Progression Of Lupus Nephritis Research Articles

M1 and M2 Macrophage Polarization Correlates with Activity and Chronicity Indices in Lupus Nephritis.

Background: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE), characterized by inflammation and immune dysregulation in the kidneys. The role of macrophage polarization in LN progression remains underexplored. Objective: This study examined the association between tubulointerstitial M1/M2 macrophage subpopulations and LN indices of activity and chronicity. Materials and Methods: We retrospectively reviewed 160 renal biopsy specimens in patients with LN (ISN/RPS classes II-V) from the database of the Department of Anatomical Pathology, the Faculty of Medicine Vajira Hospital, Navamindradhiraj University (2012-2021). Additional immunohistochemical analysis included CD68, iNOS, CD206, CD163, and evaluation of infiltration with M1 (iNOS+), M2a (CD206+), and M2c macrophages (CD163+). Moreover, clinical information at the time of the renal biopsy, including age, sex, and laboratory findings, was obtained from the electronic medical records. The data were correlated with the macrophage infiltration using the Spearman test. Results: Lupus nephritis biopsies with ISN/RPS class II-V were included (class II: 3 cases (2%), III: 30 cases (19%), III + V: 16 cases (10%), IV: 73 cases (46%), IV + V: 18 cases (11%), and V: 20 cases (12%)). In addition, the mean age of SLE patients at the time of biopsy was 33 years (range: 19-47 years). Most patients were females (n = 141; 88%). The population of CD68+ macrophages was related to serum creatinine (p < 0.001; rs = 0.34). We detected predominantly M2 macrophages across all LN classes, but M1 macrophages demonstrated significant correlations with the activity index (p < 0.001; rs = 0.43). Conversely, M2a and M2c subpopulations were strongly associated with the chronicity index (M2a: p < 0.001, rs = 0.48; M2c: p = 0.024, rs = 0.18). Total macrophages correlated with both indices (activity: p < 0.001, rs = 0.44; chronicity: p < 0.001, rs = 0.42). Conclusions: In lupus nephritis, the predominant population of macrophages is M2. Correlations were noted between the subpopulations of M1 and M2c macrophages and the activity and chronicity indices, respectively. In addition, macrophage populations correlated with disease progression, but the significance of this association in disease progression remains uncertain.

The Role of Podocytes in Lupus Pathology.

Kidney injury due to lupus nephritis (LN) is a severe and sometimes life-threatening sequela of systemic lupus erythematosus. Autoimmune injury to podocytes has been increasingly demonstrated to be a key driver of LN-related kidney injury because these cells play key roles in glomerular filtration barrier homeostasis. Irreparable podocyte injury impairs these processes and can lead to proteinuria, which is an indicator of poor prognosis in LN. This review highlights recent advances in our understanding of the involvement of podocytes in the pathogenesis of LN and discusses new podocyte-targeted therapeutic strategies. Podocytes play a key role in glomerular filtration barrier homeostasis, both by helping to secrete and organize the glomerular basement membrane and by the formation of a glomerular slit diaphragm between adjacent cells. Recent studies revealed the involvement of abnormal calcium signaling, dysregulation of actin-related proteins, and mitotic catastrophe in LN progression. In addition, podocytes express many molecules related to the innate and adaptive immune responses. IgG from patients with LN induces direct injury of podocytes, inflammasome, and interactions with immune cells which have been shown to promote the development of LN. Our understanding of the role of podocytes in the pathogenesis of LN has been improved. Recent studies have shed light on potential therapeutic strategies targeting podocytes to control kidney injury.

The Role of Sodium-Glucose Co-Transporter-2 (SGLT-2) Inhibitors in Treating Lupus Nephritis: A Systematic Review.

