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Introduction/objectives: The heterodimer exostosin-1/exostosin-2 (EXO-1/2) is a novel antigen observed in membranous nephropathy associated with systemic lupus erythematosus. This study aimed to evaluate the association between EXO-1/2 positivity in kidney biopsy and kidney outcomes., Methods: The kidney biopsy tissue from 50 class 5 lupus nephritis (LN) and 55 mixed class 3/4 + 5 LN patients was stained for EXO-1/2. Baseline clinical and histological characteristics were compared between EXO-1/2 positive and EXO-1/2 negative patients. Time-to-event analyses were performed to compare rates of response to therapy, kidney flares, and progression to a 40% decline of the glomerular filtration rate (eGFR), doubling of serum creatinine, and kidney failure., Results: Fourteen out of 50 (28%) of class 5 and 5 out of 55 (9%) of mixed class 3/4 + 5 LN stained positive for EXO-1/2. Patients with class 5 LN and EXO-1/2 positive stain were younger, with better kidney function at presentation, and lower scarring in the kidney biopsy analysis. Over a median follow-up of 100 months, patients with positive EXO-1/2 staining had significantly lower rates of progression in the full cohort. When analyzed separately in class 5 and mixed class LN subgroups, there were significantly lower rates of progression to a 40% decline of the eGFR and non-statistically significant trends for doubling of serum creatinine and kidney failure., Conclusion: EXO-1/2 is a novel antigen detected in class 5 LN and associated with a good prognosis of kidney function. The incorporation of EXO-1/2 staining in clinical practice can potentially modify the management of LN due to its prognostic implications. Key Points • Exostosin-1/exostosin-2 antigen has been found in cases of membranous nephropathy associated with autoimmune diseases such as systemic lupus erythematosus. • Exostosin-1/exostosin-2 staining in the kidney biopsy of class 5 or mixed class 3/4 + 5 lupus nephritis is associated with a good long-term prognosis of kidney function. • The incorporation of exostosin-1/exostosin-2 staining into clinical practice can potentially modify management due to its prognostic implications., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Lupus nephritis (LN) is a kidney disease that occurs after systemic lupus erythematosus (SLE) affects the kidneys. Pentraxin 3 (PTX3) is highly expressed in the serum of patients with LN. Renal PTX3 deposition is directly related to clinical symptoms such as proteinuria and inflammation. The excessive proliferation of mesangial cells (MCs) is one of the representative pathological changes in the progression of LN, which is closely related to its pathogenesis. Protopanaxadiol (PPD) is the main component of ginsenoside metabolism and has not been reported in LN. The aim of this study was to investigate the relationship between PTX3 and mesangial cell proliferation and to evaluate the potential role and mechanism of PPD in improving LN. PTX3 is highly expressed in the kidneys of LN patients and LN mice and is positively correlated with renal pathological indicators, including proteinuria and PCNA. The excessive expression of PTX3 facilitated the proliferation of MCs, facilitated the activation of the MAPK/ERK1/2 signaling pathway, and increased the expression of HIF-1α. Further studies showed that PPD can effectively inhibit the abnormal proliferation of MCs with high expression of PTX3 and significantly improve LN symptoms such as proteinuria in MRL/lpr mice. The mechanism may be related to the inhibition of the PTX3/MAPK/ERK1/2 pathway. In this study, both in vitro, in vivo, and clinical sample results show that PTX3 is involved in the regulation of MCs proliferation and the early occurrence of LN. Natural active compound PPD can improve LN by regulating the PTX3/MAPK/ERK1/2 pathway., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Background: The activation of the nuclear factor-κB (NF-κB) signaling pathway gives rise to inflammation in the pathogenesis of lupus nephritis (LN), with A20 serving as a negative feedback regulator and ubiquitin C‑terminal hydrolase L1 (UCH-L1) acting as a downstream target protein. However, their roles in the mechanism of LN remain undetermined., Methods: In the present study, the expression of A20 and UCH-L1, the activity of NF-κB and ubiquitin-proteasome system (UPS) were measured in MRL/lpr mice and A20 gene silenced podocytes. The severity of podocyte injury and immune complex deposits were detected by transmission electron microscopy., Results: The in vivo experiments revealed that A20 failed to terminate the activation of NF-κB, which was accompanied by UCH-L1 overexpression, ubiquitin accumulation, and glomerular injury in LN mice. Immunosuppression therapy did improve LN progression by attenuating A20 deficiency. In vitro experiments confirmed that tumor necrosis factor-α induced NF-κB activation, which led to UCH-L1 overexpression, UPS impairment, the upregulation of desmin and the downregulation of synaptopodin in A20 gene silenced podocytes., Conclusion: Thus, the results of the present study suggest that A20 regulates UCH-L1 expression via the NF-κB signaling pathway and A20 deficiency might play an important role in LN pathogenesis. Therefore, the A20 protein may serve as a promising therapeutic target for LN.

