Pathogenesis Of Lupus Nephritis Research Articles

OP0233 CELLULAR SENESCENCE IN A MOUSE MODEL OF LUPUS NEPHRITIS

BackgroundA third of patients with lupus nephritis (LN) show a decline in renal function despite treatment, with 5-10% developing end-stage renal disease within ten years. Prognostic markers that would allow for timely treatment decisions are hence eagerly sought, as are novel therapeutic targets. It is clear that lupus kidney is not simply a passive target of systemic autoimmunity but also hosts pathogenic mechanisms determining renal disease severity. These likely involve both the infiltrating immune and resident renal cell compartments. Cellular senescence is the irreversible arrest of the cell cycle through the accumulation of cyclin dependent kinase (CDK) inhibitors such as p16INK4a (CDKN2A). Senescent cells nevertheless remain metabolically active and undergo morphological and physiological changes including the acquisition of a pro-inflammatory, pro-fibrotic senescence-associated secretory phenotype (SASP). Aberrant accumulation of senescent cells has been observed in renal aging and pathology. We recently described the presence of p16INK4a-positive cells (a senescence hallmark) in LN renal biopsies, and their association with baseline disease severity and 5 year outcome1. In addition, we observed a spatial co-distribution between tissue-infiltrating CD8 T cells, senescent kidney cells, suggesting a pathogenic functional interaction between them.ObjectivesWe hypothesize that cellular senescence may contribute to tissue damage in a few different ways: (a) Presentation of senescence-associated antigens that attract and activate CD8 T cells. Alternatively, CD8 T cells may be summoned to the kidney by other means, and may contribute to senescence-induction through the secretion of certain cytokines; (b) Secretion of pro-fibrotic, pro-inflammatory molecules, and/or (c) Functional incapacitation of kidney cells, particularly renal progenitor cells, responsible for repairing and restoring kidney function upon damage. In parallel with our work on patient samples, we aim to establish a relevant pre-clinical model in which we may test for the effects of senescence and senescence-directed interventions, on kidney damage.MethodsHere, we assess for whether the B6.Sle1.Sle2.Sle3 spontaneous lupus-prone mouse may serve as an appropriate model in which to study the role of cellular senescence. We evaluated the presence and distribution of p16Ink4a-positive cells by immunohistochemistry, and tested for an association with CD8 T cell infiltration and renal and systemic disease, in a cohort of 21 B6.Sle1.Sle2.Sle3 female mice. This is now being followed-up by a systematic, longitudinal study for the time of onset of different renal and systemic disease parameters, as compared to the detection of renal cell senescence in this well-characterized model.ResultsAs observed in renal biopsies from LN patients, staining for p16Ink4a-positive cells was heterogenous between mouse kidney samples. Interestingly, p16Ink4a seems to be associated with CD8 T cell infiltration, renal impairment and damage, independently of age. This will now be confirmed using the “senescence-associated β-galactosidase” assay, the other classic measure of cellular senescence.ConclusionWe report the occurrence of cellular senescence, and its correlation with CD8 T cell infiltration and disease severity, in the B6.Sle1.Sle2.Sle3 mouse model of lupus. These mice provide a pre-clinical model in which to test for the role of cellular senescence in the pathogenesis of LN in vivo (by the induction vs. selective elimination of senescent cells). They also serve as an alternative source (alongside patient samples) of cells for in vitro functional assays to test for the effects of senescent renal cells on CD8 T cells and vice versa.

CD11c+ T-bet+ CD21hi B Cells Are Negatively Associated With Renal Impairment in Systemic Lupus Erythematosus and Act as a Marker for Nephritis Remission.

