Changes in macrophage infiltration and podocyte injury in lupus nephritis patients with repeated renal biopsy: Report of three cases

BACKGROUND In this study,we retrospectively analysed macrophage infiltration and podocyte injury in three patients with diffuse proliferative lupus nephritis(LN)who un-derwent repeated renal biopsy.CASE SUMMARY Clinical data of three diffuse proliferative LN patients with different pathological characteristics(case 1 was LN IV-G(A),case 2 was LN IV-G(A)+V,and case 3 was LN IV-G(A)+thrombotic microangiopathy)were reviewed.All patients underwent repeated renal biopsies 6 mo later,and renal biopsy specimens were studied.Macrophage infiltration was assessed by CD68 expression detected by immunohistochemical staining,and an immunofluorescence assay was used to detect podocin expression to assess podocyte damage.After treatment,Case 1 changed to LN III-(A),Case 2 remained as type V LN lesions,and Case 3,which changed to LN IV-S(A),had the worst prognosis.We observed reduced macro-phage infiltration after therapy.However,two of the patients with active lesions after treatment still showed macrophage infiltration in the renal interstitium.Before treatment,the three patients showed discontinuous expression of podocin.Notably,the integrity of podocin was restored after treatment in Case 1.CONCLUSION It may be possible to reverse podocyte damage and decrease the infiltrating ma-crophages in LN patients through effective treatment.

Focus on laboratory tests related to the pathological types of lupus nephritis to implement renal biopsy as early as possible:clinical and pathological analysis of 217 cases of single center lupus nephritis

Objective:To analyze the clinical and laboratory indices of patients with lupus nephritis(LN)of different pathological types and explore the related factors of LN pathological classification,it is helpful to grasp the timing of renal biopsy.Methods:The clinical manifestations,laboratory parameters and renal pathological types of LN patients in recent 20 years were analyzed retrospectively by SPSS 26.0 software.Results:In this study,the first three pathological types were V,IV,V+IV;latent nephritis was common in type II and V;nephritic syndrome was common in type V;nephrotic syndrome was common in type V+IV;chronic renal insufficiency group was mostly type IV;pathological types were correlated with serum creatinine,C3,albumin and erythrocyte sedimentation rate(r=0.315,P<0.001),and serum creatinine was moderately correlated(r=0.315,P<0.001);AI,CI and SLEDAI scores were significantly different among LN patients of different pathological types.Conclusion:LN is closely related to clinical pathology,clinical manifestations,comprehensive analysis of laboratory indicators and SLEDAI score to make a preliminary prediction of LN pathological type,help to initially assess the severity of pathology,improve the timing of renal biopsy implementation,optimize the timing of treatment.

Advances in Diagnosis and Treatment of Lupus Nephritis(Class V)

Membranous lupus nephritis(MLN),class V,is a distinct LN characterized by immune complex deposition on subepithelial kidney biopsy.MLN is often associated with nephrotic syndrome.The histology of MLN is very similar to idiopathic(primary)membranous nephropathy(pMN).However,MLN usually has abundant mesa-glomerular deposits absent in primary membranous nephropathy.The clinical manifestations,management,and prognosis of MLN differ from other types of LN(type III,IV,or mixed type III/IV+V).Although immunosuppressive therapy is often necessary for MLN,the optimal treatment regimen is yet to be determined.This review summarizes the progress in the diagnosis and treatment of MLN and discusses the selection of immunosuppressants for MLN.

Association of C-reactive protein and complement factor H gene polymorphisms with risk of lupus nephritis in Chinese population

BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN.However,genetic variations of neither CRP nor CFH show consistent influences on the risk of LN.AIM To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population.METHODS We genotyped six CRP single nucleotide polymorphisms(SNPs)(rs1205,rs3093062,rs2794521,rs1800947,rs3093077,and rs1130864)and three CFH SNPs(rs482934,rs1061170,and rs1061147)in 270 LN patients and 303 healthy subjects.RESULTS No linkage was found among CRP and CFH SNPs,indicating lack of genetic interactions between the two genes.Moreover,CRP and CFH SNPs,neither individually nor in combination,are associated with the risk or clinical manifestations of LN.Given the unambiguous pathogenic roles of the two genes.CONCLUSION These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.

