Autoantibodies against glomerular mesangial cells and their target antigens in lupus nephritis

Mesangial proliferation and deposition of immunoglobulins and complement components within glomerular mesangium was one of the important pathological features of lupus nephritis. Autoantibodies against human mesangial cells could be detected in the sera of patients with IgA nephropathy (IgAN) and Henoch-Sch?enlein nephritis. We speculated that autoantibodies against human glomerular mesangial cells might play a role in the development of lupus nephritis. OBJECTIVE: To screen autoantibodies against human glomerular mesangial cells in sera from patients with lupus nephritis and to identify their target antigens. METHODS: Sera were collected from 96 patients with lupus nephritis as well as 25 patients with IgAN and 20 patients with idiopathic membranous nephropathy (IMN). Cell lysates of in vitro cultured human glomerular mesangial cells were used as antigens in Western-blot analysis to detect autoantibodies against human mesangial cells in sera from patients with lupus nephritis as well as IgAN and IMN. The clinical and pathological significance of the autoantibodies were further investigated. RESULTS: Autoantibodies against human mesangial cells could be detected in 94/96 (97.9%) of the sera from patients with lupus nephritis in Western-blot analysis. Twelve protein bands could be blotted by the sera from patients with lupus nephritis. The prevalence of autoantibodies against human mesangial cells in IgAN was 14/25 (56.0%) and only seven protein bands could be blotted. Five autoantibodies (anti-18, 24, 36, 46, and 91 kD) could be detected only in sera from patients with lupus nephritis. In patients with lupus nephritis, some autoantibodies might have some relationship with gender, hematuria, ANA, anti-dsDNA or anti-ENA antibodies. CONCLUSIONS: There are autoantibodies directly against heterogeneous antigens of human glomerular mesangial cells in sera from patients with lupus nephritis, and some of them might be associated with different clinical manifestations.     

The possible role of ChemR23/Chemerin axis in the recruitment of dendritic cells in lupus nephritis

Dendritic cells (DCs) have a pivotal role in the autoimmune response of systemic lupus erythematosus. Plasmacytoid DCs infiltrate the kidney of patients with lupus nephritis, but factors regulating their recruitment to the kidney are unknown. Chemerin is the recently identified natural ligand of ChemR23, a receptor highly expressed by plasmacytoid DCs. We performed immunohistochemical and immunofluorescence analysis to study the ChemR23/Chemerin axis in renal biopsies from patients with lupus nephritis. We found ChemR23-positive DCs had infiltrated the kidney tubulointerstitium in patients with severe lupus nephritis. Chemerin association with tubular epithelial cells and renal lymphatic endothelial cells was found in patients with lupus nephritis but not in normal kidneys. Proximal tubular epithelial cells produced Chemerin in vitro, which was significantly down-modulated by added tumor necrosis factor (TNF)-α and interferon-γ as measured by quantitative PCR and enzyme-linked immunosorbent assay. Interestingly, TNF-α was capable of inducing a functionally active form of renal Chemerin, resulting in an efficient transendothelial migration of plasmacytoid DCs measured in transwell systems. Thus, the ChemR23/Chemerin axis may have a role in the recruitment of DCs within the kidney in patients affected by lupus nephritis.     

Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells

A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.     

抗核小体抗体与狼疮肾炎活动性关系的研究

目的探讨抗核小体抗体与狼疮肾炎活动性的关系。方法对2007年4月至2009年12月在我院住院的75例经肾活检确诊为狼疮肾炎患者的临床资料进行回顾性研究。结果抗核小体抗体在活动性增殖性狼疮肾炎中的阳性率（59．3％）较非活动性增殖性狼疮肾炎（27．3％）和非增殖性狼疮肾炎（20．0％）高（P〈0．05）。活动性狼疮肾炎组的抗核小体抗体阳性率（53．8％）较非活动性狼疮‘肾炎组阳性率（23．8％）高（P〈0．05）。抗核小体抗体阳性组的病理活动性指数（active index,AI）较阴性组高（P〈0．05）,两组慢性指数（chronic index.CI）和狼疮肾炎的临床活动性评分（renalactivity score,RAS）无显著差异（P〉0．05）。结论抗核小体抗体与狼疮肾炎的病理活动性相关,在活动性增殖性狼疮肾炎中出现较为普遍,是提示活动性增殖性狼疮肾炎的一项重要的指标。     

High prevalence of anti-C1q antibodies in biopsy-proven active lupus nephritis.