Lupus nephritis (LN) is one of the most common manifestations of systemic lupus erythematosus (SLE), characterized by abnormal B cell activation and differentiation to memory or plasma effector cells. However, the role of these cells in the pathogenesis of LN is not fully understood, as well as the effect of induction therapy on B cell subsets, possibly associated with this manifestation, like aged-associated B cells (ABCs). Consequently, we analyzed the molecules defining the ABCs subpopulation (CD11c, T-bet, and CD21) through flow cytometry of blood samples from patients with lupus presenting or not LN, following up a small sub-cohort after six months of induction therapy. The frequency of ABCs resulted higher in LN patients compared to healthy subjects. Unexpectedly, we identified a robust reduction of a CD21hi subset that was almost specific to LN patients. Moreover, several clinical and laboratory lupus features showed strong and significant correlations with this undefined B cell subpopulation. Finally, it was observed that the induction therapy affected not only the frequencies of ABCs and CD21hi subsets but also the phenotype of the CD21hi subset that expressed a higher density of CXCR5. Collectively, our results suggest that ABCs, and more importantly the CD21hi subset, may work to assess therapeutic response since the reduced frequency of CD21hi cells could be associated with the onset of LN.

Renal Tubular Cell Ferroptosis: A New Player in Pathogenesis of Lupus Nephritis

Abstract Background New research indicates that the injury to the renal tubular epithelial cells is a better predictor of renal outcomes in lupus nephritis (LN) as compared to glomerular injury. Iron accumulates mostly in the renal tubular cells of LN patients and murine models of LN. Ferroptosis is an incompletely understood form of cell death involving iron mediated lipid peroxidation, but its role in LN is not well established. Experiment LN and control patient biopsies were stained for markers of ferroptosis. Kidneys of female (MRL/lpr) and male (NZW X BXSB) F1, lupus mice were analyzed for markers of ferroptosis. Human proximal tubular cells (PTEC) were treated with LN serum with or without Liporxstatin-2, a novel ferroptosis inhibitor. Results Compared to controls, LN patients expressed higher levels of ACSL4 and 4HNE, the ferroptosis core proteins in the renal tubules. Compared to non-nephritic mice, nephritic mice had significantly higher gene expression of Aifm2, Acsl4, and Gpx1 as well as protein levels of Acsl4. Nephritic mice had an impaired renal glutathione synthesis pathway. Glutathione is an essential positive regulator of glutathione peroxidase 4 (Gpx4: ferroptosis inhibitor) which resulted in lower protein expression of Gpx4. Collectively, LN kidneys displayed a ferroptosis signature and was associated with an increase in Ngal and Kim1, PTEC injury markers. LN patients’ serum induced PTEC ferroptosis and associated pathology were significantly reduced by Liproxstatin-2. Conclusion Our data identify occurrence ferroptosis in renal tubular cell which can contribute to the pathogenesis of LN. Liproxstatin-2 mitigates human LN serum induced PTEC pathology and holds promise as an adjunct therapy to alleviate LN severity. Supported by grants from Vifor Pharma

Potential Small Molecules for Therapy of Lupus Nephritis Based on Genetic Effect and Immune Infiltration.

Lupus nephritis (LN) is the most common and significant complication of systemic lupus erythematosus (SLE) due to its poor prognosis and mortality rates in SLE patients. There is a critical need for new drugs as the pathogenesis of LN remains to be elucidated and immunosuppressive therapy comes with many deficiencies. In this study, 23 hub genes (IFI6, PLSCR1, XAF1, IFI16, IFI44, MX1, IFI44L, IFIT3, IFIT2, IFI27, DDX58, EIF2AK2, IFITM1, RTP4, IFITM3, TRIM22, PARP12, IFIH1, OAS1, HERC6, RSAD2, DDX60, and MX2) were identified through bioinformatics and network analysis and are closely related to interferon production and function. Interestingly, immune cell infiltration analysis and correlation analysis demonstrate a positive correlation between the expression of 23 hub genes and monocyte infiltration in glomeruli and M2 macrophage infiltration in the tubulointerstitium of LN patients. Additionally, the CTD database, DsigDB database, and DREIMT database were used to explore the bridging role of genes in chemicals and LN as well as the potential influence of these chemicals on immune cells. After comparison and discussion, six small molecules (Acetohexamide, Suloctidil, Terfenadine, Prochlorperazine, Mefloquine, and Triprolidine) were selected for their potential ability in treating lupus nephritis.

