Lupus nephritis progression in FcγRIIB-/-yaa mice is associated with early development of glomerular electron dense deposits and loss of renal DNase I in severe disease
Kjersti Daae HorveiHege Lynum PedersenSilje FismenDhivya ThiyagarajanAndreá SchneiderOle Petter RekvigThomas WinklerNatalya Seredkina
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FcγRIIB-/-yaa mice develop severe lupus glomerulonephritis due to lack of an inhibitory immune cell receptor combined with a Y-chromosome linked autoimmune accelerator mutation. In the present study, we have investigated nephritis development and progression in FcγRIIB-/-yaa mice to find shared features with NZB/NZW F1 lupus prone mice and human disease. We sacrificed 25 male FcγRIIB-/-yaa mice at various disease stages, and grouped them according to activity and chronicity indices for lupus nephritis. Glomerular morphology and localization of electron dense deposits containing IgG were further determined by immune electron microscopy. Renal DNase I and pro-inflammatory cytokine mRNA levels were measured by real-time quantitative PCR. DNase I protein levels was assessed by immunohistochemistry and zymography. Our results demonstrate early development of electron dense deposits containing IgG in FcγRIIB-/-yaa mice, before detectable levels of serum anti-dsDNA antibodies. Similar to NZB/NZW F1, electron dense deposits in FcγRIIB-/-yaa progressed from being confined to the mesangium in the early stage of lupus nephritis to be present also in capillary glomerular basement membranes. In the advanced stage of lupus nephritis, renal DNase I was lost on both transcriptional and protein levels, which has previously been shown in NZB/NZW F1 mice and in human disease. Although lupus nephritis appears on different genetic backgrounds, our findings suggest similar processes when comparing different murine models and human lupus nephritis.Keywords:
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Kidney biopsy findings in 48 patients suffering from nephritis, neohrotic syndrome and juvenile hypertension were compared with their clinical and laboratory findings. The results ohtained were as follows. 1) Akute nephritis : Monerately severe inflammatory reakctions of the glomeruli, such as swelling of the tuft, proliferation of inflammatory cells and adherion of glomerular capillaries were observed even in very slight cases. 2) Chronic nephritis : a) In latent chronic form with slight albuminuria and without hyportension, almost every cases showed evidences of glomerulitis and in few cases crescent formation, hyalinization of the glomeruli were also observed. b) Characteristic changes of latent chronic nephritis with moderate albuninuria without hypertension were thickning of capillary basement membrane and of mesangium of the glomerulis. c) In eases of hypeatensive chronic nephritis with slight albuminuria, glomeritlar changes were not so severe, but adhesion, narrowing and fibrosis of the capillary tuft were recognized. d) In casis of hypertensive chronic nephritis with moderate albuminuria, thickning of the basement membrane and mesangium. swelling of the glomerular capillary tuft accompanying narrowing of the lumen were observed and hyslinization of the glomeruli were also recognized in every cases. e) In chronic azotemic nephritis, s_??_vere destruction of the glomeruli, degeneratiou and atrophy of the tubles were typical and islets of reserved, functioning nephrons were scattered in the fibrosed, infiltrated interstitial tissues, Sclerotic changes of the arteries were also remorkrble. 3) Neghrctic iyndrome : In cases of nephrotjc syndrome characteristic changes of the glomeruli were thickning of capillarg basement membrane. In electron-nicroscopic examinations, there was no thickning of the lamina deusa of the basement membrane and most remarkable changes were irregular coarseness of the lamine deusa, disappearance of the cement layer and band shaped proliferation of endothelial cytoplasma along its filtrable surface. 4) Juvenile hypertension : Differential diagnosis of this clinical eutity and hypertensive nephritis is quite difficult in many cases. In cases of juvenile hypertension, there was no specific change, except the hypertrophy of the glomeruli. There were no evidences of glomerulitis.