Network pharmacology and data analysis method to explore the traditional Chinese medicine regulates ferroptosis key genes in the occurrence and prognosis of lupus nephritis

Purpose:To explore the traditional Chinese medicine(TCM)regulates ferroptosis key genes in the occurrence and development of lupus nephritis(LN)based on biological information database.Patients and methods:Ferroptosis related genes were identified based on FerrDb database and literature retrieval.Used the OMIM,Gene Cards,Drug Bank to obtain the targets of LN.Cytoscapes 3.8.2 software and STRING database were used to analyze protein-protein interaction(PPI)network.Metacape software and Weishengxin were used to analyze the gene ontology(GO)classification and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis.UniProt Database and Traditional Chinese Systems Pharmacology Database and Analysis Platform analysis platform were used to obtain the data table of key TCM and related targets.Cytoscapes 3.8.2 software was used to analyze the PPI network.Results:A total of 401 ferroptosis-related genes,361 LN related genes and 21“Ferroptosis-LN”intersection genes were obtained.Ferroptosis in the occurrence and prognosis of LN mainly involved the inflammatory response,cell activation,positive regulation of chemokine production and it was mainly involved in necroptosis,inflammatory bowel disease,ferroptosis and other pathways.A total of 412 TCMs containing key genes of“Ferroptosis-LN”were acquired.The most key genes were contained in Mahuang,Gehua,Baiguo,Chuanniuxi,Jinyinhua.15 key genes of“TCM-LN”were obtained.5 ferroptosis-related key genes in LN regulated by TCM were obtained,which were IL1β,TLR4,IFNG,STAT3 and HMOX1.Conclusion:TCM,such as Mahuang,Gehua,Baiguo,Chuanniuxi,Jinyinhua,may affect the occurrence and development of LN through the key ferroptosis genes,such as IL1B,TLR4,IFNG,STAT3 and HMOX1.

Effect of Rituximab Versus Mycophenolate Mofetil or Cyclophosphamide as Control in Lupus Nephritis:A Meta-Analysis

Objective:To evaluate the effects of rituximab versus mycophenolate mofetil or cyclophosphamide as control in lupus nephritis by meta-analysis.Methods:A systematic search was carried out up to January 2022,obtaining 7 studies involving 645 participants with lupus nephritis at the commencement of the investigation;198 of them were treated with rituximab,while 447 were treated with mycophenolate mofetil or cyclophosphamide.We determined the odds ratio(OR)and mean difference(MD)with 95%confidence index(CI)to compare rituximab’s efficacy to that of mycophenolate mofetil or cyclophosphamide as control in lupus nephritis using random-or fixed-effects model by dichotomous or continuous techniques.Results:The rituximab group showed significantly higher complete renal remission rate(OR=2.52;95%CI 1.30-4.91,P=0.006)and total renal remission rates(OR=2.22;95%CI 1.36-3.63,P=0.001)than the control group.However,there was no significant difference in terms of end Systemic Lupus Erythematosus Disease Activity Index(SLEDAI)score(MD-1.16;95%CI-2.88-0.57,P=0.19),proteinuria(MD-0.31;95%CI-0.70-0.09,P=0.013),and serum creatinine(MD 0.01;95%CI-0.04-0.07,P=0.64)between the rituximab group and the control.Conclusion:Rituximab exhibited significantly greater complete renal remission rate and total renal remission rates,with no significant difference in terms of shorter-end SLEDAI,proteinuria,and serum creatinine,compared with the control in individuals with lupus nephritis.