Systemic lupus erythematosus (SLE) is a prevalent autoimmune condition worldwide resulting from the loss of tolerance against self-antigens. The constitutional symptoms of SLE are well-known, including fatigue, fever, myalgia, weight loss, arthralgia, arthritis, malar rash, and photosensitivity. These symptoms often overshadow the impacts SLEcan have on all body systems, with the renal system frequently impacted. Inflammation of the nephrons can progress to end-stage renal disease and renal failure if not treated effectively. Currently, the medications that are being utilized for the treatment of lupus nephritis (LN), include azathioprine, hydroxychloroquine, cyclophosphamide, belimumab,voclosporin, tacrolimus, mycophenylate, and rituximab. However, the majority of these medications are used off-label, and many come with severe side effects. With the additional benefits of anti-diabetic medications being examined outside of their original purpose, sodium-glucose co-transporter-2 (SGLT-2) inhibitors have begun to be investigated for their role in LN. To determine the impact of SGLT-2 inhibitors on LN risk and progression, a preliminary systematic review was conducted. A total of 248 articles were analyzed, with six being selected. SGLT-2 inhibitors were found to improve glomerular filtration rate (GFR), reduce proteinuria and albuminuria, and reduce the inflammatory cascade. The exploration of SGLT-2 inhibitors as a therapeutic strategy for LN represents a promising and innovative approach to managing this complex condition. SGLT-2 inhibitors show potential benefits beyond glycemic control. However, due to the novelty of this treatment and the limited studies completed, further testing is required to analyze its true effectiveness in LN.

Relationship between leukocyte count and renal function in patients with lupus nephritis: a retrospective study of Chinese adults.

To explore the relationship between leukocyte count and renal function in patients with lupus nephritis (LN). We performed a retrospective cross-sectional study of 100 patients with LN admitted to the Department of Nephrology between 1 January 2015 and 30 December 2023. Based on tertile of leukocyte count, they were allocated to Low, Medium, or High groups. The demographic, clinical, and pathologic characteristics of the groups were compared and the relationship between leukocyte count and renal function was analyzed using multiple linear regression analysis. After adjustment for age, albumin, 24-hour proteinuria, serum complement factor 3, hemoglobin, blood pressure, systemic lupus erythematosus disease activity index score, and histologic parameters, a linear relationship was identified between leukocyte count and renal function (regression coefficient -2.852; 95% confidence interval: -5.161, -0.543). Therefore, for every 1 × 109/L increase in leukocyte count, the estimated glomerular filtration rate would decrease by 2.85 mL/minute. There is an independent linear relationship between leukocyte count and renal function. Leukocyte recruitment into the kidney is a critical step in the progression of LN, and as the leukocyte count increases, renal function gradually declines. Leukocyte count may represent a sensitive biomarker of the progression and prognosis of LN.

Antagonising Yin Yang 1 ameliorates the symptoms of lupus nephritis via modulating T lymphocyte signaling

Lupus nephritis (LN) is a chronic complication of systemic lupus erythematosus (SLE). At present, no drugs are capable of delaying the progression of LN without a risk of serious side effects. There is thus a pressing need for further studies of LN pathogenesis to identify novel therapeutic targets and aid in the development of new approaches to treating this debilitating disease. In this study, a multi-omics approach was used to characterize the pathogenesis of LN and to identify disease-related targets, ultimately leading to the identification and validation of Yin Yang 1 (YY1) as a promising therapeutic target in LN. A rapid approach to efficiently screening for candidate YY1 ligands was implemented using drug databases that established rebamipide as a YY1 antagonist suitable for use in the management of LN. Specifically, the YY1 antagonist activity of rebamipide was found to regulate lymphocyte activity, reduce autoantibody production, limit immune complex deposition, and suppress macrophage activation while improving symptoms in a murine model of LN. Results supportive of a similar pathologic mechanism of action were also obtained when analyzing renal tissue sections from LN patients, underscoring the potential clinical significance of YY1 and its antagonist rebamipide, suggesting that rebamipide may have positive effects on lymphocytes and may improve symptoms in treated patients. This study provides a robust foundation for further research focused on the pathogenesis and treatment of LN.