BACKGROUND: Anti-C1q antibodies (anti-C1q) have been shown to correlate positively with systemic lupus erythematosus (SLE) nephritis. Several clinical studies indicated a high negative predictive value, suggesting that active lupus nephritis is rarely seen in patients with no anti-C1q. However, the true prevalence of anti-C1q at the time of active lupus nephritis has not been well established. The aim of this study was to determine prospectively the prevalence of anti-C1q in proven active lupus nephritis at the time of the renal biopsy. METHODS: In this prospective multi-centre study, we investigated adult SLE patients undergoing renal biopsy for suspected active lupus nephritis. Serum samples were taken at the time of the biopsy and analysed for the presence of anti-C1q in a standardized way. The activity of lupus nephritis was classified according to the renal histology. Biopsies were also analysed for the presence of glomerular IgG, C1q and C3 deposition. RESULTS: A total of 38 patients fulfilling at least 4/11 American College of Rheumatology (ACR) criteria for the diagnosis of SLE were included. Out of this, 36 patients had proliferative (class II, III or IV) and two had class V lupus nephritis. All but one patient with proliferative lupus nephritis were positive for anti-C1q (97.2%) compared with the 35% of control SLE patients with inactive lupus nephritis and 25% of SLE patients without lupus nephritis ever. All patients were positive for glomerular C1q (36/36) and 37/38 patients had glomerular IgG deposits. Anti-C1q strongly decreased during successful treatment. CONCLUSIONS: Anti-C1q have a very high prevalence in biopsy-proven active lupus nephritis, thus a negative test result almost excludes active nephritis. The data support the hypothesis of a pathogenic role of anti-C1q in lupus nephritis.     

血浆抗内皮细胞抗体检测在弥漫增生性狼疮性肾炎中的临床价值

目的:探讨抗内皮细胞抗体与弥漫增生性狼疮性肾炎的相关性。方法:将39例狼疮患者分为弥漫增生性狼疮性肾炎组和非弥漫增生性狼疮性肾炎组。用间接免疫荧光法检测上述两组血浆抗内皮细胞抗体的阳性率及浓度。结果:在39例狼疮患者中,抗内皮细胞抗体的阳性率为38.5%。弥漫增生性狼疮性肾炎组AECA的阳性率和浓度均高于非弥漫增生性狼疮性肾炎组,但差异无统计学意义。AECA预测弥漫增生性狼疮性肾炎的ROC曲线下面积为0.63,95%可信区间为0.45～0.81,P=0.20。结论:血浆抗内皮细胞抗体在弥漫增生性狼疮性肾炎中有较高的阳性率,但不能作为预测指标。     

儿童狼疮性肾炎的临床特征

目的探讨儿童狼疮性肾炎(LN)的临床特征和实验室检查。方法74例小儿LN和130例成人LN进行临床及血液学、免疫学检查比较。结果表明小儿LN表现为肾病综合征、肾综并肾脏损害、心脏、神经精神和血液系统等损害明显多于成人LN；无症状蛋白尿血尿、关节炎和雷诺征明显低于成人；但免疫学检查与成人无明显差异。结论小儿LN的临床表现及实验室检查有其自身特点。了解小儿LN的临床特征及实验室意义．有助于正确诊断儿童LN。     

Chemokines and chemokine receptors as therapeutic targets in lupus nephritis

Recruitment of leukocytes is a characteristic feature of tissue injury in systemic lupus erythematosus, including lupus nephritis. Locally secreted chemokines and their receptors are important mediators of leukocyte recruitment to the specific sites of immune complex injury, and contribute to renal inflammatory disease in the initiation and progression phase. Therefore, chemokines and chemokine receptors represent potential therapeutic targets in lupus nephritis. In this review we summarize available experimental and human data supporting their functional role in lupus nephritis. Moreover, interventional studies with chemokine and chemokine receptor antagonists that show the therapeutic potential of chemokine antagonists in experimental models of lupus nephritis and potentially in human renal disease are discussed.     

Renal tubular dysfunction in children with systemic lupus erythematosus

Renal tubular and glomerular function was studied in patients under 18 years of age with childhood-onset systemic lupus erythematosus (SLE) in relation to disease activity in two groups: patients with clinical or laboratory evidence of lupus nephritis and those without (lupus non-nephritis). We reviewed 11 patients with lupus non-nephritis and 10 patients with lupus nephritis over a 12-month period. The measured glomerular filtration rates had a tendency to be lower in the lupus nephritis group. Glomerular dysfunction was manifest in the lupus nephritis group with elevated urinary albumin/creatinine ratios (P <0.001). Markers of tubular function were measured and compared with data from 94 controls. The lupus nephritis group had elevated urinary NAG [ N -acetyl-- d -glucosaminidase (P =0.001)] and RBP [retinol-binding protein (P =0.03)] levels. Tubular dysfunction with elevated urinary NAG levels was present in 2 lupus non-nephritis patients with no evidence of glomerular disease. The cohort of patients in this study was followed and 2 lupus non-nephritis patients with the highest urinary RBP levels developed evidence of glomerular dysfunction and biopsy-proven lupus nephritis. Evidence of tubular dysfunction in lupus non-nephritis patients may help to identify lupus nephritis prior to the onset of albuminuria.     