Objectives: To evaluate the neutrophil extracellular traps (NETs) assay and NADPH oxidase (Nox2) activity in pediatric systemic lupus erythematosus (pSLE) in relation to each other and SLE characteristics., Methods: This cross-sectional study included 50 children and adolescents with pSLE who were clinically evaluated and underwent routine laboratory work up of SLE (CBC, ESR, 24 hrs urinary proteins, serum creatinine, complement-3 (C3), anti-dsDNA, and antiphospholipid antibodies). NETs assay and dihydrorhodamine (DHR) test were done for patient group and 50 age- and sex-matched control group., Results: The level of NETs was found significantly elevated among the patients (median 74.6 mU/ml) as compared to the controls (median 8.9 mU/ml) (p < 0.001), while values of DHR test were comparable between patients (median 95.5%) and controls (median 96.1%) (P = 0.55). There was a significant negative correlation between levels of NETs and DHR (p < 0.001). A significant positive correlation was noted between the 24 hrs urinary protein and NETs level (p < 0.001), but a significant negative correlation with DHR (p < 0.0001). Both NETs and DHR test values did not differ significantly between classes of lupus nephritis. NETs showed a significant positive correlation with anti-dsDNA titer (p = 0.004) and SLEDAI (p < 0.001), but a negative correlation with C3 (p < 0.001). DHR test was positively correlated with C3 levels (p = 0.003), but negatively correlated with anti-dsDNA titers (p = 0.008) and SLEDAI (p < 0.001)., Conclusion: NETs seem to have strong association with biomarkers of pSLE activity. On the other hand, Nox2 activity of the neutrophils was noted to be linked to quiescent state of SLE., Key Points: • Neutrophils have displayed different actions in pSLE through the NETs and Nox2 activity. • The inverse correlation between NETs and Nox2 activity makes the later a non-fundamental pathway for NETs formation. • NETs are associated with pSLE flare and LN activity, while neutrophil Nox2 activity is related to disease remission.

Elevated IL-17 levels with higher Th17 numbers are identified in systemic lupus erythematosus (SLE). STAT3 signaling plays a crucial role in the Th17 generation, and SOCS3 negatively regulates their formation. We investigated IL-17, STAT3, and SOCS3 expression, and analyzed their correlations to elucidate the regulatory mechanisms of IL-17 production in SLE. This study enrolled 32 patients, and venous mononuclear cells (MNCs) were isolated with further purification of CD4-positive T cells. IL-17 and SOCS3 levels were measured by real-time quantitative PCR, and pSTAT3/STAT3 expression was analyzed by immunoblot. Elevated IL-17 and SOCS3 levels were identified in lupus patients. There were higher IL-17 levels in lupus nephritis (class IV) than in SLE without renal involvement. Positive correlations were found between IL-17 levels and SOCS3 expression, lupus activity (SLEDAI-2K), or daily proteinuria. There were higher intensities of pSTAT3/β-actin and STAT3/β-actin in SLE, and a positive correlation between IL-17 expression and pSTAT3/β-actin or STAT3/β-actin intensity. Lupus nephritis (class IV) had higher STAT3/β-actin intensity than SLE without renal involvement. These results suggest upregulated STAT3/IL-17 expression in lupus patients. Such findings might facilitate the development of novel compounds and the application of existing therapeutics targeting the STAT3/IL-17 signal in SLE.