The Protective Effect of Esculentoside A on MPL/lpr Mice by Upregulating the Expression of CD19+IL-35+Breg Cells and Interleukin-35

Introduction: Esculentoside A (EsA) is one of the main components of the traditional Chinese medicine Phytolacca esculenta. The possible mechanism of action of EsA in the treatment of lupus nephritis (LN) was explored by observing the effects of EsA on CD19+ IL-35+regulatory B (IL-35+Breg) cells. Methods: Twenty-four MRL/lpr mice were randomly divided into control, EsA, and EsA+IL-12p35 antibody groups. Mice were administered the respective treatments intraperitoneally once a day for 4 weeks. The urine protein/creatinine ratio (UPCR) and blood creatinine (Cr) and IL-35, IL-10, and IL-17 expression levels were measured. Body and spleen weight were measured to calculate the splenic index (SI). Flow cytometry was performed to determine the proportion of CD19+ IL-35+ Breg cells in the spleen. Hematoxylin-eosin and PASM-Masson staining of renal tissues were performed, and the “Austin” acute index (AI) system for LN was determined. Results: The most severe conditions were seen in mice in the control group, with the highest UPCR, Cr, and IL-17 levels and SI and AI scores; the most severe renal histopathology, and the lowest proportion of CD19+ IL-35+ Breg cells and IL-35 and IL-10 levels. This was followed by the EsA+IL-12p35 antibody group. The EsA group had the lowest UPCR, Cr, and IL-17 levels and SI and AI scores; the mildest renal lesions; and the highest proportion CD19+ IL-35+ Breg cells and IL-35 and IL-10 levels. Conclusion: EsA delayed the progression of LN by promoting the proliferation of CD19+ IL-35+ Breg cells, upregulating the expression of IL-35, and decreasing the secretion of IL-17.

Downregulation of ferroptosis-related ATF3 alleviates lupus nephritis progression

BackgroundThe role of ferroptosis in lupus nephritis (LN) is unclear. This study aimed to explore the effects of ferroptosis-related genes in LN through bioinformatics prediction and experimental validation. MethodsSample data were collected from the GEO dataset and divided into glomeruli and tubulointerstitium. We collected 382 ferroptosis-related genes. The intersection of ferroptosis-related genes with glomeruli and tubulointerstitium data, respectively, was performed. Machine learning methods (including unsupervised cluster typing and random forests) were operated to identify ferroptosis subtyping and ferroptosis important genes in LN. Immune infiltration and functional analysis were performed. The expression of ferroptosis important gene ATF3 was validated in vivo and in vitro. Results6 ferroptosis important genes common to glomeruli and tubulointerstitium were screened, including ATF3, CD44, CYBB, JUN, NCF2, and NNMT. ATF3 decreased in the LN group compared to the Control. Silencing ATF3 mitigated LPS/erastin-induced ferroptosis. Functional analysis showed that ATF3 was markedly enriched in the interferon-gamma-mediated signaling pathway, ECM-receptor interaction, and cell adhesion. In glomeruli, T cells regulatory (Tregs) infiltration decreased and Macrophages M1 levels increased with elevated ATF3 expression. Levels of immune cell infiltration were altered in different ferroptosis subtypes of LN glomeruli and tubulointerstitium. ConclusionsFerroptosis-related ATF3 levels decreased in LN. Inhibition of ATF3 might alleviate LN development by affecting the macrophage M1 and Treg cell infiltration. These implied that ATF3 might be a potential target for developing LN therapeutic strategies.

Reviewing Genetic Testing for Lupus: Implications for Nephritis

Genetic testing has significantly changed our understanding and treatment of systemic lupus erythematosus (SLE), particularly its severe manifestation, lupus nephritis (LN). Nephrology faces great difficulty with LN, which is characterized by severe inflammation and kidney damage. To create individualized treatments, it is essential to identify the genetic variables that influence the LN susceptibility and progression. This review highlights the importance of genetic testing in diagnosing and managing LN, covering genetic predispositions, common markers, the role of ethnicity, specific renal genes, and epigenetic factors. Key genetic markers such as HLA-DRB1, ITGAM, FCGR2A, and IRF5 have been linked to LN, impacting immune regulation and disease progression. Asians, African Americans, and Hispanics have greater prevalence rates of genetic susceptibility than Caucasians, suggesting that ethnicity plays a major role in genetic vulnerability. Genes like APOL1, PDGFRA, and HAS2 play vital roles in renal function and fibrosis, affecting disease outcomes. New treatment targets are provided by epigenetic mechanisms that control gene expression in LN, such as DNA methylation and histone alterations. The progress made in genome-wide association studies (GWAS) has led to the discovery of new genetic loci linked to LN, which has improved our knowledge of its pathogenesis. This review highlights the critical role of genetic testing in LN, emphasizing its potential to improve diagnosis, treatment, and patient outcomes through personalized medicine.

