, several investigators have suggested that the glomerular IgA deposits in IgAN are antibodies (Ab) to viral, bacterial or dietary antigens. Thus, the Ab are probably produced as part of the specific host immune response to various environmental antigens. Such reports strengthen the possibility of a relationship between mucosal immunity and the pathogenesis of IgAN. Nevertheless, attempts to isolate a specific IgA circulating immune complex-associated antigen in patients with IgAN have been unsuccessful. We have shown that mucosal infections such as pharyngitis are often associated with the acute onset of IgAN.1 IgAN is, then, an immune complex disease that is caused by a poor mucosal immune response to environmental antigens to which the patient has been chronically exposed. We have observed previously that Haemophilus parainfluenzae (HP) is more commonly isolated from the pharynx of patients with IgAN than from those with other glomerular diseases.2 We have also identified the glomerular deposition of outer membranes of HP antigens (OMHP) and an increased serum concentration of IgA-Ab against OMHP in patients with IgAN.2 Furthermore, we have shown that patients with IgAN have a specific increase in the production of IgA-Ab against OMHP via polyclonal activation against these, with switching of production from one isotype to another (e.g. from IgM to IgA3), and that a significant relationship between IgA-Ab against OMHP and renal lesions exists in patients with IgAN,4 and that OMHP stimulate tonsillar B-lymphocytes to produce specific IgA1-Ab against OMHP and tonsillar T-lymphocytes in patients with IgAN.5,6 Our objective was to investigate the production of IgA and several cytokines by tonsillar lymphocytes from patients with IgAN induced by stimulation with OMHP. We used tonsillar lymphocytes from the palatine tonsils of 18 patients with IgAN and 25 patients with chronic tonsillitis but without renal diseases as controls. There were no significant differences in the backgrounds of the two groups. Haemophilus parainfluenzae was detected in the tonsils of all 43 patients before tonsillectomy. We examined production of total IgA, IgA-Ab against OMHP, IL-4, IL-6, IL-10, and TGF-β in the culture supernatants after lymphocyte incubation with OMHP. The spontaneous production of total IgA and TGF-β by tonsillar lymphocytes from patients with IgAN was higher than that by tonsillar lymphocytes from controls (P < 0.05). Stimulation with OMHP in vitro enhanced the production of HP-specific IgA by tonsillar lymphocytes from patients with IgAN (P < 0.01), but not by tonsillar lymphocytes from controls. Outer membranes of HP stimulation also enhanced the production of TGF-β and IL-10 by tonsillar lymphocytes from patients with IgAN (P < 0.001). Our results suggest that the infection of HP in the tonsil may be involved in the aetiology of IgAN.

Prognostic factors in mesangioproliferative glomerulonephritis.

The aim of our study was to examine patients with mesangioproliferative glomerulonephritis (MPGN), with or without glomerular IgA deposits, and to analyse the effect of different clinical and histopathological variables at the time of biopsy on progression to end-stage renal failure (ESRF) and death. We retrospectively examined 273 patients who got this diagnosis in Norway from April 1988 to December 1990 after a renal biopsy. All patients were followed for a median duration of 34.8 months (0.8-68 months). The mean age at the time of biopsy was 40+/-17 years (range 1.1-79 years). Glomerular IgA deposits were present in 45% of the patients; IgA deposits did not affect prognosis. Three years after the time of biopsy, 7% had developed ESRF (chronic dialysis treatment or kidney transplantation) and 8% had died. By Kaplan-Meier analyses, the following clinical variables indicated progression to ESRF: increased serum creatinine, proteinuria > or =1 g/24 h, systolic blood pressure (BP) > or =160 mmHg, diastolic BP > or =90 mmHg, serum albumin <35 g/l, presence of urinary granular casts and age > or =60 years. Morphological variables indicating progression to ESRF were presence of focal mesangial sclerosis, focal glomerular crescents or necroses, benign nephrosclerosis and increased interstitial score. In the multivariable analysis, the following variables indicated progression to ESRF: increased serum creatinine (P<0.001), decreased serum albumin (P<0.05), increased diastolic BP (P<0.05), low age (P<0.05) and increased interstitial score (P<0.001). It is possible from clinical and histopathological variables to identify low-risk and high-risk patients at the time of biopsy. There is, however, considerable convergence. A major new observation is the finding of young age, decreased serum albumin and the presence of urinary granular casts as important clinical risk factors. Interstitial damage was the most important histopathological predictor of ESRF.