Objectives: A prospective, multi-center, randomized controlled study was conducted to evaluate the efficacy and safety of a 24-week course low-dose leflunomide combined with prednisone in the induction treatment of proliferative lupus nephritis in Chinese patients., Method: Patients (n = 100) with biopsy-proved proliferative lupus nephritis were enrolled in this study. They were randomized into two groups and received either leflunomide or cyclophosphamide in conjunction with prednisone for 24 weeks. Leflunomide was given orally with a loading dose of 40 mg/day for 3 days followed by 20 mg/day. Intravenous cyclophosphamide was administered monthly at a dosage of 0.8-1.0 g. The primary efficacy outcome was the frequency of complete remission and partial remission at week 24. The secondary outcomes included changes of urinary protein excretion, serum albumin, complement 3, anti-dsDNA antibody level, and systemic lupus erythematosus disease activity index (SLEDAI) after 24-week therapy., Results: Of 100 patients, 48 received leflunomide combined with prednisone and other 52 received cyclophosphamide with concomitant prednisone. There were no statistically significant differences between groups in complete remission rate and partial remission rate. At week 24, 23% of patients in the leflunomide group and 27% of patients in the cyclophosphamide group achieved complete remission (P = 0.64), while 56% of patients in the leflunomide group and 42% of patients in the cyclophosphamide group achieved partial remission at week 24 (P = 0.16). SLEDAI, serum albumin, complement 3, anti-dsDNA antibody level, and urinary protein excretion improved significantly in both groups. No significant difference was seen in the changes of clinical parameters after therapy between the two groups. There was no significant difference in side effects in both groups., Conclusions: Compared with cyclophosphamide, low-dose leflunomide in combination with prednisone showed both effectiveness and safety in the induction therapy of proliferative lupus nephritis in Chinese patients.

Mer and Axl receptor tyrosine kinases (MerTK and AxlTK) play important roles in the clearance of apoptotic cells and the inhibition of inflammatory responses. Previous studies demonstrated that they might participate in glomerular injury in mice model. This study aimed to elucidate the expression of MerTK and AxlTK on glomeruli and analyze their clinical significance in lupus nephritis (LN) patients. Twenty-nine LN and 10 primary nephrotic syndrome (NS) patients were recruited. The expression of MerTK and AxlTK on glomeruli was measured by immunohistochemistry. Correlations between the levels of MerTK and AxlTK and clinical data were investigated. Statistical differences in each group were calculated by one-way analysis of variance, t test, or Mann-Whitney U test. Correlations were evaluated with Pearson's or Spearman's correlation tests. Both MerTK and AxlTK were expressed mainly on mesangial cells. LN patients demonstrated more expression of MerTK and AxlTK than primary NS patients (1.19 ± 1.01 × 10 -2 vs 0.21 ± 0.29 × 10 -2 , 7.25 ± 2.69 × 10 -2 vs 3.10 ± 1.22 × 10 -2 , p < 0.01). In LN patients, MerTK expression correlated with AxlTK (r = 0.529, p < 0.01). LN patients with class IV expressed more MerTK and AxlTK (1.50 ± 1.03 × 10 -2 and 7.56 ± 2.93 × 10 -2 ). The expression of MerTK and AxlTK varied according to the deposition of immunoglobulin and complements on glomeruli. Both MerTK and AxlTK expressions were increased on glomeruli and varied according to pathological classifications. Thus, we assumed that both two subsets might participate in the pathogenesis of LN.

Urinary MCP-1 (uMCP-1) levels reflect lupus nephritis (LN) disease activity. However, long-term prospective studies evaluating it as a biomarker are lacking. SLE patients with active nephritis (AN), active disease without nephritis (ANR), and inactive disease (ID) were enrolled. AN patients were followed up every 3 months for 1 year. Urine and serum samples were collected at baseline from all and at follow-up visits in AN group. Urine samples from healthy subjects (HC), rheumatoid arthritis (RA), and diabetic nephropathy (DM) patients (20 each) served as controls. Serum (sMCP-1) and uMCP-1 was measured using ELISA. Urinary values were normalized for creatinine excretion. Nonparametric tests were used. A total of 121 SLE patients were enrolled. Baseline uMCP-1 was significantly higher in AN as compared to ANR, ID, HC, and RA (p < 0.001), but it was not different from DM and showed good correlation with rSLEDAI and SLEDAI (r = 0.52 and 0.47, p < 0.001) but not with sMCP-1. On ROC analysis to differentiate between AN and ANR, uMCP-1 performed better than sMCP-1, anti-dsDNA antibodies, C3 and C4. uMCP-1 and not sMCP-1 decreased significantly at all follow-up visits (p < 0.001). uMCP-1 remained persistently elevated in a patient who developed CKD and rose before conventional markers in two patients with relapse of LN. uMCP-1 correlates well with LN disease activity and helps differentiate between AN and ANR patients. Its levels fall with treatment and may have a potential to predict poor response and relapse of LN. uMCP-1 is most likely generated locally in the kidney.

