Ferroptosis and secondary nephrosis. / é“æ­»äº¡ä¸Žç»§å‘æ€§è‚¾è„ç— .

Secondary nephrosis is a series of chronic kidney diseases secondary to other underlying diseases, mainly manifesting as structural and functional abnormalities of the kidneys and metabolic disorders. It is one of the important causes of end-stage renal disease, with high morbidity and significant harm. Iron is an essential metal element in human cells, and ferroptosis is a non-traditional form of iron-dependent cell death, and its main mechanisms include iron accumulation, lipid metabolism disorders, abnormal amino acid metabolism, and damage to the antioxidant system. Recently studies have found that ferroptosis is involved in the occurrence and progression of secondary nephrosis, and the mechanism of ferroptosis in different secondary nephrosis vary. Therefore, an in-depth and systematic understanding of the association between ferroptosis and secondary nephrosis, as well as their specific regulatory mechanisms, can provide a theoretical basis for the diagnosis, prevention, treatment, and prognosis assessment of secondary nephrosis, laying the foundation for exploring new clinical therapeutic targets for secondary nephrosis.

Imbalance of programmed cell death patterns mediated by dendritic cell subsets in systemic lupus erythematosus and lupus nephritis. / æ ‘çªçŠ¶ç»†èƒžäºšç¾¤ä»‹å¯¼ç³»ç»Ÿæ€§çº¢æ–‘ç‹¼ç–®å’Œç‹¼ç–®è‚¾ç‚Žçš„ç¨‹åºæ€§ç»†èƒžæ­»äº¡æ¨¡å¼å¤±è¡¡ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Abnormal programmed cell death in immune cells is associated with autoimmune diseases, but the patterns of programmed cell death in systemic lupus erythematosus (SLE) and especially lupus nephritis (LN) remain unclear. This study aims to explore the association between SLE, LN, and immune cell death patterns. METHODS: Bulk RNA sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) data were downloaded from the Gene Expression Omnibus (GEO) database. Bioinformatic analysis was conducted to explore the expression levels of genes related to 3 cell death patterns in peripheral blood mononuclear cells of SLE patients. Key cell subsets involved in the imbalance of cell death patterns were identified through scRNA-seq. Immunofluorescence was used to detect the expression levels of receptor interacting serine/threonine kinase 3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), phosphorylated MLKL (pMLKL), caspase 1 (CASP1), CD1c molecule (CD1C), C-type lectin domain containing 9A (CLEC9A), and X-C motif chemokine receptor 1 (XCR1) in dendritic cells (DC). scRNA-seq was performed on kidney tissues collected from LN patients and healthy controls (HC) at the Third Xiangya Hospital of Central South University, followed by bioinformatic analysis to identify key cell subsets involved in the imbalance of cell death patterns. Pseudotime analysis and ligand-receptor analysis were used to explore the differentiation direction and cell communication of different DC subsets. Transient transfection was used to transfect RAW264.7 cells with empty plasmid, empty plasmid+dsDNA (HSV-DNA), empty plasmid+200 µmol/L tert-butyl hydroperoxide (TBHP), stimulator of interferon genes (STING) shRNA plasmid, STING shRNA plasmid+dsDNA (HSV-DNA), and STING shRNA plasmid+200 µmol/L TBHP. Annexin V-mCherry and SYTOX Green staining were used to detect cell death in each group. Western blotting was used to detect the activation of CASP1, gasdermin D (GSDMD), RIPK3, and MLKL in each group. RESULTS: Bioinformatic analysis showed an imbalance in 3 cell death patterns in SLE and LN patients: Pro-inflammatory pyroptosis and necroptosis were activated, while anti-inflammatory apoptosis was inhibited. The key cell subsets involved were DC subsets, particularly focusing on CLEC9A+cDC1. Immunofluorescence results showed that the expression levels of RIPK3, MLKL, and CASP1 in DCs were higher in the SLE group compared to the HC group. pMLKL and CASP1 expression levels in renal cDC1 marked by CLEC9A and XCR1 were higher in the LN group than in the HC group. Pseudotime analysis and ligand-receptor analysis suggested that the CLEC9A+cDC1 subset in LN kidney tissues originated from peripheral circulation. Annexin V-mCherry and SYTOX Green staining results showed that the number of dead cells decreased in the STING shRNA transfection group compared to the empty plasmid group in RAW264.7 cells. Western blotting results showed that the activation of CASP1, GSDMD, RIPK3, and MLKL was decreased in the STING shRNA transfection group compared to the empty plasmid group. CONCLUSIONS: This study provides novel insights into the role of CLEC9A+cDC1 in the imbalance of cell death patterns in SLE and LN.