Urine Proteomics and Renal Single-Cell Transcriptomics Implicate Interleukin-16 in Lupus Nephritis.

Current lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the longitudinal urinary proteomic profiles in LN patients undergoing treatment. We quantified 1,000 urinary proteins in 30 patients with LN at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single-cell transcriptomics of renal biopsy sections from LN patients. Our analysis revealed multiple biologic pathways, including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization, which could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with LN, as compared to controls without systemic lupus erythematosus. Interleukin-16 (IL-16), CD163, and transforming growth factor β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single-cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in LN kidneys. IL-16-producing cells were found at key sites of kidney injury. Urine proteomics may profoundly change the diagnosis and management of LN by noninvasively monitoring active intrarenal biologic pathways. These findings implicate IL-16 in LN pathogenesis, designating it as a potentially treatable target and biomarker.

Glomerular endothelial expression of type I IFN-stimulated gene, DExD/H-Box helicase 60 via toll-like receptor 3 signaling: possible involvement in the pathogenesis of lupus nephritis

Background Sustained type I interferon (IFN) activation via Toll-like receptor (TLR) 3, 7 and 9 signaling has been reported to play a pivotal role in the development of lupus nephritis (LN). Although type I IFN activation has been shown to induce interferon-stimulated genes (ISGs) expression in systemic lupus erythematosus, the implication of ISGs expression in intrinsic glomerular cells remains largely unknown. Methods We treated cultured human glomerular endothelial cells (GECs) with polyinosinic-polycytidylic acid (poly IC), R848, and CpG (TLR3, TLR7, and TLR9 agonists, respectively) and analyzed the expression of DExD/H-Box Helicase 60 (DDX60), a representative ISG, using quantitative reverse transcription-polymerase chain reaction and western blotting. Additionally, RNA interference against IFN-β or DDX60 was performed. Furthermore, cleavage of caspase 9 and poly (ADP-ribose) polymerase (PARP), markers of cells undergoing apoptosis, was examined using western blotting. We conducted an immunofluorescence study to examine endothelial DDX60 expression in biopsy specimens from patients with LN. Results We observed that endothelial expression of DDX60 was induced by poly IC but not by R848 or CpG, and RNA interference against IFN-β inhibited poly IC-induced DDX60 expression. DDX60 knockdown induced cleavage of caspase 9 and PARP. Intense endothelial DDX60 expression was observed in biopsy specimens from patients with diffuse proliferative LN. Conclusion Glomerular endothelial DDX60 expression may prevent apoptosis, which is involved in the pathogenesis of LN. Modulating the upregulation of the regional innate immune system via TLR3 signaling may be a promising treatment target for LN.

Immunomodulatory Activity of Mesenchymal Stem Cells in Lupus Nephritis: Advances and Applications.

Lupus nephritis (LN) is a significant cause of various acute and chronic renal diseases, which can eventually lead to end-stage renal disease. The pathogenic mechanisms of LN are characterized by abnormal activation of the immune responses, increased cytokine production, and dysregulation of inflammatory signaling pathways. LN treatment is an important issue in the prevention and treatment of systemic lupus erythematosus. Mesenchymal stem cells (MSCs) have the advantages of immunomodulation, anti-inflammation, and anti-proliferation. These unique properties make MSCs a strong candidate for cell therapy of autoimmune diseases. MSCs can suppress the proliferation of innate and adaptive immune cells, such as natural killer cells (NKs), dendritic cells (DCs), T cells, and B cells. Furthermore, MSCs suppress the functions of various immune cells, such as the cytotoxicity of T cells and NKs, maturation and antibody secretion of B cells, maturation and antigen presentation of DCs, and inhibition of cytokine secretion, such as interleukins (ILs), tumor necrosis factor (TNF), and interferons (IFNs) by a variety of immune cells. MSCs can exert immunomodulatory effects in LN through these immune functions to suppress autoimmunity, improve renal pathology, and restore kidney function in lupus mice and LN patients. Herein, we review the role of immune cells and cytokines in the pathogenesis of LN and the mechanisms involved, as well as the progress of research on the immunomodulatory role of MSCs in LN.