Background: Aberrant expression of T helper cell (Th) cytokines is believed to play a central role in the pathogenesis of systemic lupus erythematosus (SLE). While the glomerulus is one of the major targets of lupus inflammation, little is known about the cytokine expression in glomeruli. The current study aimed to explore the profiles of Th cytokine gene expressions in isolated glomeruli of lupus-prone mice., Methods: Glomeruli were purified from lupus-prone MRL/lpr mice using the magnetic microbead method. Expressions of cytokine genes representing the Th subset and FoxP3 were examined using real-time polymerase chain reaction. Serum levels of these cytokines were also measured by enzyme-linked immunosorbent assay. MRL/n mice were used as controls. Histologic glomerular damages were scored semiquantitatively. To examine the role of TNF-α in glomerular damage, we administered etanercept, a TNF-α antagonist, into the subjects., Results: Glomerular gene expressions of TNF-α in lpr mice increased with week postpartum and reached statistically significant levels at 16 weeks compared with those of the glomeruli from control mice. Expressions of IFN-γ, IL-4 and FoxP3 also increased, but the difference was not significant. There was a significant increase in serum levels of TNF-α, IFN-γ, and IL-17 and decrease in those of IL-4. Among the genes examined, TNF-α significantly correlated with glomerular damage score. Administration of etanercept did not affect glomerular cytokine expressions or proteinuria and failed to ameliorate histologic glomerular damages., Conclusion: Our data suggest that Th1 cytokines, especially TNF-α, are dominantly expressed in the glomeruli of lupus-prone mice, but its pathophysiological role remains unclear.

Background: Mesangial proinflammatory chemokine/cytokine expressions via innate immunity play a pivotal role in the pathogenesis of glomerulonephritis. CXCL1/GROα is a strong neutrophil chemoattractant cytokine and reportedly plays an important role in regional inflammatory reactions. However, detailed signaling of mesangial CXCL1 expression induced by viral or "pseudoviral" immunity remains to be determined., Methods: We treated normal human mesangial cells (MCs) in culture with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, and analyzed the expression of CXCL1 by reverse transcription-polymerase chain reaction (RT-PCR), real-time quantitative RT-PCR and enzyme-linked immunosorbent assay. To elucidate the poly IC-induced signaling pathway for CXCL1 expression, we subjected the cells to RNA interference against Toll-like receptor (TLR) 3, retinoic acid-inducible gene-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), interferon (IFN)-β, nuclear factor (NF)-κB p65 and IFN regulatory factor (IRF) 3. We also conducted an immunofluorescence study to examine mesangial CXCL1 expression in biopsy specimens from patients with lupus nephritis (LN) and IgA nephropathy (IgAN)., Results: We found that activation of TLR3 signaling could induce the expression of CXCL1 in MCs. NF-κB, IRF3 and IFN-β, but neither RIG-I nor MDA5, were found to be involved in mesangial CXCL1 expression in this setting. Induction of CXCL1 by poly IC was inhibited by pretreatment of cells with dexamethasone. Intense glomerular CXCL1 expression was observed in biopsy specimens from patients with LN, whereas only a trace staining occurred in specimens from patients with IgAN., Conclusion: TLR3 signaling also contributes to the CXCL1 expression in MCs. These observations further support the implication of viral and "pseudoviral" immunity in the pathogenesis of inflammatory renal diseases, especially in LN.

T regulator lymphocytes (Tregs) play a key role in the maintenance of immune tolerance and in the development of autoimmune diseases. Expression of Foxp3 is specific for Tregs, and can be used for the identification of these cells. This study investigated the variations of Tregs Foxp3+ in the kidney biopsies inflammatory infiltrate of different lupus nephritis classes compared to that of ANCA glomerulonephritis, acute tubulointerstitial nephritis and nephroangiosclerosis. Sections of paraffin-embedded tissue have been stained by immunohistochemistry with anti-CD3 and anti-FoxP3 antibodies. We find that the ratio of FoxP3+/CD3+ cells is significantly lower in patients with lupus nephritis class IV and in patients with vasculitides than in the course of nephroangiosclerosis, tubulointerstitial nephritis and lupus nephritis class V. The data presented herein demonstrate a decrease of FoxP3+ Treg cells in the inflammatory infiltrate of lupus nephritis, particularly during the most active phases of lupus nephritis, as observed in the course of a IV class nephritis.