Acute-Onset Blindness in a Patient Diagnosed With Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOG-AD): A Case Report.

Myelin oligodendrocyte glycoprotein antibody disease (MOG-AD) poses a diagnostic challenge, often masquerading as other neurological disorders such as multiple sclerosis and aquaporin-4-positive neuromyelitis optica spectrum disorder. The deceptive clinical similarities demand a nuanced approach to differentiate these conditions effectively. This entails an extensive evaluation encompassing a meticulous medical history, advanced magnetic resonance imaging (MRI), cerebrospinal fluid analysis, and serum studies. In this context, we present a compelling case involving a 28-year-old Hispanic female with a history of migraine headache. She sought medical attention due to acute peripheral vision loss, ultimately diagnosed as MOG-AD through a comprehensive clinical assessment coupled with specific diagnostic tests. This case underscores the critical importance of precision in diagnostic procedures to ensure accurate identification and subsequent tailored treatment for MOG-AD, avoiding potential pitfalls associated with its resemblance to other neurological disorders.

Comparison of the Quantitative Values of Peripapillary, Macular and Choriocapillary Microvascular Structures According to the Presence of Lupus Nephritis in Patients with Systemic Lupus Erythematosus.

PURPOSE: To determine whether there are quantitative changes in macular, choriocapillary, and peripapillary microvascular structures using optical coherence tomography angiography (OCTA) due to the presence of lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE) and to investigate the correlation between these quantitative values and disease duration. METHODS: Fifty -five patients followed up in the rheumatology clinic with an SLE diagnosis were evaluated. As the control group, 61 eyes of 61 age- and gender-matched healthy individuals were included. The patients with SLE were further divided into two groups: those with LN (29 eyes) and those without LN (26 eyes). Macular, choriocapillary, and peripapillary microvascular structures were quantitatively analyzed with OCTA and compared between the three study groups. A correlation analysis of the measured quantitative values and disease duration was also performed. RESULTS: In macular microvascular (MMV) analysis, the vessel densities (VDs) of the superficial capillary plexus (SCP) decreased in both SLE groups, while those of the deep capillary plexus (DCP) decreased only in the SLE group with LN. The foveal density significantly decreased in the SLE group with LN compared to the control group, there were no significant differences in terms of the radial peripapillary capillary VDs or the choriocapillaris flow area. Disease duration was not correlated with any of the quantitative parameters measured by OCTA in either SLE group. CONCLUSIONS: Identifying differences in retinal microvascular circulation in SLE patients with kidney damage helps predict possible nephropathy and therefore guides the treatment process of this patient.

Factors influencing self-management behaviors in persons with lupus nephritis: A cross-sectional study.