Analysis of TNF-like weak inducer of apoptosis for detecting lupus nephritis.

Lupus is an autoimmune disease that has various manifestations in various organs. One of the manifestations of lupus is lupus nephritis (LN), which often causes kidney failure and death. Cytokines play an essential role in the pathogenesis of LN and might be helpful for LN biomarkers. This study aimed to evaluate urine TNF-like weak inducer of apoptosis (TWEAK) for detecting LN since this is not an invasive procedure and is more cost-effective. The gold standard procedure for diagnosing LN needs a biopsy of the kidney. However, the procedure is invasive, high cost, and takes time. Thus, a biomarker from urine is needed for early diagnosis of LN. This research conducted was cross-sectional. The total participants were 57, consisting of 29 lupus nephritis and 28 lupus without nephritis. TWEAK levels were determined by ELISA method; urine protein, urine erythrocyte, and leukocyte were examined by a urine autoanalyzer. Statistical analysis using Mann–Whitney, Spearman correlation, Kruskal–Wallis, ROC curve analysis, and a 2 × 2 contingency table. This study showed a significant difference in TWEAK levels between lupus nephritis and lupus without nephritis (p < 0.05), but no significant difference between TWEAK level and renal domain scores of SLEDAI. There were significant correlations between TWEAK level and urine erythrocyte and urine protein, but there was no significant correlation with urine leukocytes. The sensitivity and specificity of TWEAK for determining LN were 72.4% and 72.5%, respectively, with AUC 0.77. TWEAK had a good diagnostic test for detecting lupus nephritis and substantially correlated with urine erythrocyte and urine protein.

The Anti-DNA Antibodies: Their Specificities for Unique DNA Structures and Their Unresolved Clinical Impact-A System Criticism and a Hypothesis.

Systemic lupus erythematosus (SLE) is diagnosed and classified by criteria, or by experience, intuition and traditions, and not by scientifically well-defined etiology(ies) or pathogenicity(ies). One central criterion and diagnostic factor is founded on theoretical and analytical approaches based on our imperfect definition of the term “The anti-dsDNA antibody”. “The anti-dsDNA antibody” holds an archaic position in SLE as a unique classification criterium and pathogenic factor. In a wider sense, antibodies to unique transcriptionally active or silent DNA structures and chromatin components may have individual and profound nephritogenic impact although not considered yet – not in theoretical nor in descriptive or experimental contexts. This hypothesis is contemplated here. In this analysis, our state-of-the-art conception of these antibodies is probed and found too deficient with respect to their origin, structural DNA specificities and clinical/pathogenic impact. Discoveries of DNA structures and functions started with Miescher’s Nuclein (1871), via Chargaff, Franklin, Watson and Crick, and continues today. The discoveries have left us with a DNA helix that presents distinct structures expressing unique operations of DNA. All structures are proven immunogenic! Unique autoimmune antibodies are described against e.g. ssDNA, elongated B DNA, bent B DNA, Z DNA, cruciform DNA, or individual components of chromatin. In light of the massive scientific interest in anti-DNA antibodies over decades, it is an unexpected observation that the spectrum of DNA structures has been known for decades without being implemented in clinical immunology. This leads consequently to a critical analysis of historical and contemporary evidence-based data and of ignored and one-dimensional contexts and hypotheses: i.e. “one antibody - one disease”. In this study radical viewpoints on the impact of DNA and chromatin immunity/autoimmunity are considered and discussed in context of the pathogenesis of lupus nephritis.

The Shifting Landscape of Lupus Nephritis Management: A Review.