Background: Membranous glomerulonephritis is typically classified as idiopathic or secondary to systemic lupus erythematosus (SLE), hepatitis B, drugs, toxins, other infections, or malignancy. Not infrequently in some patients without a definite diagnosis of SLE, pathologic features of secondary membranous nephropathy are seen e.g., mesangial and/or subendothelial deposits, tubuloreticular inclusions, and full house immunofluorescence. In these patients, there is uncertainty about the etiology, response to therapy, and prognosis of membranous GN., Methods: We retrospectively reviewed the charts of 98 patients with membranous GN at San Francisco General Hospital and John Stroger Hospital of Cook County over a 10-year period. Data were collected and analyzed using SPSS.18., Results: Thirty-nine (40 %) had idiopathic membranous GN (Group 1), thirty-six (37 %) had lupus membranous GN (Group 2) and twenty-three (23 %) had some pathological features of secondary membranous GN, but no definite etiology of membranous GN (Group 3). At baseline (at time of renal biopsy) and after mean follow-up of 3.5 years, the average serum creatinine (in mg/dL) in Group 1 was (1.6 ± 1.0 versus 1.6 ± 1.7), Group 2 was (1.8 ± 2.5 versus 1.2 ± 0.9) and Group 3 was (1.1 ± 0.4 versus 1.27 ± 0.83), respectively. For the same time points, the average urine protein to creatinine ratio (g/g) in Group 1 was (9.8 ± 7.1 versus 5.7 ± 6.7), Group 2 was (4.2 ± 3.9 versus 1.7 ± 2.2), and Group 3 was (7.4 ± 5.7 versus 3.1 ± 3.8). In addition, during the follow-up period, eleven of 39 (28 %) in Group 1, two of 36 (6 %) in Group 2, and three of 23 (13 %) in Group 3 progressed to end-stage renal disease and were started on dialysis., Conclusions: It appears that patients with lupus membranous GN have better renal prognosis than patients with idiopathic membranous GN. The renal prognosis for patients with pathological features of lupus membranous but no diagnosis of systemic lupus (lupus-like membranous GN) falls in between. Further studies are needed to determine if Group 3 patients can (a) definitively be classified as true idiopathic membranous GN or lupus membranous GN or (b) they have a separate disease from either M-type phospholipase A2 receptor membranous nephropathy or systemic lupus-induced membranous nephropathy.

Background: It has been reported matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), play important roles in the decomposition of the extracellular matrices of the glomerulus during the pathological processes in various glomerular diseases. Although the activity of these enzymes in cases of experimental glomerulonephritis has been described, the expression sites in the glomeruli of human renal diseases have been identified in only a few articles and remain controversial., Methods: The expression of the gelatinase group of MMPs (MMP-2 and MMP-9) and their inhibitors (TIMP-2 and TIMP-1) were evaluated in 19 renal biopsies of several types of glomerular diseases by immunofluorescence (IF) labeling. In addition, several samples of immunoglobulin A nephropathy (IgAN) were also investigated by in situ hybridization (ISH) and immunoelectron microscopy (IEM)., Results: The expression of MMP-2 was observed in all the cases examined by IF and ISH. TIMP-2 expression varied from negative to positive among 11 cases of IgAN, but was negative in the cases with lupus nephritis (LN) (n = 3), membranoproliferative glomerulonephritis (MPGN) (n = 2), and post-streptococcal glomerulonephritis (n = 1). However, it was weakly positive in the cases of diabetic nephropathy (DMN) (n = 2). MMP-2 was mainly observed along glomerular capillary loops (GCLs) and Bowman's capsules, whereas TIMP-2 was found in the mesangial area. The expression of MMP-9 in cases of IgAN varied, and was local, not diffuse, if it was present. MMP-9 expression in cases of LN, MPGN, and DMN was diffuse, but the intensity of staining varied. MMP-9 was primarily expressed in the mesangium. TIMP-1 expression was negative in all cases except for those with IgAN. The localization of MMP-2 in patients with IgAN, which was investigated by IEM, was revealed to be mainly on the endothelial cell membranes of GCLs, podocyte membranes, the parietal cell membranes of Bowman's capsules, and some on the membranes of mesangial cells., Conclusion: The study results suggest that the expression levels and patterns of MMPs and TIMPs are generally similar in several types of glomerular diseases, even though each case has a somewhat different distribution and intensity of expression. When these enzymes were present, their main sites were as follows: MMP-2 was found along glomerular basement membrane, TIMP-2 was located in the acellular mesangial area, MMP-9 was seen in the mesangium, and TIMP-1 was hardly detected. MMP-2 expression is clearly demonstrated to exist at the above-described sites by IEM in patients with IgAN.