Background: Patients with lupus nephritis experience disease symptoms and side effects from treatment. Although self-management behaviors are important in patients with this disease, there is limited research on the factors influencing these behaviors. Objective: This study aimed to examine the factors influencing self-management behaviors in patients with lupus nephritis. Methods: This cross-sectional study was conducted in 240 patients with lupus nephritis at a university hospital in Thailand between August 2019 and December 2020 using a random sampling method. Data were collected using a demographic and clinical characteristic questionnaire, Self-Management Behavior Questionnaire, Self-efficacy for Managing Chronic Disease: A 6-item Scale, Knowledge about Lupus Nephritis Questionnaire, Family Support Scale, Social Networks in Adult Life Questionnaire, and Memorial Symptom Assessment Scale for Lupus Nephritis. Descriptive statistics and multiple linear regression analyses were employed. Results: The participants reported a moderate level of self-management behaviors. Multiple regression analyses revealed that disease duration, income, symptoms, self-efficacy, knowledge, family support, social networks, and classes of lupus nephritis significantly explained 21% of the variance in self-management behaviors (R2 = 0.21; F(8,231) = 7.73; p <0.001). Family support (ß = 0.32, p <0.001) and symptoms (ß = -0.23, p <0.001) were significant determinants of self-management behaviors in patients with lupus nephritis. Conclusion: The findings provide valuable insight for nurses to better understand the factors influencing self-management behaviors in patients with lupus nephritis. Patients with low family support and high symptom severity may face difficulty in performing self-management behaviors. Nurses should pay more attention to these patients and provide family-based interventions to optimize self-management behaviors in this population.

Investigation of ferroptosis-associated molecular subtypes and immunological characteristics in lupus nephritis based on artificial neural network learning.

BACKGROUND: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) with poor treatment outcomes. The role and underlying mechanisms of ferroptosis in LN remain largely unknown. We aimed to explore ferroptosis-related molecular subtypes and assess their prognostic value in LN patients. METHODS: Molecular subtypes were classified on the basis of differentially expressed ferroptosis-related genes (FRGs) via the Consensus ClusterPlus package. The enriched functions and pathways, immune infiltrating levels, immune scores, and immune checkpoints were compared between the subgroups. A scoring algorithm based on the subtype-specific feature genes identified by artificial neural network machine learning, referred to as the NeuraLN, was established, and its immunological features, clinical value, and predictive value were evaluated in patients with LN. Finally, immunohistochemical analysis was performed to validate the expression and role of feature genes in glomerular tissues from LN patients and controls. RESULTS: A total of 10 differentially expressed FRGs were identified, most of which showed significant correlation. Based on the 10 FRGs, LN patients were classified into two ferroptosis subtypes, which exhibited significant differences in immune cell abundances, immune scores, and immune checkpoint expression. A NeuraLN-related protective model was established based on nine subtype-specific genes, and it exhibited a robustly predictive value in LN. The nomogram and calibration curves demonstrated the clinical benefits of the protective model. The high-NeuraLN group was closely associated with immune activation. Clinical specimens demonstrated the alterations of ALB, BHMT, GAMT, GSTA1, and HAO2 were in accordance with bioinformatics analysis results, GSTA1 and BHMT were negatively correlated with the severity of LN. CONCLUSION: The classification of ferroptosis subtypes and the establishment of a protective model may form a foundation for the personalized treatment of LN patients.

Lupus mesenteric vasculitis with gastrointestinal bleeding as the primary manifestation: a case report.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease where the body loses tolerance to its own antigens, particularly nuclear antigens. Abnormal responses from T and B cells lead to the production of autoantibodies and the formation of immune complexes in tissues, triggering complement activation, inflammation, and irreversible organ damage. SLE can affect any part of the body, resulting in diverse clinical symptoms. One rare manifestation of SLE is lupus mesenteric vasculitis (LMV), which presents with vague symptoms, abnormal laboratory findings, and specific imaging features. LMV, although uncommon, can progress to severe complications such as bowel perforation, haemorrhage, and even mortality. Here, we report a case of LMV with the involvement of multiple organ systems (including mucocutaneous, musculoskeletal, serosal cavities, and haematological systems), presenting initially with life-threatening intractable gastrointestinal bleeding, and complicated by severe pulmonary infection. By sharing this case, we aim to enhance clinicians' confidence in managing critical SLE cases and raise awareness about disease surveillance.

[COVID-19 and Lupus Nephritis Flares in Unvaccinated Patients: A Case Report and Literature Review].