Treatment of young patients with lupus nephritis using calcineurin inhibitors

Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contribut-ed to a favorable outcome in children and adolescents with systemic lupus erythematosus （SLE）. Neverthe-less, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are re-viewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide （IVCY） are effective for preserving renal function in adult pa-tients, CPA is a potent immunosuppressive agent thatinduces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malig-nancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A （CsA） and tacrolimus （Tac） are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting thetranscription of the early activation genes of interleu-kin （IL）-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone （PDN）, Tac, and mycophenolate mofetile （MMF） has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and Tac may bean attractive option for young patients with SLE and lupus nephritis

LUPUS NEPHRITIS COMPLICATED WITH MALIGNANT HYPERTENSION:FROM RENAL VASCULAR PATHOLOGY TO CLINICAL RELEVANCE

Objective To investigate the clinical and pathological characteristics of lupus nephritis patients complicated with malignant hypertension.Methods We retrospectively studied 19 patients with lupus nephritis complicated with malignant hypertension who underwent renal biopsy between January 2002 and December 2006.Results Of 19 patients,3 were men and 16 were women,with a mean age of 24.4±7.7 years old.All had positive antinuclear antibodies and low serum complement was found in 13 patients.All were anemic and 12 of them were thrombocytopenic.Impaired renal function was found in 17 patients with an average serum creatinine of 184.5±88.9 μmol/L.Severe intrarenal arteriolar lesion was found in all patients.Six patients had lupus vasculopathy,11 patients had renal thrombotic microangiopathy lesion,2 had severe arteriosclerosis.All patients received steroids and immunosuppressive drugs,15 received angiotensin-converting enzyme inhibitor(ACEI)/angiotensin receptor blocker(ARB)with resultant well-controlled blood pressure.Thrombocytopenia and hemolytic anemia resolved remarkably.The renal function improved or recovered in 14 of 17 patients,and 3 developed end-stage renal disease on maintenance dialysis.Conclusions Severe intrarenal vascular lesion complicated with renal nephritis parallels clinical manifestation of malignant hypertension.Renal pathology is the key of treatment strategy emphasizing on the significance of renal vascular involvement and type.On the basis of immunosuppressive drugs and steroids to control systemic lupus activity,timely initiation of ACEI/ARB could be of benefit to blood pressure control and long term renal survival.

Cytomegalovirus enteritis mimicking Crohn's disease in a lupus nephritis patient:A case report

Cytomegalovirus(CMV)infection of the gastrointestinal (GI)tract has been reported in both immunocompetent and,more frequently,in immunocompromised patients.We describe a case of a 19-year-old male who developed CMV infection of the terminal ileum while receiving immunosuppression for lupus nephritis. This was a distinctly unusual site of infection which clinically mimicked Crohn's ileitis.We note that reports of terminal ileal CMV infection have been infrequent. Despite a complicated hospital course,ganciclovir therapy was effective in resolving his symptoms and normalizing his ileal mucosa.This report highlights the importance of accurate histological diagnosis and clinical follow-up of lupus patients with GI symptoms undergoing intense immunosuppression.

Pediatric lupus nephritis: Management update

Childhood-onset systemic lupus erythematosus （cSLE） is a severe multisystem autoimmune disease. Renal involvement occurs in the majority of cSLE patients and is often fatal. Renal biopsy is an important investigation in the management of lupus nephritis. Treatment of renal lupus consists of an induction phase and main-tenance phase. Treatment of childhood lupus nephritis using steroids is associated with poor outcome and excess side-effects. The addition of cyclophosphamide to the treatment schedule has improved disease control. In view of treatment failure using these drugs and a tendency for non-adherence, many newer agents such as immune-modulators and monoclonal antibodies are being tried in patients with cSLE. Trials of these novel agents in the pediatric population are still lacking making a consensus in the management protocol of pediatric lupus nephritis diffcult.