Pathogenic role of the IgA molecule in IgA nephropathy

SUMMARY: Deposits of IgA together with complement in different body tissues support the hypothesis that IgA can trigger inflammatory mechanisms. IgA nephropathy (IgAN) is characterized by predominant mesangial IgA1 deposits of a polymeric nature. So far, the mechanism of polymeric IgA1 deposition in the kidney mesangium is poorly understood in IgAN. The exact pathophysiological sequel preceding renal fibrosis following the mesangial deposition of IgA immune complexes remains speculative. Recent in vitro studies revealed that binding of IgA to mesangial cells led to increased expression of growth factors, cytokines, and integrins. The release of these proinflammatory factors is likely to enhance inflammatory injury. In addition, the local renin–angiotensin system present in renal tissues also contributes to renal fibrosis through the activation of transforming growth factor‐β. The question of whether polymeric IgA isolated from patients with IgAN exerted any upregulatory effect on the synthesis of macrophage migration inhibitory factor (MIF) and components of the renin–angiotensin system in human mesangial cells was explored. The in vitro studies revealed that polymeric IgA from IgAN patients upregulated the gene expression of renin and MIF in human mesangial cells in a dose‐dependent manner. These findings further support the notion that glomerular deposition of IgA is not only a pathological epiphenomenon of IgAN, but that polymeric IgA exerts a pathophysiologic effect on the mesangial cells leading to renal fibrosis.

Pathogenic role of the IgA molecule in IgA nephropathy

SUMMARY: Deposits of IgA together with complement in different body tissues support the hypothesis that IgA can trigger inflammatory mechanisms. IgA nephropathy (IgAN) is characterized by predominant mesangial IgA1 deposits of a polymeric nature. So far, the mechanism of polymeric IgA1 deposition in the kidney mesangium is poorly understood in IgAN. the exact pathophysiological sequel preceding renal fibrosis following the mesangial deposition of IgA immune complexes remains speculative. Recent in vitro studies revealed that binding of IgA to mesangial cells led to increased expression of growth factors, cytokines, and integrins. the release of these proinflammatory factors is likely to enhance inflammatory injury. In addition, the local renin‐angiotensin system present in renal tissues also contributes to renal fibrosis through the activation of transforming growth factor‐β. the question of whether polymeric IgA isolated from patients with IgAN exerted any upregulatory effect on the synthesis of macrophage migration inhibitory factor (MIF) and components of the renin‐angiotensin system in human mesangial cells was explored. the in vitro studies revealed that polymeric IgA from IgAN patients upregulated the gene expression of renin and MIF in human mesangial cells in a dose‐dependent manner. These findings further support the notion that glomerular deposition of IgA is not only a pathological epiphenomenon of IgAN, but that polymeric IgA exerts a pathophysiologic effect on the mesangial cells leading to renal fibrosis.

Experimental Nephropathy Induced by Haemophilus parainfluenzae Antigens

Background: We have demonstrated that outer membrane antigens of Haemophilus parainfluenzae (OMHP) are potentially involved in IgA nephropathy (IgAN). In this study, we established an experimental model of IgAN using OMHP antigens and investigated the nephritogenicity of OMHP antigens. Methods: One hundred and twenty C3H/HeN mice were administered OMHP antigens orally (PO group) or intraperitoneally (IP group). Mice were sacrificed at 10, 20, 30, 40, and 50 weeks of age to examine sequential glomerular changes and to measure levels of IgG, IgA, and IgM antibody against OMHP by ELISA. Results: Glomerular deposition of IgA and increases in the amount of mesangial matrix were observed in the PO group and the IP group from 40 and 30 weeks of age, respectively. Mice in both groups showed glomerular deposition of OMHP antigens from 30 or 40 weeks of age. Levels of IgA antibodies against OMHP were significantly increased in the PO and IP groups compared with controls. There was a significant correlation between mesangial proliferation and glomerular deposition of IgA. Conclusions: Administration of OMHP antigens to mice may induce glomerular deposition of IgA and mesangial proliferation, resembling the changes seen in IgAN, with increases in IgA antibodies against OMHP antigens. This is the first use of OMHP antigens to establish an active model of IgAN.