Autoantibodies Against Glomerular Mesangial Cells and Their Target Antigens in Lupus Nephritis

Mesangial proliferation and deposition of immunoglobulins and complement components within glomerular mesangium was one of the important pathological features of lupus nephritis. Autoantibodies against human mesangial cells could be detected in the sera of patients with IgA nephropathy (IgAN) and Henoch-Schöenlein nephritis. We speculated that autoantibodies against human glomerular mesangial cells might play a role in the development of lupus nephritis. Objective. To screen autoantibodies against human glomerular mesangial cells in sera from patients with lupus nephritis and to identify their target antigens. Methods. Sera were collected from 96 patients with lupus nephritis as well as 25 patients with IgAN and 20 patients with idiopathic membranous nephropathy (IMN). Cell lysates of in vitro cultured human glomerular mesangial cells were used as antigens in Western-blot analysis to detect autoantibodies against human mesangial cells in sera from patients with lupus nephritis as well as IgAN and IMN. The clinical and pathological significance of the autoantibodies were further investigated. Results. Autoantibodies against human mesangial cells could be detected in 94/96 (97.9%) of the sera from patients with lupus nephritis in Western-blot analysis. Twelve protein bands could be blotted by the sera from patients with lupus nephritis. The prevalence of autoantibodies against human mesangial cells in IgAN was 14/25 (56.0%) and only seven protein bands could be blotted. Five autoantibodies (anti-18, 24, 36, 46, and 91 kD) could be detected only in sera from patients with lupus nephritis. In patients with lupus nephritis, some autoantibodies might have some relationship with gender, hematuria, ANA, anti-dsDNA or anti-ENA antibodies. Conclusions. There are autoantibodies directly against heterogeneous antigens of human glomerular mesangial cells in sera from patients with lupus nephritis, and some of them might be associated with different clinical manifestations.     

Recent advances in the pathogenesis of lupus nephritis: autoantibodies and B cells

Although many factors contribute to the clinical presentation and subsequent course of individuals with lupus nephritis, the formation of glomerular immune deposits is typically one of the initial events. In general, breakdown in immunologic tolerance leads to the production of autoreactive B and T cells that, either through direct infiltration and/or their secretory products, initiate inflammation. Immune deposition within glomeruli results in complement activation and recruitment of inflammatory cells, along with activation of endogenous renal cells. This inflammatory cascade leads to secretion of cytokines and chemokines, which in turn attract more infiltrating cells. Up-regulation of lymphoid-derived chemokines further enhance the cellular influx, augmenting inflammation and resulting in further tissue damage. The degree of inflammation is determined by the extent of this invasion along with both the systemic and local responses to the assault. This review focuses mainly on the contributions of pathogenic autoantibodies, autoreactive B cells to lupus nephritis, and potential immunologic therapies for lupus nephritis. Manipulation of both the cells and soluble mediators that initiate and perpetuate the disease are essential to suppressing autoreactivity and inflammation and preventing disease progression.     

狼疮肾炎终末期肾病患者肾移植临床分析

目的：探讨系统性红斑狼疮肾炎终末期肾病患者行肾移植术治疗的效果和可行性。方法：统计我院2004年1月～2008年12月间,原发病为终末期狼疮肾病的肾移植患者的临床资料和手术后随访情况进行分析。结果：4例患者均为女性,行移植手术时全身病情稳定,无狼疮活动;手术后均使用免疫抑制剂抗排斥反应;术后平均随访时间41.5个月;至今其中3例移植肾功能良好,未发生排异反应,1例移植肾功能异常者经移植肾病理活检证实为慢性排斥反应,4例均无狼疮肾病复发。结论：终末期狼疮肾病患者肾移植效果良好,肾移植治疗终末期狼疮肾病是有效和可行的。     