Clinical and Immunological Factors Associated with the Progression of Lupus Nephritis in a Population from the Colombian Caribbean.

to identify clinical and immunological factors associated with the progression of lupus nephritis in a population from the Colombian Caribbean. we evaluated 401 patients diagnosed with SLE and lupus nephritis, treated at a reference center in the Colombian Caribbean, gathering data recorded in medical records. A proportion of 87% were female, with a median age of 42 years. Most patients presented with proliferative classes (90%), with class IV being the most common (70%). A proportion of 52% of patients did not respond to treatment, which is described as the lack of complete or partial response, while 28% had a complete response. A significant decrease in hemoglobin, glomerular filtration rate, and proteinuria was identified by the third follow-up (p < 0.001), along with an increase in creatinine, urea, and hematuria (p < 0.001). Patients with initial proteinuria > 2 g/day were found to be 27 times more likely to be non-responders (p < 0.001). Mortality was associated with the presence of serum creatinine >1.5 mg/dL (p = 0.01) (OR: 1.61 CI 95% 0.75-3.75) and thrombocytopenia (p = 0.01) (OR: 0.36; CI 95% 0.12-0.81). identifying factors of progression, non-response, and mortality provides an opportunity for more targeted and personalized intervention, thereby improving care and outcomes for patients with lupus nephritis.

Serum Levels of CXCL10 in Patients with Lupus Nephritis and its Relation with Disease Activity

Abstract Objective To evaluate the levels of CXCL10 in lupus nephritis (LN) patients and its relation with the activity of lupus nephritis. Patients and Methods Thirty four lupus patients were enrolled in our study, 17patients had lupus nephritis (LN) and 17 patients were without evidence of had lupus nephritis (LWN). Seventeen healthy subjects were also participated as a control group. Complete biochemical and serological parameters were measured and their correlation with serum levels of CXCL10 were assessed in the studied groups. Results The mean age of the LN patients was 31.94 ± 6.37,the mean age of LWN patient was 31.11± 6.42 and the mean age of the controls was 30.471± 4.705, Serum levels of CXCL10 were significantly elevated in LN patients group than LWN and control group with p-value &amp;lt;0.001,While serum CXCL10 in LWN was statistically increased than control group with p-value&amp;lt;0.001. Based on the receiver operator characteristic (ROC) curve analysis the efficacy of Serum CXCL10 levels in LN in a sample of Egyptian SLE patient This biomarker may be useful due to its high accuracy, with a sensitivity 94.12% and specificity of 76.47% as a biomarker of nephritis in SLE. There were statistically significant positive correlations between CXCL10 and 24 urinary protein (p-value = 0.031) (r = 0.524), creatinine (p-value = 0.003) (r = 0.682), renal activity (RSLEDAI) (p-value = 0.013) (r = 0.590) and Activity index (p-value = 0.003) (r = 0.669), whereas there was negative correlations between them and C3 (p-value = 0.021) (r=-0.554). Conclusion Being higher in patients with LN, CXCL10 might play a role in the pathogenesis of the disease. In addition to its excellent diagnostic performance for discriminating patients with lupus nephritis from other SLE patients, it might be helpful to predict the onset and progression of lupus nephritis in SLE patients and to detect renal flares.

STAT1 aggravates kidney injury by NOD-like receptor (NLRP3) signaling in MRL-lpr mice.

Systemic lupus erythematosus (SLE) is a persistent autoimmune disorder that can culminate in lupus nephritis (LN), an intricate renal complication. In pursuit of unraveling the intricate molecular underpinnings governing LN progression, we conducted bioinformatics analysis employing gene expression data sourced from the GSE32591 dataset. Our scrutiny revealed a panoply of differentially expressed genes (DEGs) within the glomerulus and tubulointerstitial compartments of LN patients. Enrichment analysis for DEGs engaged in diverse processes, encompassing virus defense, viral life cycle, cell adhesion molecules, and the NOD-like receptor signaling pathway. Notably, STAT1 emerged as an eminent central hub gene intrinsically tied to NOD-like receptor signaling. To explore the functional significance of STAT1 in the context of LN, MRL-lpr mice model was used to knockout STAT1. The results unveiled that STAT1 silencing yielded a migratory effect on kidney injury, concurrently curbing inflammatory markers. Meanwhile, knockout STAT1 also reduced NLRP3 expression and Cleaved caspase-1 expression. These findings offer tantalizing prospects for targeting STAT1 as a potential therapeutic conduit in the management of LN.