Complications of IgA nephropathy in a non-insulin-dependent diabetes model, the Akita mouse.

The Akita mouse, which has a mutation (Cys96Tyr) in the insulin 2 gene (Ins2(Akita)), is a model for diabetes. The male Akita mouse has diabetes, while females develop mild diabetes. This study aimed to investigate renal complications in the Akita mouse model, which has been maintained in a heterozygous state Ins2(Akita) (+/-) with a C57BL/6 background (B6). Renal function (BUN, creatinine), serum IgA concentrations and histological changes in the kidneys were evaluated in diabetic and control mice in a B6 background. Five each of male and female mice per group (diabetes vs. control) were killed at 10, 20, 30 and 40 weeks of age. The influence of major histocompatibility antigens (MHC) on renal complications was tested using male diabetic mice in a C3H/He (C3H) background. When compared with controls, diabetic males, but not females, developed impaired renal function with elevation of serum IgA after 30 weeks of age. Diabetic glomerulosclerosis advanced with age in both sexes. Diffuse granular mesangial deposits of IgA were detected by immunofluorescence microscopy in diabetic males after 20 weeks. We tested whether the IgA-associated lesions were influenced by MHC using diabetic males in a C3H background. Similar degrees of diabetic glomerulosclerosis and glomerular IgA deposition were found in mice with C3H and B6 backgrounds. Akita mouse is a unique mouse model showing both mesangial sclerosis and IgA nephropathy.

Immunoglobulin A nephropathy and disease prognostic factors

Immunoglobilin A nephropathy (IgAN) is a clinicopathological entity characterized by diffuse glomerular mesangial deposition of IgA as the predominant immunoglobulin. Renal biopsy reveals a spectrum of changes in glomerula, tubulointerstitium and blood vessels. 20-50% of all patients develop end-stage renal failure 20 years after onset of disease. The aim of this study was to investigate the incidence of IgAN and to analyze clinicopathological changes and prognosis of IgAN. The study included 60 patients with biopsy-proved IgAN without some other systemic diseases or Henoch-Schonlein purpura. We analyzed clinical features of the disease, laboratory findings, findings of immunofluorescence and light microscopy and prognosis of IgAN. The study is partly retrospective and partly prospective. Incidence of the disease in the period 1981-1997 was 9.78%. At the moment of renal biopsy 63.16% of patients had normal renal function, 31.58% had stage I and 5.25% had stage II chronic renal failure. At the end of study 21.05% of investigated patients were included into the worse stage of renal failure in regard to the initial stage. Progression of renal damage correlated with special tubulointerstitial damage and heavy proteinuria. In this study we found severe histopathological changes in the group with already impaired renal function and these changes correlated with laboratory findings, clinical features and prognosis. Normal renal function at the moment of renal biopsy pointed to risk for further damage. Changes in the tubulointerstitium and mesangium, heavy proteinuria and hypertension affect the disease prognosis. Evolution to the higher stage of renal failure was 1.24% per year and this requires long-term follow-up of patients with IgAN.

Comparison of immunological and histopathological changes between oral and intraperitoneal immunization of outer membrane of Haemophilus parainfluenzae antigens in mice