Human clinical trials in lupus nephritis

Improved patient survival after treatment of lupus nephritis with corticosteroids, immunosuppressants, and renal replacement therapy allows greater emphasis on long-term management issues. In particular, the recent focus has been on therapies to treat nephritis with fewer adverse effects compared with cyclophosphamide and immunosuppressive regimens. Issues complicating clinical trial design in lupus nephritis have severely limited comparisons across trials. These issues, including recognition and stratification of high-risk populations, comparable remission and response criteria, and appropriate use and interpretation of activity and damage indices have been the subject of much discussion and emerging consensus. Mycophenolate mofetil (MMF) has been used in the field of transplantation for more than 10 years. After initial anecdotal reports describing the benefits of MMF in the treatment of lupus nephritis, randomized controlled trials have established a role for MMF in the treatment of lupus nephritis. A host of newer agents including rituximab, abatacept, and monoclonal antibodies blocking costimulatory targets are in current clinical trials for lupus nephritis. As long-term outcomes in lupus nephritis improve, the toxicity of therapy and risk of relapse become increasingly important determinants of the choice of therapeutic agents.     

Internalization of antibodies by endothelial cells via fibronectin implicating a novel mechanism in lupus nephritis

BACKGROUND: One of the crucial events in lupus nephritis is the glomerular deposition of immunoglobulins (Igs), of which pathogenic properties have been proposed mostly to be either type IIor type III allergic reactions. Some of IgG3-producing hybridoma clones established from an MRL/MpTn-gld/gld (MRL/gld) lupus mouse generate wire loop-like lesions in glomeruli resembling lupus nephritis when injected into SCID mice. These clones are useful for analyzing the mechanisms of glomerular deposition of antibodies in lupus nephritis at the monoclonal level. METHODS: Glomerular lesions of SCID mice injected with the hybridoma clones, 17H8a or 1G3 as control were analyzed by light and electron microscopy. Interaction of the antibodies with human glomerular endothelial cells (HGECs) and human umbilical vein endothelial cells (HUVECs) in vitro was studied by fluorescence microscopy, electron microscopy, and flow cytometry. RESULTS: Both antibodies did not show any antigen specificity for mouse glomeruli. The glomerular lesions generated by 17H8a, but not by 1G3, contained electron-dense deposits not only in subendothelial regions but also in the cytoplasm of endothelial cells, suggesting internalization of the 17H8a antibodies by endothelial cells. In cell culture studies, internalization of only 17H8a antibodies by HGECs and HUVECs was observed, but the antibodies did not have antigen specificity for both types of endothelial cells. The internalization by HUVECs was mediated by actin polymerization, and it was inhibited by RGDS (Arg-Gly-Asp-Ser) tetrapeptide, antihuman fibronectin and antihuman integrin beta1 monoclonal antibodies. CONCLUSION: The interaction between particular antibodies and endothelial cell surface integrins via fibronectin may be involved in their subsequent internalization by endothelial cells leading to antibody deposition in glomeruli. This may be one of the mechanisms of glomerular injury in lupus nephritis.     

Mycophenolate mofetil therapy for children with lupus nephritis refractory to both intravenous cyclosphosphamide and cyclosporine

We describe mycophenolate mofetil (MMF), a new immunosuppressive agent, to be a therapy of two children with lupus nephritis which were refractory to both cyclophosphamide (CyP) and cyclosporine (CsA). After 11- to 12-month course of MMF treatment, all clinical symptoms of lupus disappeared and serum antibodies became negative. MMF might be a promising curative for cyclophosphamide-resistant lupus nephritis in children. Cyclophosphamide intravenous bolus therapy is generally considered to be the treatment for patients with lupus nephritis. However, there is little guidance about what to do if such therapy fails. Recently, a new immunosuppressive agent, mycophenolate mofetil (MMF), has been used to treat cyclophosphamide-resistant lupus nephritis [Dooley et al. 1999, Gaubitz et al. 1999, Glicklich and Acharga 1998] in adults and has been recognized as a promising curative for lupus nephritis. Up to now, MMF has been adopted widely with solid organ transplantation to prevent or reverse acute rejection [Mathew 1998, Morris-Stiff and Jurewicz 1998] and has been used successfully to treat for rheumatoid arthritis refractory to a variety of other drugs. But there is no report about MMF treatment in children with cyclophosphamide-resistant lupus nephritis. We describe our experience with MMF treatment in two Chinese children with lupus nephritis that were refractory not only to cyclophosphamide but also to cyclosporine.     