Anti-double-stranded DNA (dsDNA) antibodies have been indicated to play a major role in the pathogenesis of lupus nephritis (LN), which is characterized by mesangial alterations, including phenotypic changes. To explore the effects of anti-dsDNA antibodies on the phenotype of mesangial cells (MCs), the anti-dsDNA IgG in sera and histological features of glomeruli were analyzed in the mice models of immune-complex glomerulonephritis. The MCs were cultured in vitro with the addition of anti-dsDNA or non-anti-dsDNA IgG. Compared to the anti-dsDNA-negative controls, the serum positive mice had increased extracellular matrix accumulation and higher alpha-smooth muscle actin expression in the mesangial region. The anti-dsDNA IgG enhanced the synthesis of transforming growth factor beta, alpha-smooth muscle actin, and fibronectin, and even induced the myofibroblast-like morphological features in cultured MCs. Our results indicated that anti-dsDNA antibodies contribute to the phenotypic changes in MCs, which suggests another mechanism of renal injuries in LN induced by anti-dsDNA antibodies.

Background: In the lupus mouse and systemic lupus erythematosus (SLE) patients, DNA fragments isolated from plasma may mimic microbial DNA and trigger Toll-like receptor 9 (TLR9) signaling with formation of autoantibodies against DNA fragments and nucleosomes. Vascular endothelial growth factor (VEGF) is a tightly regulated angiogenic cytokine in the kidney. The present study investigated glomerular and tubular expression of both TLR9 and VEGF in biopsies from human subjects with lupus nephritis (LN) and normal controls., Methods: Kidney biopsies in LN (n=8) and normal controls (n=10) were evaluated for expression of TLR9 and VEGF. The degree of kidney damage was analyzed according to the International Society of Nephrology / Renal Pathology Society classification. Immunohistochemistry was performed, and slides were incubated with antibodies against VEGF and TLR9 monoclonal antibody, stained with hematoxylin and eosin, mounted and microscopically scored at ×10 and ×20., Results: We observed intense staining of glomeruli and tubules for TLR9 up to 3+ from patients with LN. Samples from LN subjects showed 3+ staining of glomeruli but only up to 2+ in tubules for VEGF. There was less significant staining for TLR9 and none for VEGF in controls. There was no correlation observed between LN class severity and intensity of staining for VEGF or TLR9., Conclusion: This is the first study that investigated combined expression of TLR9 and VEGF, which could be an important tool for understanding the role of TLR9 and VEGF in LN, with insights into the early detection and targeted treatment of this disease.

The aim of this study is to investigate the association of serum anti-C1q antibody levels with renal pathological characteristics in SLE patients with lupus nephritis. Fifty-two patients with biopsy-proven lupus nephritis were enrolled. Serum anti-C1q levels (units per milliliter) were measured before renal biopsy using ELISA kit. A cross-sectional study analyzed the association of anti-C1q antibody levels with SLE global activity, nephritic activity, and renal histopathology. Thirty-nine of 52 patients (75 %) were positive for anti-C1q antibody. Anti-C1q antibody levels were positively correlated with the values for the SLE Disease Activity Index (r = 0.628, p < 0.001), anti-nucleosome (r = 0.591, p < 0.001), and anti-dsDNA antibody (r = 0.507, p < 0.001), but negatively correlated to serum C3 (r = -0.626, p < 0.001) and C4 (r = -0.57, p < 0.001). The prevalence of anti-C1q in patients with proliferative LN (class III + class IV) was higher than those with mesangial LN (class II), but there is no statistical significance. Among different ISN/RPS classification, serum anti-C1q antibody level was highest in patients with class IV, followed by class III. The concentration of anti-C1q in patients with class IV was higher than those in class II [50.00 (23.00, 97.70) vs 20.25 (7.16, 54.78) U/ml, p<0.05]. The levels of anti-C1q antibody were positively correlated with renal active indices (r = 0.59, p < 0.001) while negatively correlated with chronic indices (r = -0.326, p < 0.05). Moreover, anti-C1q antibody was found to be positively associated with glomerular C1q deposition. These findings indicate that serum anti-C1q antibody is a valuable noninvasive biological marker for prediction of renal histopathology in lupus nephritis. Low or negative anti-C1q antibody titers might influence therapeutic decisions in SLE.