Systemic lupus erythematosus (SLE) is commonly the first autoimmune disease that comes to mind for most people when rheumatology is mentioned. It remains an enigma that many of us, including patients and healthcare providers, do not fully understand. Although an ancient disease, it still remains difficult to both diagnose and treat. Historically, there has always been a paucity of therapeutic interventions for SLE as a whole. One of the most distressing manifestations for the patient and diagnostic and therapeutically challenging aspects of SLE is lupus nephritis (LN). There has historically been some difficultly in the development of LN drugs that provide significant therapeutic benefits while having an acceptable side-effect profile. This difficulty led to decades in which no drugs were approved for LN. With a better understanding of the pathogenesis of SLE and LN and improvement in trial design, great therapeutic strides have recently been made. The immunosuppressive landscape of LN has changed recently with the approval of two newer agents as well as a number of promising trials in LN. With the increased number of therapeutic agents (both immunosuppressive and non-immunosuppressive), the clinical question is how and when to use these medications, and, more importantly, which agents to use first. With the increased number of agents, the answers to these questions are becoming more difficult to answer. The purpose of the paper is to review updates in LN diagnosis and management.

The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.

Exploring the Differences in Molecular Mechanisms and Key Biomarkers Between Membranous Nephropathy and Lupus Nephritis Using Integrated Bioinformatics Analysis.

Background: Both membranous nephropathy (MN) and lupus nephritis (LN) are autoimmune kidney disease. In recent years, with the deepening of research, some similarities have been found in the pathogenesis of these two diseases. However, the mechanism of their interrelationship is not clear. The purpose of this study was to investigate the differences in molecular mechanisms and key biomarkers between MN and LN. Method: The expression profiles of GSE99325, GSE99339, GSE104948 and GSE104954 were downloaded from GEO database, and the differentially expressed genes (DEGs) of MN and LN samples were obtained. We used Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analysis of DEGs. A protein-protein interaction (PPI) network of DEGs was constructed using Metascape. We filtered DEGs with NetworkAnalyst. Finally, we used receiver operating characteristic (ROC) analysis to identify the most significant DEGs for MN and LN. Result: Compared with LN in the glomerulus, 14 DEGs were up-regulated and 77 DEGs were down-regulated in MN. Compared with LN in renal tubules, 21 DEGs were down-regulated, but no up-regulated genes were found in MN. According to the result of GO and KEGG enrichment, PPI network and Networkanalyst, we screened out six genes (IFI6, MX1, XAF1, HERC6, IFI44L, IFI44). Interestingly, among PLA2R, THSD7A and NELL1, which are the target antigens of podocyte in MN, the expression level of NELL1 in MN glomerulus is significantly higher than that of LN, while there is no significant difference in the expression level of PLA2R and THSD7A. Conclusion: Our study provides new insights into the pathogenesis of MN and LN by analyzing the differences in gene expression levels between MN and LN kidney samples, and is expected to be used to prepare an animal model of MN that is more similar to human.

Autoantigen spermatid nuclear transition protein 1 enhances pro-inflammatory cytokine production stimulated by anti-DNA autoantibodies in macrophages

IntroductionLupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), is associated with high fatality rate in patients. The pathogenesis of lupus nephritis is complex and has not been fully elucidated. Kidney inflammation, renal cell damage, and accumulation of immune complexes in the glomerular basement membrane often occur in patients with lupus nephritis. Spermatid nuclear transition protein 1 (TNP1) might be a potentially interesting autoantigen in exploring the pathogenesis and therapy of lupus nephritis.ObjectiveThis study aimed to explore the effect of TNP1 and its complexes with anti-double-stranded DNA antibodies on the levels of interleukin-6 (IL-6) and interferon-α (IFN-α) in vitro.MethodsWe studied the effect of the synthetic peptide of the autoantigen on the pathogenic characteristics of the G2-6 and G5-8 antibodies in mouse macrophages, using enzyme-linked immunosorbent assay, quantitative RT-PCR, western blotting, and flow cytometry.ResultsThe antibodies exhibited cross-reactivity to spermatid TNP1 in direct-binding and competitive enzyme-linked immunosorbent assay. Results of quantitative RT-PCR and western blotting revealed that the antibodies alone enhanced the levels of IL-6 and IFN-α transcripts and proteins, respectively. Flow cytometry revealed that treatment with the autoantigen enhanced the cell-penetrating activities of G2-6 and G5-8 and remarkably increased the cytokine levels.ConclusionTNP1 enhanced the cell-penetrating activities of anti-dsDNA auto-Abs, G2-6 and G5-8, and remarkably increased the levels of IL-6 and IFN-α in macrophages, suggesting that TNP1 and cell-penetrating pathogenic anti-dsDNA auto-Abs is potential targets for future therapeutic approaches to treat LN/SLE.