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Albuminuria
Glomerular mesangium
Hyaline
Interstitial nephritis
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BACKGROUND: Apoptosis is a mechanism of cellular death involved in the deletion of cells in hyperplasic processes which has been observed in proliferative glomerulonephritis. Patients with systemic lupus erythematosus (SLE) are known to have defective apoptosis but there is scarce information about apoptosis in the renal lesions of this disease. The present studies were done to evaluate apoptosis in relation to the intensity of proliferation in several glomerulonephritis and the possible association between this relationship and the chronic histologic changes in lupus nephritis. METHODS: Studies were done in renal biopsies from 19 patients with lupus nephritis (types, IV, Va, Vb) classified with respect to chronicity and activity indexes, five patients with acute poststreptococcal glomerulonephritis, five with idiopathic mesangioproliferative glomerulonephritis, four with membranous glomerulonephritis, four with minimal-change nephrotic syndrome, and three patients with focal segmental sclerosis. Seven normal kidneys which could not be used for transplantation were used as a control group. Apoptosis was determined by in situ DNA nick-end labelling techniques and proliferating cells were identified with a monoclonal antibody antiproliferating cell nuclear antigen (PCNA). RESULTS: Decreased number of apoptotic cells and a high ratio of PCNA: apoptosis were observed in glomerulus and tubulointerstitium of patients with lupus nephritis when compared to other proliferative glomerulonephritis and controls. In lupus nephritis, glomerular apoptosis had a negative correlation with the chronicity index (r = -0.606 P = 0.005). The number of apoptotic cells in the glomeruli was not correlated with the number of PCNA positive cells in lupus nephritis, in contrast with a striking linear correlation observed in acute poststreptococcal nephritis (r = 0.925, P = 0.024), a disease with excellent prognosis. CONCLUSIONS: Apoptosis is decreased in proliferative lupus nephritis. Intense proliferation without increment in apoptosis (a high PCNA: apoptosis ratio) is a characteristic of lupus nephritis associated with chronic renal histological changes.
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Mesangial proliferative glomerulonephritis
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Membranous glomerulonephritis was diagnosed in five dogs with patent Dirofilaria immitis infections. Electron-dense deposits were present on the epithelial side of the glomerular basement membrane. An immunofluorescent study demonstrated immunoglobulins in the capillary wall and mesangium of the glomeruli. The glomerular lesions were considered to represent an immune complex form of glomerulonephritis induced by the D. immitis infection.
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Müftüoǧlu, Asuman U., Erbengi, Türkân, Harmanci, M., Karayel, T., Gürsoy, E., and Tahsinoǧlu, M.: Acute glomerulonephritis. Immunofluorescent and electron-microscopic observations in sporadic cases. Am J Clin Pathol 63: 300–309, 1975. The authors studied by immunofluorescent and electron microscopy renal biopsy specimens from 29 patients with various glomerular diseases. Poststreptococcal glomerulonephritis was characterized by the presence of complement (β1C) in the mesangium and/or on the basement membrane in all cases. Immunoglobulin G (IgG) was also present in less than half of the cases in the same distribution. Electron microscopy, carried out in six cases, revealed no uniform ultrastructural change: minimal subepithelial deposits were observed in three cases, intra-membranous deposits were seen in two cases, and the basement membrane was normal in one case. Glomerular abnormalities during the courses of some systemic diseases were similar. Mild renal involvement was characterized by only β1C deposition. This finding raises the question whether a mechanism other than or in addition to that involving immune complexes is operative in the pathogenesis of acute glomerulonephritis. There is circumstantial experimental evidence that an alternate pathway of complement activation and deposition may be operative in acute glomerulonephritis.
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Abstract Introduction Treatment with sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to be efficacious in the MRL/lpr and NZB × NZW F1 mouse models of lupus nephritis, indicating a critical role for the mTOR pathway in both models. This type of demonstration of efficacy in animal models is usually a pre-requisite for advancement into clinical development. However, efficacy in an animal model often has not translated to the desired activity in the clinic. Therefore, a more profound understanding of the mechanistic similarities and differences between various animal models and human diseases is highly desirable. Methods Transcriptional profiling was performed on kidneys from mice with lupus nephritis; from mice who had efficacious drug treatment; and from mice before they developed nephritis. Analysis of variance with false discovery rate adjusted to p < 0.05 and an average fold change of two or more was used to identify transcripts significantly associated with disease and response to therapy. Pathway analyses (using various bioinformatics tools) were carried out to understand the basis for drug efficacy in the mouse model. The relevance in human lupus of the pathways identified in the mouse model was explored using information from several databases derived from the published literature. Results We identified a set of nephritis-associated genes in mouse kidney. Expression of the majority of these returned to asymptomatic levels on sirolimus treatment, confirming the correlation between expression levels and symptoms of nephritis. Network analysis showed that many of these nephritis genes are known to interact with the mTOR pathway. This led us to ask what human diseases are linked to the mTOR pathway. We constructed the mTOR pathway interactome consisting of proteins that interact with members of the mTOR pathway and identified a strong association between mTOR pathway genes and genes reported in the literature as being involved in human lupus. Conclusions Our findings implicate the mTOR pathway as a critical contributor to human lupus. This broad pathway-based approach to understanding the similarities in, and differences between, animal models and human diseases may have broader utility.