Analysis of Albumin to Globulin Ratio as A Prognostic Predictor in Lupus Nephritis Patients

Lupus Nephritis (LN) is a manifestation of Systemic Lupus Erythematosus (SLE), which targets the kidney. Based on histopathology, the World Health Organization divides the disease into five classes: normal pattern, mesangial, focal, diffuse proliferative, and membranous. Albumin to Globulin Ratio (AGR) compares serum albumin with serum globulin levels. Low AGR value is associated with poor prognosis of diseases such as cancer, liver cirrhosis, and other chronic inflammatory diseases such as LN. This study aimed to analyze the AGR value as a prognostic predictor in LN patients based on disease classes with a retrospective descriptive cross-sectional approach. Total subjects were 109, which consisted of class 1 (n=15), class 2 (n=37), class 3 (n=9), class 4 (n=21), and class 5 LN (n=27). Data of disease classes, serum albumin, and serum globulin/total protein levels were collected. SPSS version 25, Mann-Whitney, Kruskal-Wallis, Chi-Square, and Spearman's correlation test were used for statistical analysis. The ROC curve determined the cut-off. Test results were significant if p &lt;0.05. The lowest mean AGR value (0.79) was found in class 4 LN (p&lt;0.05). The optimal cut-off AGR was 1.10 to categorize mild-moderate and severe degrees. AGR prognostic value: sensitivity=95.8%; specificity=78.8%; Positive Prediction Value (PPV)=78.0%; Negative Prediction Value (NPV)=96.0%, accuracy = 86.2%. There was a negative strong correlation between the AGR value and LN class with a correlation coefficient R of -0.777 (p&lt;0.001). AGR marker has a good sensitivity and specificity as a predictor of LN progression.

#525 SGLT2 inhibition in non-diabetic CKD: results in experimental lupus nephritis

Abstract Background and Aims Sodium glucose cotransporter type 2 inhibitors (SGLT2i) potently attenuate cardiovascular morbidity and progression of CKD in patients with type 2 diabetes. It has been proposed that SGLT2 inhibition may also elicit renoprotective effects in non-diabetic CKD. The aim of this work is to evaluate whether the treatment with an SGLT2i improves kidney disease progression in a mouse model of lupus nephritis (LN). Method We performed a single center randomized controlled preclinical trial using female MRLlpr/lpr mice. The animals were randomly assigned to (1) vehicle or (2) empagliflozin (EMP, 10 mg/kg/day) treatment once signs of active systemic lupus erythematosus (SLE) appeared: proteinuria &amp;gt;100 mg/dL (++ in reactive strips) or lymphadenopathy in minimum 2 bilateral sites with proteinuria &amp;gt;30 mg/dL (+ in reactive strips). We included 13 mice per group that were treated during 4 weeks. Empagliflozin was given as an admix into standard chow diet. Reduction of urinary albumin to creatine ratio (UACR) was considered the primary endpoint whereas glomerular filtration rate (GFR), renal histology (LN activity/chronicity index, glomerulosclerosis, interstitial fibrosis) and SLE markers (total serum IgG, anti-dsDNA IgG, glomerular IgG deposits, lymph node weight, spleen weight) were considered secondary endpoints. Results After 4 weeks of treatment, no significant differences in fasting blood glucose levels were found between the experimental groups. As expected, empagliflozin administration notably inhibited SGLT2 in the tubular cells demonstrated by a significant increase of urinary glucose (p &amp;lt; 0.0001). This is consistent with the increased water intake observed in MRLlpr/lpr mice treated with empagliflozin (p &amp;lt; 0.0001). At the end of the experiment, vehicle treated MRLlpr/lpr mice showed a significant increase in UACR (p = 0.0012) consistent with LN progression that was not attenuated by empagliflozin. In line, empagliflozin did not modify GFR and LN activity/chronicity indexes, glomerulosclerosis or interstitial fibrosis in kidney. Finally, regarding SLE markers, 4-weeks empagliflozin treatment was not able to decrease total serum IgG, anti-dsDNA IgG, glomerular IgG deposits or lymph node weight. Only spleen weight was significantly decreased in empagliflozin treated MRLlpr/lpr mice (p = 0.003). Conclusion In our experimental setting, empagliflozin treatment reduced spleen weight suggesting a protective role in SLE in MRLlpr/lpr mice. However, empagliflozin did not modify LN progression in MRLlpr/lpr mice probably because the acute LN phase. It is expected that the positive effect in terms of reducing proteinuria will be observed in patients with LN and residual proteinuria