Effect of sera from lupus patients on the glomerular endothelial fibrinolysis system.

Dysregulation of the coagulation fibrinolysis system in resident glomerular cells is associated with the pathogenesis of lupus nephritis. However, the role of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in resident glomerular cells remains undetermined. We examined the expression of PAI-1 and tPA mRNA in cultured normal human glomerular endothelial cells (GECs) treated with serum from patients with systemic lupus erythematosus (SLE) using quantitative reverse transcription polymerase chain reactions. We determined the relationship between PAI-1/tPA mRNA expression and several clinical/laboratory parameters. Serum from 16 patients (nine patients with new-onset SLE and seven patients with stable SLE) was used in the study. Plasminogen activator inhibitor-1 and tPA mRNA expression was significantly higher in GECs treated with serum of patients with new-onset SLE than other groups. The PAI-1 and tPA mRNA levels were also significantly correlated in GECs treated with serum from patients with SLE. Interestingly, both PAI-1 and tPA mRNA levels in GECs were inversely correlated with serum C4 level and positively correlated with SLE disease activity. These results suggest that serum from patients with SLE may activate the fibrinolysis system in glomerulus, which may be involved in the pathogenesis of lupus nephritis.

Rapamycin relieves lupus nephritis by regulating TIM-3 and CD4+CD25+Foxp3+ Treg cells in an MRL/lpr mouse model

Lupus nephritis (LN) is a severe consequence of systemic lupus erythematosus (SLE) and is an important driver of morbidity and mortality in SLE. Treg cells and TIM-3 play an important role in the pathogenesis of LN. The beneficial effect of rapamycin on LN has been confirmed in both mouse models and patients, but the effect of rapamycin on Treg cells and TIM-3 is not yet completely understood. In this study, rapamycin treatment attenuated proteinuria, histological damage, and renal deposition of C3, and improved renal function. Spleen and renal draining lymph node weight and serum levels of anti-dsDNA antibodies were also improved by rapamycin. Furthermore, the frequency of Treg cells and Treg functional molecules, such as cytotoxic T cell antigen 4 (CTLA-4), interleukin 10 (IL-10), and transforming growth factor β1 (TGF-β1), increased significantly after treatment with rapamycin in MRL/lpr mice. We also found that expression of TIM-3 was significantly decreased in CD4+ T cells and Treg cells in mice treated with rapamycin. In summary, the study demonstrated that rapamycin treatment induced preferential expansion of CD4+CD25+Foxp3+ Tregs with increased expression of CTLA-4, IL-10, and TGF-β1, and decreased TIM-3 expression, thereby ameliorating lupus nephritis in the MRL/lpr mouse model.

Kidney infiltrating NK cells and NK-like T-cells in lupus nephritis: presence, localization, and the effect of immunosuppressive treatment.

Systemic lupus erythematosus (SLE) is a multi-organ inflammatory disease with kidney inflammation, lupus nephritis (LN), being one of the most severe manifestations. Immune complex deposits, particularly in glomeruli, and T cells, B cells, and myeloid cells, mainly with extraglomerular localization, contribute to the inflammatory process. Natural killer (NK) cells have been suggested to play a role in autoimmune diseases, but have not been investigated in detail in renal lupus before. In this exploratory study, we performed the first characterization of NK cell number and distribution in LN kidney biopsies. Twelve SLE patients were analyzed in the active phase of disease and five patients following immunosuppressive therapy. CD56+ cells, corresponding to NK cells or NK-like T-cells, were identified in all patients; however, with reduced numbers in four out of five patients at follow-up. Furthermore, cells were present in the kidney interstitium and peri-glomerular areas, but only rarely in glomeruli. Fluorescent co-staining of CD56 or NKp46 and CD3 revealed the presence of both CD56+/NKp46+CD3-NK cells and CD56+/NKp46+CD3+NK-like T-cells. Compared to healthy kidney sections, one out of four LN patients showed increased numbers of NK cells. A correlation between CD56+ and NK cells with clinical parameters could not be observed, perhaps due to the small patient cohort. In conclusion, we have identified NK cells and NK-like T-cells in the LN kidney and performed the first detailed analysis of their localization during active and inactive diseases. Their role in LN pathogenesis is, however, unclear and deserves further studies.