Background: Apoptosis is involved in glomerular injuries leading to glomerulonephritis. However, the role of renal cellular apoptosis in the pathogenesis and progression of human lupus nephritis (LN) is controversial, and studies on the expression of apoptosis-related proteins, such as FasL, Bax and caspase-3, in different classifications of human LN renal tissues are limited., Methods: Thirty-two samples of LN tissues, including 10 cases of class II and 22 cases of class IV LN, and 5 cases of human normal renal tissues were obtained. Expression of FasL, Bax and caspase-3 proteins in LN tissues was examined by immunohistochemical staining. Apoptotic cells were evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay., Results: Expression of FasL, Bax and caspase-3 and TUNEL-positive cells in glomerular parenchymal cells, renal tubular epithelial cells and interstitial inflammatory cells were higher in LN tissues compared with controls. Expression of Bax and caspase-3, but not FasL, was significantly higher in glomeruli of class IV LN than those of class II LN. The apoptotic cell count per glomerulus was significantly higher in class IV LN than class II LN (p<0.05)., Conclusions: Increased apoptosis and the expression of FasL, Bax and caspase-3 in human LN suggest that apoptosis might be induced through pathways of these proteins in the pathogenesis process and play an important role in LN progression through Bax and caspase-3, but not FasL.

The purpose of this study is to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) for inducing and/or maintaining remission of lupus nephritis (LN). This is a retrospective study of 25 LN patients consecutively treated with MMF. The primary outcome was complete renal remission (CR) defined by urine protein/creatinine ratio < or =0.5 g/g and inactive urine sediment and serum creatinine within <15% above baseline. For induction, 21 episodes of active, moderate to severe LN were treated with MMF. Twelve cases (57%) achieved CR over a median of 8.5 months. Of 13 patients who had LN for <12 months and took > or =2 g/day of MMF, 11 achieved CR, compared to one out of the eight patients who did not meet both criteria (p = 0.0022). For maintenance therapy, 15 patients received MMF for a median of 20 months (range 5-55 months). Two patients (13%) experienced renal flares while taking MMF. Most adverse events were transient and did not require change in therapy. This study suggests that MMF is an effective treatment for both induction and maintenance of remission of moderate to severe LN with a relatively favorable safety profile. Early treatment and a dose > or =2 g/day are essential for optimal outcome. CR may take >6 months.

Cardiovascular events are markedly increased in systemic lupus erythematosus (SLE), and the mechanism of atherogenesis remains poorly understood. Several methods have been employed to assess endothelial function, among these is the measurement of biomarkers of endothelial activation and dysfunction [intercellular adhesion molecule (ICAM-1)]. It has been reported that such biomarkers play a more important role than traditional risk factors in cardiovascular disease. The objectives of this study were to determine the level of ICAM-1 as markers of endothelial dysfunction in 40 Egyptian patients who have SLE with various degrees of activity and to investigate their relationship to disease activity. Sixty people (40 with SLE and 20 healthy as the control group) were the subject of this study; their clinical disease activity was scored according to the SLE disease activity index (SLEDAI), and serum sampling was obtained for ICAM-1 level assay. Renal biopsy was carried out and examined by light microscopy by a pathologist blinded to the clinical activity. The mean level of ICAM-1 was significantly higher in SLE patients with active disease (826.05 +/- 367.1 Pg/ml) compared to those with inactive disease (441.33 +/- 225.19 Pg/ml) and the healthy control volunteers (111.5 +/- 17.36 Pg/ml). There was a positive correlation between serum ICAM-1 and SLEDAI (r = 0.66). A high concentration of soluble ICAM-1 in SLE patients with nephritis is reported in this paper. Our finding of increased concentrations of ICAM-1 in SLE patients with nephritis underlines the importance of inflammation and endothelial involvement in this disease, but their predictive value in the disease monitoring need to be further studied.

Background: Fas ligand (FasL) is a well-known death factor; however, the role of FasL in the regulation of human glomerulonephritis remains unclear., Methods: We investigated the renal expression and localization of FasL in various forms of human glomerulonephritis by immunohistochemistry, utilizing confocal laser scanning microscopy. We further evaluated cytokine-induced FasL expression via nuclear factor (NF)kappaB in cultured human mesangial cells (HMC). The level of soluble FasL was measured by a specific enzyme-linked immunosorbent assay (ELISA)., Results: The frequency of glomerular FasL-positive cases was higher in lupus nephritis (37.9%) as compared with other forms of glomerulonephritis (8.7%). The glomerular FasL score in proliferative lupus nephritis was significantly higher than that in nonproliferative forms. Patients with a high apoptosis score, severe microhematuria, proteinuria, or decreased renal function had a high FasL score. Double immunolabelling demonstrated that the most prevalent phenotypes of FasL-positive cells were mesangial cells. In cultured HMC, interleukin (IL)1beta, lipopolysaccharide (LPS), or gamma interferon (IFN) upregulated membrane-bound FasL. IL1beta significantly, and LPS or gammaIFN weakly activated NFkappaB, but none of these agents activated NFkappaB/Rel-related nuclear factor of activated T cells (NFATc) or IFN regulatory factor-1. IL1beta-mediated NFkappaB was completely inhibited in the presence of lactacystin, a potent inhibitor of NFkappaB. Lactacystin-mediated inhibition of NFkappaB reduced FasL protein levels. Matrix metalloproteinase (MMP)-7, but not other MMPs (1, 2, 3, 8, or 9), significantly sensitized HMC to release soluble FasL after IL1beta stimulation., Conclusions: The results suggest that: (1) upregulation of mesangial FasL may contribute to the glomerular inflammation in proliferative lupus nephritis in vivo; (2) proinflammatory cytokines, in particular IL1beta, produced in nephritis can upregulate FasL via the transcription factor NFkappaB in HMC; and (3) MMP-7-mediated release of soluble FasL could control the mesangial inflammation.