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SUMMARY In order to assess the ability of various serologic assays to correlate with lupus nephritis, we analysed sera obtained from 60 patients with systemic lupus erythematosus (SLE), Patients were categorized as having active nephritis (group 1), active lupus without nephritis (group 2), inactive lupus with prior nephritis (group 3), or inactive lupus without prior nephritis (group 4), Three parameters were assessed including anti-dsDNA antibodies (Farr assay), immune complexes (C1q binding), and anti-C1q antibodies (salt-stable C1q binding). Additionally, glomerular binding activity (GBA) was measured using a new solid-phase immunoassay that detects immune elements by their ability to bind glomerular tissue. We found that patients with nephritis (group 1) exhibited higher mean values for each assay than patients in each of the other three groups (P= 0·001,0·009, 0·14, and 0·23 in the GBA, C1q, anti-dsDNA, and anti-C1q assays, respectively). The only assay which distinguished patients with nephritis (group 1) from patients having active disease without nephritis (group 2) was the GBA (mean 0·48 ± 0·09 versus 0·15 ± 0·04, (P 0·05), In terms of utility, all tests were specific for diagnosing nephritis among patients with lupus; however, only the GBA was reasonably sensitive. The information provided by the anti-dsDNA and C1q assays were not correlated with one another, nor additive to the GBA, Patients with false negative GBA tended to have received more intensive immunosuppression. The qualitative characteristics of GBA varied among patients with nephritis. These data suggest the pathogenesis of lupus nephritis is complex, and may be mediated by an array of immune elements. Moreover, the data indicate the potential utility for a broad tissue-based approach to detection of pathogenic immune elements over other, specific immunologic markers.
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Immune complex
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To evaluate the usefulness of Bb, a split product of complement factor B, as a clinical marker for disease activity of lupus nephritis, we measured the Bb concentration of sera from 42 patients with lupus nephritis. Serum Bb levels were significantly higher in patients with active nephritis (active nephritis group, n=30) than in patients with nephritis in remission (remission group, n=12) (14.3±8.3 versus 7.4±5.9 μg/ml; p=0.012). In contrast, there was no significant difference in serum C3 levels between active nephritis group and remission group (42.5±20.9 versus 44.7±15.9 mg/dl; p=0.77). In the comparison of Bb levels between active nephritis group and remission group, the sensitivity was 66.6%, specificity was 83.3%, and the positive and negative likelihood ratios were 3.95% and 0.41%, respectively. The present results suggest that serum Bb level is a useful clinical marker for disease activity in lupus nephritis.
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We describe two children with poststreptococcal glomerulonephritis associated with prolonged oligoanuria (12, 13 days). Kidney biopsies at 10 and 6 days, respectively, revealed acute glomerulonephritis with prominent mesangiolysis. Both patients recovered uneventfully. It is proposed that damage to the mesangium accounts for the clinical course.
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Objective To explore the significance of the urine microalbumin,transferrin,alpha 1-microglobulin,beta 2-microglobulin in SLE patients with early renal damage.Methods One hundred and eight patients with SLE,based on whether had the clinical manifestations of the kidney,were divided into two groups,obvious lupus nephritis group and silent lupus nephritis group,sixty-five healthy donors for normal control group.Immunol scatter turbidity test was used to assay microalbumin,transferrin,alpha 1-microglobulin,beta 2-microglobulin.The automatic biochemistry analyzer(Toshiba 120) was used to assay Serum BUN and Cr.Results The four kinds of microprotein in obvious lupus nephritis group were higher than that in silent lupus nephritis group and the control(P0.05).The four kinds of microprotein in silent lupus nephritis group were higher than those in the control group(P0.05).There were no statistical significance of four performance alone in obvious lupus nephritis group and in silent lupus nephritis group(P0.05).The four kinds of microprotein were jointly tested in Silent Lupus nephritis group.It's found that there was no statistical significance in positive frequency comparing to one index and two indexes,three indexes and four indexes(P 1,2;P3,40.05).However there was statistical difference in comparing one index and three indexes,one index and four indexes,two indexes and three indexes,two indexes and four indexes(P 1,3;P 1,2;P 2,3;P 2,40.05).The result in obvious lupus nephritis group was the same.There was no relationship between urine microalbumin,transferrin,alpha 1-micro globulin,beta 2-micro globulin and serum BUN.There was no statistics correlation between urine transferrin,alpha 1-micro globulin,beta 2-micro globulin and serum creatinine(P0.05).While there was positive relationship between urinary microalbumin and serum creatinine(r=0.737,P0.05).Conclusion The four index united detection can greatly improve the positive rate,indicating the significiance of dynamic monitoring the types and content of urine microprotein to early diagnosis of renal injury in SLE.
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Beta-2 microglobulin
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