#2006 CircMTND5 participated in tubulointerstitial fibrosis progression of lupus nephritis by binding with A1CF

Abstract Background and Aims lupus nephritis (LN) is the most common and severe complication of systemic lupus erythematosus (SLE). CircRNA MTND5 participated in the pathogenesis of LN by sponging miR6812. However, it remains unclear what RNA binding role of circMTND5 play in LN. We aim to investigate whether circMTND5 can interact with RBP in the development and progression in LN, and to clarify the corresponding mechanisms. Method A1CF, a RNA binding protein, E-cadherin, α-SMA, TGF-β, and Fibronectin were analyzed by immunohistochemistry on paraffin-embedded section of LN patients and NC kidney tissues. The above parameters and circMTND5 were also examined in Fcgr2b-/- spontaneous LN mice kidneys by Western blotting and qPCR. In human kidney (HK) -2 cells, the binding of circMTND5 to A1CF protein was examined by RNA immunoprecipitation (RIP) assay. After knockdown in HK-2 cells and overexpression in hTGF-β stimulated HK-2 cells, we examined the all above indices. Results the expression of A1CF was down-regulated in the kidneys of LN patients and was localized in tubular epithelial cells. E-cadherin was down-regulated while α-SMA was up-regulated. The expression of circMTND5 was down-regulated in kidneys of Fcgr2b-/- spontaneous LN mice. In HK-2 cells, the binding of circMTND5 to A1CF was confirmed by RIP. A1CF and E-cadherin were down-regulated, while α-SMA, TGF-β and FN were up-regulated in HK-2 cells with knockdown of circMTND5. The overexpression of circMTND5 reverted the changes of the those above parametered induced by hTGF-β in both mRNA and proteins levels. Conclusion The expression level of circMTND5 in renal tissue of LN mice was downregulated. CircMTND5 might play an important role in tubulointerstitial fibrosis of lupus nephritis by binding with A1CF protein.

Urinary Biomarkers for Lupus Nephritis: A Systems Biology Approach.

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder. Kidney involvement, termed lupus nephritis (LN), is seen in 40-60% of patients with systemic lupus erythematosus (SLE). After the diagnosis, serial measurement of proteinuria is the most common method of monitoring treatment response and progression. However, present treatments for LN-corticosteroids and immunosuppressants-target inflammation, not proteinuria. Furthermore, subclinical renal inflammation can persist despite improving proteinuria. Serial kidney biopsies-the gold standard for disease monitoring-are also not feasible due to their inherent risk of complications. Biomarkers that reflect the underlying renal inflammatory process and better predict LN progression and treatment response are urgently needed. Urinary biomarkers are particularly relevant as they can be measured non-invasively and may better reflect the compartmentalized renal response in LN, unlike serum studies that are non-specific to the kidney. The past decade has overseen a boom in applying cutting-edge technologies to dissect the pathogenesis of diseases at the molecular and cellular levels. Using these technologies in LN is beginning to reveal novel disease biomarkers and therapeutic targets for LN, potentially improving patient outcomes if successfully translated to clinical practice.

Upregulation of PD-1 and its ligands and expansion of T peripheral helper cells in the nephritic kidneys of lupus-prone BXSB-Yaa mice.