Plasminogen activator inhibitor-1 gene polymorphism 4G/4G genotype and lupus nephritis in Chinese patients

BACKGROUND: Abnormal regulation in the coagulation and fibrinolytic system may play an important role in mediating glomerular damage in lupus nephritis. Indeed, glomerular thrombosis occurs frequently in lupus nephritis and predicts the future development of glomerular sclerosis. In the murine model of active lupus nephritis, plasminogen activator inhibitor-1 (PAI-1) gene was overexpressed throughout the kidney, both within the glomeruli and also in tubules and vessels. The level of PAI-1 expression in the tissues appeared to correlate with the progression of lupus nephritis. Recently, a single base pair insertion/deletion 4G/5G polymorphism of the PAI-1 gene has been identified and shown to alter plasma PAI-1 activity. This study was therefore conducted to determine the association of the 4G/5G polymorphism of the PAI-1 gene with the development and severity of lupus nephritis. METHODS: The PAI-1 gene polymorphism of 118 systemic lupus erythematosus (SLE) patients and 103 healthy controls who were gender and age matched was determined using standard polymerase chain reaction. PAI-1 genotype results were studied in relationship to the development and severity of lupus nephritis. RESULTS: Allele frequencies of 4G/5G allele were 0.59/0.41 in lupus patients and 0.59/0.41 in controls (P = 1.000). No significant difference was noted in the genotype distribution between SLE patients with and without nephritis. However, lupus nephritis patients with the 4G4G genotype showed significantly heavier proteinuria (5.0 vs. 3.7 g/day; P = 0.023) when compared with patients with 4G5G and 5G5G genotypes. Also, 73.3% patients with 4G4G had an activity index > or =8 versus 37.3% patients with 4G5G and 5G5G (P = 0.003). Extensive necrotizing lesions were seen in 51.7% patients with 4G4G as compared with 23.5% patients with 4G5G and 5G5G (P = 0.014). The association of the 4G4G gene polymorphism with a higher nephritis activity and more severe necrotizing lesions persisted when only class III and class IV nephritis patients were studied. On the other hand, no significant association was noted between the PAI-1 gene polymorphism and the chronicity of the nephritis. CONCLUSION: These findings suggest that the 4G/5G polymorphism of the PAI-1 gene is associated with the activity but not the chronicity of lupus nephritis. The presence of the 4G4G genotype does not increase the risk of developing SLE or lupus nephritis, but predicts the development of higher nephritis activity and more extensive necrotizing lesions.     

The role of kidney biopsy in the management of lupus nephritis

PURPOSE OF REVIEW: This review evaluates the role of kidney biopsy as a tool in the diagnosis, prognostication and therapeutic management of lupus nephritis. The renal biopsy is the only method available for diagnosing and classifying lupus nephritis. However, disagreements persist regarding the appropriate role of a renal biopsy in the management and identification of predictors of short and long-term outcomes. RECENT FINDINGS: Recent modifications to the classification of lupus nephritis, the emergence of newer scoring indices, and the availability of a variety of therapeutic options predicate a reassessment of the role of the renal biopsy in the management of lupus nephritis, especially for high-risk patients. SUMMARY: Despite some controversy, the renal biopsy has been shown to provide information over and above that provided by the clinical variables, and remains a pivotal element in optimizing therapy and the rational management of lupus nephritis.     

Studies on the outcome of lupus nephritis according to long-term treatment employing different modes of immunotherapy.

The outcome of long-term treatment of lupus nephritis under different immunotherapies, together with the factors affecting the outcome of lupus nephritis, was studied. A total of 212 lupus nephritis patients were classified into 5 groups according to their different modes of treatment: (1) initial dose of prednisolone (PSL) below 39 mg/day, (2) initial dose of PSL above 40 mg/day, (3) pulse therapy and steroids, (4) steroids and immunosuppressants, and (5) combination therapy of plasmapheresis with other therapies. The outcome of lupus nephritis was evaluated into 5 grades. As a result, the complete remission rate of lupus nephritis was 9.4%. The 5-year survival rates increased with all modes of treatment. However, it was impossible to identify which mode of therapy could bring about the highest rate of remission. Decreases in extrarenal involvement and low complement levels were observed together with increases in IgM anti-DNA antibodies among the lupus nephritis patients with remission.     

C1q的沉积对V型狼疮性肾炎和原发性膜性肾病的鉴别诊断意义

目的:研究C1q在V型狼疮性肾炎、原发性膜性肾病及病理组织学为不典型膜性肾病肾活检标本中的沉积,分析其不同及意义。方法:对V型狼疮性肾炎、原发性膜性肾病和不典型膜性肾病的患者的肾活检组织进行C1q免疫组化染色,并收集临床和血清学指标,进行统计学分析。结果:V型狼疮性肾炎会出现C1q的沉积,原发性膜性肾病不会出现C1q的沉积,一些病理组织学表现不典型的膜性肾病,会出现C1q的沉积,后者阳性率与狼疮性肾炎接近,与膜性肾病相比,差异有统计学意义。结论:C1q阳性且病理组织学为不典型膜性肾病的患者,极有可能是早期的V型LN。