Dan Bai Xiao Formula combined with glucocorticoids and cyclophosphamide for pediatric lupus nephritis:A pilot prospective study

BACKGROUND Patients with lupus nephritis(LN)typically undergo long-term treatment with glucocorticoids(GCs)and immunosuppressants.There is a growing demand for optimal therapy with better remission results and fewer side effects.Sustained traditional Chinese medicine(TCM)might be quite valuable for multitarget therapy,reducing the total dosage of GCs and minimizing the side effects of immunosuppressants.AIM To evaluate whether Dan Bai Xiao Formula(DBXF)can reduce the exposure to GCs and cyclophosphamide(CYC)and to assess the efficacy and safety of DBXF for the resolution of proteinuria and hematuria in children with LN.METHODS A 24-wk pilot study was conducted at Beijing Children’s Hospital.Children with active LN were divided into either a TCM group or a control group.Children in the TCM group received DBXF combined with GCs and CYC,and the ones in the control group received GCs and CYC every 4 wk for 24 wk.The primary endpoints of this trial were urinary protein excretion of<150 mg/d and normal serum albumin concentration and renal function.RESULTS The trial included 78 children,of whom 38 received GCs and CYC treatment(control group)and the remaining 40 received DBXF combined with GCs and CYC treatment(TCM group).At week 24,the TCM group showed a better rate of complete remission(42.5%);however,there was no significant difference compared with the control group(31.5%,P>0.05).The urine red blood cell count and urine protein level were significantly lower in the TCM group than in the control group at weeks 4,12,and 24(P<0.05).Furthermore,patients in the TCM group had a lower proportion of methylprednisolone pulses than those in the control group(1.30±1.41 vs 3.05±2.02,P<0.0001).The ending GC dose was significantly lower in the TCM group than in the control group(P<0.001).Moreover,more hepatic function damage,gastrointestinal adverse effects,and hypertension were observed in the control group than in the TCM group(P<0.05).CONCLUSION The findings suggest that DBXF treatment is effective and safe as a supplementary therapy for LN and is superior to routine GC and CYC therapy.DBXF containing combination treatment possibly results in a faster resolution of proteinuria and hematuria,smoother GC reduction,fewer methylprednisolone pulses,and fewer adverse events.

Alport syndrome combined with lupus nephritis in a Chinese family:A case report

BACKGROUND Alport syndrome(ATS)is a rare hereditary disease caused by mutations in genes such as COL4A3,COL4A4,and COL4A5.ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities.Although ATS can be combined with other diseases or syndromes,ATS combined with lupus nephritis has not been reported before.CASE SUMMARY A Chinese family with ATS was recruited for the current study.Clinical characteristics(including findings from renal biopsy)of ATS patients were collected from medical records,and potential causative genes were explored by whole-exome sequencing.A heterozygous substitution in intron 22 of COL4A3(NM_000091 c.2657-1G>A)was found in the patients,which was further confirmed by quantitative polymerase chain reaction.CONCLUSION Heterozygous substitution of a COL4A3 gene splice site was identified by wholeexome sequencing,revealing the molecular pathogenic basis of this disorder.In general,identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.

Pneumothorax during retroperitoneal laparoscopic partial nephrectomy in a lupus nephritis patient:A case report

BACKGROUND Downgrading target treatment and laparoscopic partial nephrectomy have become increasingly popular in patients with renal cell carcinomas.Rare as it is,pneumothorax is one of the most severe intraoperative complications which needs immediate recognition.On the other hand,as a rheumatological disease,lupus nephritis requires a long period of hormone therapy.Cases of pneumothorax in hormone-consuming renal cancer patients are even fewer.CASE SUMMARY A 39-year-old woman was admitted to our department to take a laparoscopic partial nephrectomy.The patient had a medical history of lupus nephritis and renal clear cell carcinoma with hormone and target treatment.Her blood oxygen saturation dropped to 92%during the operation,and pneumothorax was detected by ultrasound.O2 inhalation and lung dilation were performed.Her vital signs were monitored closely throughout the operation.The operation was accomplished,and she regained consciousness smoothly.A postoperative bedside chest X-ray was conducted after she was transferred to the urosurgery ward,while no evidence of further pneumothorax or lib injury was observed.CONCLUSION Pneumothorax is a severe complication in laparoscopic or robotic-assisted laparoscopic operations,especially in retroperitoneal ones.It is easily neglected unless the injury of the diaphragm is found.Low insufflation pressure and shorter operation time are necessary for patients with a history of long-term hormone consumption or chronic immune system disease.