This study aimed to investigate the role of the programmed cell death protein 1 (PD-1) pathway and T peripheral helper (Tph) cells in the pathogenesis of lupus nephritis using lupus-prone BXSB-Yaa mice. Male BXSB-Yaa mice and age-matched male C57BL/6 mice were used. The expression of PD-1 and its ligands (programmed cell death 1 ligand-1, PD-L1 and programmed cell death 1 ligand-2, PD-L2) and the phenotypes of kidney-derived cells and splenocytes expressing these molecules were analyzed by immunofluorescence and flow cytometry. Nephritis spontaneously developed in 16-week-old but not in 8-week-old BXSB-Yaa or C57BL/6 mice. PD-1 was expressed on CD4+ mononuclear cells (MNCs) that infiltrated the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of CD4+PD-1+CXCR5-ICOS+ kidney-derived Tph cells was higher in 16-week-old than in 8-week-old BXSB-Yaa and C57BL/6 mice, whereas the frequency of CD4+PD-1+CXCR5+ICOS+ kidney-derived T follicular helper (Tfh) cells was not significantly different between the mice. PD-L1 was constitutively expressed in the renal tubules. PD-L2 was expressed in the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of PD-L1highCD11c+CD3-CD19- and PD-L2+CD11c+CD3-CD19- kidney-derived MNCs in 16-week-old BXSB-Yaa mice was significantly higher than that of the control mice. The percentage of kidney-derived Tph cells but not Tfh cells was correlated with the urinary protein levels in the nephritic mice. The results of this study suggest that kidney-infiltrating PD-1+ Tph cells expanded concomitantly with the upregulation of PD-L1 and PD-L2 in the kidneys and the progression of lupus nephritis.

Protopanaxadiol improves lupus nephritis by regulating the PTX3/MAPK/ERK1/2 pathway.

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.

Smith-specific regulatory T cells halt the progression of lupus nephritis

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy.

Systemic lupus erythematosus (SLE) is a prototype inflammatory autoimmune disease, characterized by breakdown of immunotolerance to self-antigens. Renal involvement, known as lupus nephritis (LN), is one of the leading causes of morbidity and a significant contributor to mortality in SLE. Despite current pathophysiological advances, further studies are needed to fully understand complex mechanisms underlying the development and progression of LN. Transcription factors (TFs) are proteins that regulate the expression of genes and play a crucial role in the development and progression of LN. The mechanisms of TF promoting or inhibiting gene expression are complex, and studies have just begun to reveal the pathological roles of TFs in LN. Understanding TFs in the pathogenesis of LN can provide valuable insights into this disease's mechanisms and potentially lead to the development of targeted therapies for its management. This review will focus on recent findings on TFs in the pathogenesis of LN and newly developed TF-targeted therapy in renal inflammation.

Roles of macrophages in lupus nephritis.

LN is a serious complication of systemic lupus erythematosus (SLE), affecting up to 60% of patients with SLE and may lead to end-stage renal disease (ESRD). Macrophages play multifaceted roles in the pathogenesis of LN, including clearance of immune complexes, antigen presentation, regulation of inflammation, and tissue repair. Macrophages are abundant in the glomeruli and tubulointerstitium of LN patients and are positively correlated with serum creatinine levels and the severity of renal pathology. It has been shown that the infiltration of macrophages is closely associated with several clinical indicators, such as serum creatinine and complement C3 levels, anti-dsDNA antibody titers, Austin score, interstitial fibrosis and renal tubular atrophy. Moreover, cytokines expressed by macrophages were upregulated at LN onset and downregulated after remission, suggesting that macrophages may serve as markers of LN pathogenesis and remission. Therapies targeting macrophages have been shown to alleviate LN. There are two main types of macrophages in the kidney: kidney-resident macrophages (KRMs) and monocyte-derived macrophages (MDMs). KRMs and MDMs play different pathological roles in LN, with KRMs promoting leukocyte recruitment at sites of inflammation by expressing monocyte chemokines, while MDMs may exacerbate autoimmune responses by presenting immune complex antigens. Macrophages exhibit high plasticity and can differentiate into various phenotypes in response to distinct environmental stimuli. M1 (proinflammatory) macrophages are linked to the progression of active SLE, whereas the M2 (anti-inflammatory) phenotype is observed during the remission phase of LN. The polarization of macrophages in LN can be manipulated through multiple pathways, such as the modulation of signaling cascades including TLR 2/1, S1P, ERS, metabolic reprogramming, and HMGB1. This paper provides a comprehensive overview of the role of macrophages in the progression of lupus nephritis (LN), and elucidates how these cells and their secretory products function as indicators and therapeutic targets for the disease in the context of diagnosis and treatment of LN.