IgA nephropathy (IgAN) was first reported by Berger in 1968, and characterized by diffuse IgA deposits in glomerular mesangium and mesangial proliferative glomerulonephritis. Clinically, patients with IgAN have frequently episodic macroscopic haematuria accompanied with pharyngitis, tonsillitis, gastroenteritis, bronchitis, or sinusitis. These findings suggest that IgAN is related to inflammatory and immune responses to mucosal infections. We have reported that primary IgAN patients with acute onset are often associated with mucosal infections such as pharyngitis and tonsillitis, and Haemophilus parainfluenzae (HP) is more frequently isolated from the pharynx of patients with IgAN than from those with other diseases.1 We also demonstrated glomerular deposition of outer membrane of HP (OMHP) antigens and the presence of IgA antibody against OMHP in patients with IgAN.1 These findings suggest that HP has a role in the aetiology of primary IgAN. In the present study, we attempt to develop an experimental model of IgAN induced by oral and intraperitoneal immunization of OMHP antigens, and evaluate the difference in immunological and histopathological changes between these two administration routes. Four-week-old female C3H/HeN mice were fed mouse chow. One hundred and twenty mice were divided into oral (PO group) and intraperitoneal (IP group) administration groups of OMHP antigens and each control groups. Mice of the PO group received OMHP antigens for daily drinking water and intragastric intubation once a week, and mice in the IP group received intraperitoneal injection of 0.1 mL of OMHP antigens, once a week. Six mice from each group were killed at 10, 20, 30, 40 and 50 weeks of age to examine sequential glomerular changes. We also measured serum IgG, IgA, IgM antibody against OMHP antigens, and serum IL-10 and IFN γ by ELISA. Throughout experiments, haematuria and proteinuria were analysed every 5 weeks. IgA antibodies against OMHP significantly increased in PO and IP groups compared with the control, and the degree of increase in IgA antibodies against OMHP was more prominent in the PO group. In the IP group, IgG and IgM antibodies against OMHP increased more markedly. Glomerular deposition of IgA and increase of mesangial matrix were observed in the PO group from 40 weeks of age and in the IP group from 30 weeks of age, respectively. Mice in both groups showed glomerular deposition of OMHP antigens. Haematuria was not detected in any group. Serum IL-10 tended to increase in the PO and IP groups, and IFN γ did not increase significantly in any group. These results suggest that oral administarion of OMHP antigens induce glomerular deposition of IgA and mesangial proliferation with increase of IgA antibodies against OMHP antigens in mice, and these observations in the PO group resemble the changes of human IgAN more closely than in the IP group.

Effect of soluble form CTLA‐4 on spontaneous IgA nephropathy in ddY mice

The aim of the present study was to examine the role of CD28‐B7 signalling in the development of glomerulonephritis in ddY mice, an animal model for IgA nephropathy. To achieve this aim, we investigated whether the CTLA‐4 (CD152) fusion protein, which binds to B7.1 (CD80) and B7.2 (CD86), affects glomerular pathological changes (including IgA deposition), or functional parameters (such as serum creatinine and proteinuria). Each group (n = 4) was given either human CTLA‐4 fused with human IgG (CTLA4Ig) or control human IgG1. All treated groups of mice were injected intraperitoneally at a dose of 0.1 mg twice a week for the duration of the study. Mice given control human IgG1 progressively developed typical mesangioproliferative glomerulonephritis, with remarkable glomerular IgA deposits. In contrast, mice treated with CTLA4Ig showed a significant reduction in proteinuria and mesangioproliferative change, with an expansion of the mesangial matrix at 40 weeks of age. The serum IgA levels of these mice were considerably lower than those in mice given the control human IgG1. A direct immunofluorescence study showed the reduction of glomerular IgA deposits in CTLA4Ig‐treated mice. We have demonstrated for the first time that the development of spontaneously occurring IgA nephropathy can be prevented in ddY mice by blocking the CD28‐B7 interaction using a soluble form of CTLA4Ig. These results suggest that a costimulatory signal via CD28‐B7 may play a crucial role in the development and progression of IgA nephropathy.

Clinical and histological improvement with long-term, low-dose cyclosporin A in a patient with severe IgA nephropathy

We report the case of an 11-year-old girl with nephrotic syndrome with massive proteinuria and microscopic hematuria. Her first renal biopsy specimen (June 1997) showed diffuse/segmental mesangial proliferative glomerulonephritis with capillary wall thickening, crescent, and sclerosis by light microscopy, as well as diffuse/global moderate deposition of IgA, C3, and fibrinogen predominantly in the mesangium, and partly along the capillary wall, by immunofluorescent microscopy. After the patient failed to show remission with the usual dose of prednisolone and azathioprine, cyclosporin A was administered, in addition to dipyridamole, warfarin, and prednisolone (on alternative days). In consequence, the proteinuria had completely disappeared after 6 weeks of this regimen and microscopic hematuria had disappeared after 8 months of the regimen. A second renal biopsy was performed in August 1998. The epithelial proliferation and crescent seen in the first biopsy specimen had disappeared, and only mesangial proliferation and sclerosis persisted, without histological evidence of cyclosporin-induced nephrotoxicity. A third renal biopsy was performed in March, 2000. IgA deposition in glomeruli had disappeared in this biopsy specimen. Low-dose cyclosporin A therapy resulted in dramatic improvements in both clinical manifestations and renal histological findings, without detrimental effects on renal function.