Outcome of Leflunomide in the Treatment of Proliferative Lupus Nephritis Compared to Cyclophosphamide

Background: Lupus nephritis (LN) is one of the most common presentations of Systemic lupus erythematosus (SLE). Cyclophosphamide is one of the key immunosuppressive agents for the management of LN. Leflunomide is an isoxazole immunomodulatory agent has been shown to be safe, well tolerated and effective in SLE and LN. Objective: To evaluate the outcome of leflunomide in the treatment of proliferative lupus nephritis compared to cyclophosphamide. Method: This randomized clinical trial was held in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2017 to August 2019. A total of 66 patients of proliferative lupus nephritis who need induction therapy were enrolled in this study. Leflunomide 100 mg/day for consecutive 3 days followed by 0.5 mg/kg/day in divided dose was given in experimental group (n = 32) and intravenous cyclophosphamide 0.5 gm/m2 of body surface area monthly pulse was given in control group (n = 34). All study patients have received prednisolone and hydroxychloroquine according to KDIGO guideline then followed up monthly for 6 months. Outcomes were measured at 6th month by renal function [S. Creatinine, 24 hours urinary total protein (24-hr UTP)], changes in SELENA-SLEDAI score, anti-ds DNA level, serum complement levels (serum C3 & C4), remission (complete/partial) and adverse drug responses. Result: In experimental group, remission occurred in 18 (56.3%) patients and no remission in 14 (43.7%) patients. In control group, remission occurred in 24 (70.6%) patients and no remission in 10 (29.4%) patients. Adverse effects in experimental group were: elevated ALT (6.3%), hypertension (12.5%), infection (6.3%) and amenorrhea (12.5%). In control group, adverse effects were mainly leucopenia (5.9%), infection (17.7%) and amenorrhea (29.4%). Intergroup analysis for treatment responses and adverse effects showed no significant difference (p > 0.05). Conclusion: Leflunomide combined with prednisolone is effective in the induction treatment of proliferative lupus nephritis in Bangladeshi patients in terms of response rate and adverse effects.

Lupus Nephritis Class II: A Challenging Entity

Most of the literature focused on the proliferative forms of the lupic Glomerulonephritis. Clinicians are increasingly confronted with cases of lupic nephropathy purely mesangial (class II). The aim of our study is to describe the mode of presentation of the class II Lupus nephropathy, evaluate its evolutionary profile, and investigate possible risk factors for therapeutic misresponse, relapse or histological transformation. This is a retrospective descriptive and analytical study conducted in nephrology depratement at the Hassan II university hospital Fez from January 2009 until September 2018. We included 20 patients. The average age was 33.8 ± 7.25 years [22 - 50 years]. Nephropathy was inaugurated in half of the cases. The mean time of onset of nephropathy in relation to the lupic disease was 36.7 ± 45.4 months [1 - 144 months]. The main reason for consultation was non-nephrotic proteinuria (65%). Renal failure revealed diagnosis in three patients. All patients had a positive immunologic assessment. 90% of our patients received oral corticosteroid therapy with immunosuppressive therapy in 3 cases. Remission has been noted in all of our patients. After an average follow-up period of 39 ± 23 months [6 - 92 months], 45% relapsed. A second biopsy was performed in 80% of patients showing histologic transformation in four patients, requiring immunosuppressive therapy. The analytical study showed that the occurrence of relapse was significantly related to the presence of a known Lupus and its seniority. Proteinuria at 12 months was also significantly higher in the relapsed group. One patient died as a result of neurological complications. Another has Evolved into chronic end stage renal failure and has been put on hemodialysis.