Viral infections are one of the most common triggers of Systemic Lupus Nephritis (SLE) flare-ups. COVID-19 pneumonia can be severe in patients affected by SLE representing a risk factor for lupus nephritis flare. We report the case of a 28-year-old woman with a history of lupus nephritis (LN), who relapsed with severe nephritic-nephritic syndrome after the resolution of COVID-19 pneumonia. In addition, we conducted a literature review to analyze all described cases of LN, vaccinated and unvaccinated, in COVID-19 showing that the course of COVID-19 is more severe in SLE patients with renal involvement, especially in those who have not been vaccinated. Vaccination is the most important measure for preventing COVID-19 in people with rheumatic diseases such as SLE. The case and data we present suggests that LN relapses can occur even after the infection has resolved and illustrates the benefit of vaccination, the role of modulation of immunosuppression during COVID-19 and the specific risk of disease relapse during SARS-CoV-2 infection.

Lupus nephritis: management challenges during pregnancy.

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), leads to significant kidney inflammation and damage and drastically increases mortality risk. Predominantly impacting women in their reproductive years, LN poses specific risks during pregnancy, including pre-eclampsia, growth restrictions, stillbirth, and preterm delivery, exacerbated by lupus activity, specific antibodies, and pre-existing conditions like hypertension. Effective management of LN during pregnancy is crucial and involves carefully balancing disease control with the safety of the fetus. This includes pre-conception counseling and a multidisciplinary approach among specialists to navigate the complexities LN patients face during pregnancy, such as distinguishing LN flare-ups from pregnancy-induced conditions. This review focuses on exploring the complex dynamics between pregnancy and LN, emphasizing the management difficulties and the heightened risks pregnant women with LN encounter.

Urinary complement biomarkers in immune-mediated kidney diseases.

The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement system including the classical, alternative, and mannose-binding lectin pathways have been implicated in complement-mediated kidney injury. Although complement components are thought to be mainly synthesized in the liver and activated in the circulation, emerging data suggest that complement is synthesized and activated inside the kidney leading to direct injury. Urinary complement biomarkers are likely a better reflection of inflammation within the kidneys as compared to traditional serum complement biomarkers which may be influenced by systemic inflammation. In addition, urinary complement biomarkers have the advantage of being non-invasive and easily accessible. With the rise of therapies targeting the complement pathways, there is a critical need to better understand the role of complement in kidney diseases and to develop reliable and non-invasive biomarkers to assess disease activity, predict treatment response and guide therapeutic interventions. In this review, we summarized the current knowledge on urinary complement biomarkers of kidney diseases due to immune complex deposition (lupus nephritis, primary membranous nephropathy, IgA nephropathy) and due to activation of the alternative pathway (C3 glomerulopathy, thrombotic microangiography, ANCA-associated vasculitis). We also address the limitations of current research and propose future directions for the discovery of urinary complement biomarkers.

Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis.

Introduction: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. Methods: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n = 41) and active nonrenal lupus (n = 62) versus healthy controls (HCs) (n = 497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n = 26) and a replication (n = 15) set of active LN cases. Results: Replicated gene modules qualified for correlation analyses with serologic markers, and regulatory network and druggability analysis. Unsupervised coexpression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into 3 distinct subgroups. These subgroups were characterized by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the "B cell" and "plasma cells/Ig" modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 (CCR1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, and irinotecan; whereas the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the "plasma cells/Ig" signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B-cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab whereas daratumumab appeared beneficial to the intermediate-IFN and high-IFN subgroups. Conclusion: IFN upregulation and B and plasma cell gene dysregulation patterns revealed 3 subgroups of LN, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN.

Clinical and histological comparison of IgA nephritis and renal IgA vasculitis.