Current Evidence for IL-17/23 Blockade for the Treatment of Lupus Nephritis.

In the current medical literature, there is increasing evidence for the involvement of the interleukin (IL)-17/23 axis and the potential role of Th17 cells in the pathogenesis of lupus nephritis. Knowledge about the interaction of these immunological pathways in the development of autoimmune diseases has led to the identification of new therapeutic strategies aimed at blocking them. For this reason, the main objective of this review focuses on knowing the recent evidence of the different anti-IL-17/23 treatment strategies in lupus nephritis and their future perspectives. A non-systematic narrative review of the literature was carried out following the objective of having the most representative information on the different anti-IL-17/23 drugs available together with the description of the pathophysiological mechanisms of this pathway involved in systemic lupus erythematosus and lupus nephritis. Despite the great existing theoretical foundation, today few clinical studies support the use of these therapies in both contexts. Nevertheless, the publication of research with a better methodology is expected to approve the indication of some of these drugs in lupus nephritis. However, the clinical response seen with ustekinumab and secukinumab in clinical studies and case reports published to date has been encouraging.

Dysregulation of tRNA-derived small RNAs and their potential roles in lupus nephritis.

Lupus nephritis (LN) is a major end-organ complication of systemic lupus erythematosus (SLE), and the molecular mechanism of LN is not completely clear. Accumulating pieces of evidence indicate the potential vital role of tRNA-derived small RNAs (tsRNAs) in human diseases. Current study aimed to investigate the potential roles of tsRNAs in LN. We herein employed high-throughput sequencing to screen the expression profiles of tsRNAs in renal tissues of the LN and control groups. To validate the sequencing data, we performed quantitative real-time PCR (qRT-PCR) analysis. Correlational analysis of verified tsRNAs expression and clinical indicators was conducted using linear regression. The potential target genes were also predicted. The biological functions of tsRNAs were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Our findings revealed that the expression profiles of tsRNAs were significantly altered in the kidney tissues from LN patients compared with control. Overall, 160 tsRNAs were significantly dysregulated in the LN group, of which 79 were upregulated, whereas 81 were downregulated. Subsequent qRT-PCR results confirmed the different expression of candidate tsRNAs. Correlation analysis results found that expression of verified tsRNAs were correlated to clinical indicators. The target prediction results revealed that verified tsRNAs might act on 712 target genes. Further bioinformatics analysis uncovered tsRNAs might participate in the pathogenesis of LN through several associated pathways, including cell adhesion molecules, MAPK signaling pathway, PI3K-Akt signaling pathway and B cell receptor signaling pathway. This study provides a novel insight for studying the mechanism of LN.

The Role of NLRP3 Inflammasome in Lupus Nephritis.

Lupus nephritis (LN) is the most frequent and severe of systemic lupus erythematosus (SLE) clinical manifestations and contributes to the increase of morbidity and mortality of patients due to chronic kidney disease. The NLRP3 (NLR pyrin domain containing 3) is a member of the NLR (NOD-like receptors), and its activation results in the production of pro-inflammatory cytokines, which can contribute to the pathogenesis of LN. In this review manuscript, we approach the relation between the NLRP3 inflammasome, SLE, and LN, highlighting the influence of genetic susceptibility of NLRP3 polymorphisms in the disease; the main functional studies using cellular and animal models of NLRP3 activation; and finally, some mechanisms of NLRP3 inhibition for the development of possible therapeutic drugs for LN.

High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis.

Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.