A Case Report of Lupus Panniculitis in a Hemodialysis Patient with Lupus Nephritis

Background: Systemic lupus erythematosus and lupus nephritis are relatively common autoimmune diseases that can cause damage to multiple systems. Aim: To investigate the lupus activity of patients with lupus nephritis on hemodialysis and the combined occurrence of lupus panniculitis. Case introduction: A patient with lupus nephritis on regular hemodialysis had a symmetrical hard mass under the skin of his abdomen. After surgical resection and pathological examination, she was diagnosed with lupus panniculitis and was treated with glucocorticoids and hydroxychloroquine. After that, no new subcutaneous masses appeared, and the unresectable part of the masses did not increase. Conclusion: 1) Lupus activities in patients with lupus nephritis entering end-stage renal disease still need to be paid attention to. 2) Lupus panniculitis can occur on the skin of the abdomen, and it needs to be differentiated from connective tissue panniculitis, sclerosing panniculitis and other diseases.

Infectious Complications in Lupus Nephritis and Associated Factors: A Multicenter Study

Introduction: The prevalence of infections in patients with systemic lupus erythematosus ranges from 26% to 78%. Patients with systemic lupus erythematosus are particularly susceptible to infections due to a dysfunction of immune response and the immunosuppressive therapy. Patients and method: We carried out this study with the aim of describing the prevalence of infections in lupus nephritis and determining the associated risk factors. This was a multi-center, observational, retrospective, descriptive and analytical study over a 10-year period from November 1, 2010 to October 31, 2020. The study was carried out in the nephrology departments of six hospitals in Dakar. Results: During the study period, 98 patients were included. The mean age was 32.32 ± 11.33 years with a sex ratio of 0.21. Among the included patients, fifty-four (55.1%) had at least one infectious episode, of which 53.7% had 1 infection, 24.1% had 2 infectious episodes and 22.2% had 3 infectious episodes. The overall incidence was 55.1 infections per 100 patient-years. 57.2% of these infectious episodes occurred within the first six months after the lupus was diagnosed. The main sites of infection were urinary (30.7%), gastrointestinal (22.0%) and pleuropulmonary (16.5%). The incriminated germ was a bacterium in 78.18% of cases, a virus in 5.46%, a parasite in 9.09 and a fungus in 7.27. The most frequently germ found was Escherichia coli (29.09%). The evolution was marked by recovery in 93.4% of cases. Deaths occurred in 15 patients of which 33.3% were related to infections. Factor significantly associated with the onset of infection in multivariate analysis was the presence of a proliferative class of lupus nephritis (p = 0.013). Conclusion: Infections were common during lupus nephritis. The presence of a proliferative class was risk factors for infection.

Targeted therapies for lupus nephritis:Current perspectives and future directions

Lupus nephritis(LN),a severe manifestation of systemic lupus erythematosus,poses a substantial risk of progression to end-stage renal disease,with increased mortality.Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids,mycophenolate mofetil,and calcineurin inhibitors.Although therapeutic regimens have evolved over the years,they have inherent limitations,including non-specific targeting,substantial adverse effects,high relapse rates,and prolonged maintenance and remission courses.These drawbacks underscore the need for targeted therapeutic strategies for LN.Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity.This review provides an overview of the current evidence on targeted therapies for LN,elucidates the biological mechanisms of responses and failure,highlights the challenges ahead,and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.

B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

Podocyte injury and death:New insights into lupus nephritis pathogenesis and therapy

Lupus nephritis(LN),an immune complex-mediated glomerulonephritis,is one of the most severe complications of systemic lupus erythematosus.Current therapeutic regimens for LN mainly involve nonspecific immunosuppressants and biologics targeting immune cells,but these treatments are not always effective and some patients are nonresponsive and susceptible to recurrence.Podocytes are essential for maintaining the glomerular filtration barrier.Injury to and loss of podocytes lead to proteinuria,a hallmark of renal involvement and LN.Podocytes are,therefore,emerging as prospective therapeutic targets for LN.There are numerous mechanisms underlying podocyte malfunction in LN,with autophagy,mitochondrial dysregulation,and programmed cell death being the main processes behind podocyte loss.This review summarizes recent advances in understanding podocyte dysfunction in LN pathogenesis and discusses potential therapeutic interventions targeting podocytes in LN.