Our earlier studies have shown that calorie restriction and n-3 fatty acids inhibit autoimmune disease and prolong life span. Experiments were designed to study the alteration of apoptosis and its mediators in B/W mice fed either n-6 fatty acids [5% corn oil (CO)] or n-3 fatty acids [5% fish oil (FO)] and either allowed access to the diet ad libitum (AL) or restricted in caloric intake by 40% (CR), from 4 weeks of age. At 4 months (young) and 9 months (old) mice were killed, splenic lymphocytes were isolated, and apoptosis was measured with Annexin V and PI staining. Apoptosis was decreased in splenic lymphocytes from both young and old CR mice compared to their respective AL-fed control groups regardless of fat source. Increasing apoptosis with age was observed in CO/AL, CO/CR, and FO/AL mice which correlated closely with significantly higher cellular peroxides measured by flow cytometry using dichlorofluourescein diacetate (DCFH-DA), whereas in both CO/CR and FO/CR peroxide levels remained low in old mice. Furthermore, CR increased the proliferative response of splenic lymphocytes and decreased the Fas (CD95) and Fas-L protein expression in CD4+ lymphocytes from old mice. Higher levels of Fas and Fas-L expression were observed in old mice compared to young mice. Bcl-2 levels were elevated in both young and old CR groups compared to the respective AL groups. Calorie restriction prevented the loss of CD8 cells in old mice fed both the CO and the FO diet. In summary, CR resulted in decreased apoptosis accompanied by alterations in Fas, Fas-L, and Bcl-2 expression in old mice, increased life span, and delayed onset of kidney disease.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease marked by immune-complex mediated lesions in small blood vessels of various organs, especially the kidneys, although other factors may also be implicated in the pathogenesis of the disease. This article focuses on the role of lipids in the progression of glomerular, vascular and tubulo-interstitial lesions in two patients with lupus nephritis associated with pronounced hyper- and dyslipidemia. The pathogenesis of progressive glomerulosclerosis in both patients appears to be multifactorial. In addition to immune complex mediated lupus glomerulonephritis, progressively active in the first patient, severe nephrotic-range persistent proteinuria, arterial hypertension associated with hyperfiltration and hyperperfusion injuries and, to a minor extent, hyper- and dyslipidemia were observed. Immunological and non-immunological factors were shown to contribute to the development of tubulo-interstitial lesions. In both patients, in addition to local immune deposits, prominent tubulo-interstitial lipid deposits were probably causally related to both hyperlipidemia and the increased permeability of the glomerular filtration barrier. Tubular lesions were highlighted by intracytoplasmic lipid droplets as well as small cleft-like spaces found to be impacted in the tubular lumina. They were seen to penetrate tubular epithelial cells and eventually lodge in the interstitium, surrounded by mononuclear cell infiltrates and foam cells. In both patients, hypertensive angiopathy and extraglomerular vascular immune deposits were demonstrated. In addition, in the second patient, arteriolar and small arterial hyaline was found at the age of 28 years to be full of lipids and calcium precipitates, suggesting a peripheral atherosclerosis-like process which never occurs as a natural age-related condition. In conclusion, all parts of the nephron may be involved in the pathogenetic process causally related or influenced by hyper- or dyslipidemia. Associated either with endothelial cell injury and consequent insudation of lipids in the vascular walls, glomerular filtration barrier injury with hyperfiltration, or tubulo-interstitial lipid deposition, the mechanism of tissue damage by lipids in all parts of the nephron shares similarities with the pathogenesis of systemic atherosclerosis.