BACKGROUND: IgA nephritis (IgAN) and renal IgA vasculitis (IgAV) show renal IgA deposits, but whether these two diseases are distinct entities or a spectrum of the same condition is under debate. In this study, we add perspective by contrasting the clinical course and histological presentation using the Oxford classification and the National Institutes of Health lupus nephritis activity index (LN-AI) and chronicity index (LN-CI) in IgAN and IgAV. METHODS: In this single-center, retrospective study, kidney biopsies of 163 adult patients with IgAN and 60 adult patients with IgAV were compared according to the Oxford MEST-C Score, LN-AI, and LN-CI. At the time of biopsy, clinical presentation was compared in terms of age, arterial hypertension, diabetes mellitus, extrarenal manifestations, as well as estimated glomerular filtration rate, proteinuria, and urine sediment. IgAV patients and all IgAN patients with crescents received immunosuppressive treatment. After biopsy, kidney function was followed until patients reached end-stage renal disease (ESRD) or they died. RESULTS: The clinical course and kidney histology differ in IgAN and IgAV. IgAV patients showed more microhematuria and nephritic sediment, while IgAN patients had a greater history of arterial hypertension, more proteinuria, and a higher risk for ESRD. These clinical differences were associated with histological differences, as kidney biopsies of IgAN patients were characterized by glomerulosclerosis and tubular atrophy, while kidney biopsies of IgAV patients were characterized by endocapillary hypercellularity and crescents. Overall, tubular atrophy and a LN-CI ≥ 4 were associated with a higher risk for ESRD in IgAN and IgAV. CONCLUSION: Our study supports the notion that IgAN and IgAV follow distinct courses, suggesting that they require different treatment strategies. Moreover, we make a point that the Oxford classification and LN-CI can be useful in categorizing and predicting long-term prognosis not only in IgAN, but also in IgAV.

Risk factors for acute kidney injury and kidney relapse in patients with lupus podocytopathy.

Background: Patients with lupus podocytopathy show a high incidence of acute kidney injury (AKI) and relapse, but the risk factors and mechanisms were unclear. This study analysed the clinicopathological features and risk factors for AKI and relapse in lupus podocytopathy patients. Methods: The cohort of lupus podocytopathy was generated by screening the biopsies of patients with lupus nephritis (LN) from 2002 to 2022 and was divided into the mild glomerular lesion (MGL) and focal segmental glomerulosclerosis (FSGS) groups based on glomerular morphological characteristics. The acute (ATI) and chronic (CTI) tubulointerstitial lesions were semi-quantitatively scored. Logistic and Cox regressions were employed to identify the risk factors for AKI and relapse, respectively. Results: Among 6052 LN cases, 98 (1.6%) were diagnosed as lupus podocytopathy, with 71 in the MGL group and 27 in the FSGS group. All patients presented with nephrotic syndrome and 33 (34.7%) of them had AKI. Seventy-seven (78.6%) patients achieved complete renal response (CRR) within 12 weeks of induction treatment, in which there was no difference in the CRR rate between glucocorticoid monotherapy and combination therapy with glucocorticoids plus immunosuppressants. Compared with the MGL group, patients in the FSGS group had significantly higher incidences of hypertension and haematuria; in addition, they had higher Systemic Lupus Erythematosus Disease Activity Index 2000, ATI and CTI scores but a significantly lower CRR rate. Urinary protein ≥7.0 g/24 h and serum C3 ≤0.750 g/l were independent risk factors for AKI. During a median follow-up of 78 months, 57 cases (60.0%) had relapse and none reached the kidney endpoint. Failure to achieve CRR within 12 weeks, maintenance with glucocorticoid monotherapy and AKI at onset were independent risk factors for kidney relapse. Conclusions: In this study, histological subtypes of lupus podocytopathy were found to be associated with clinical features and treatment response. In addition, several risk factors associated with AKI occurrence and kidney relapse were identified.

A nomogram to predict the risk of proliferative lupus nephritis in patients with systemic lupus erythematosus involving the kidneys.

Proliferative lupus nephritis (PLN) is a serious organ-threatening manifestation of systemic lupus erythematosus (SLE) that is associated with high mortality and renal failure. Here, we analyzed data from 1287 SLE patients with renal manifestations, including 780 of which were confirmed as proliferative or non-proliferative LN patients by renal biopsy, divided into a training cohort (547 patients) and a validation cohort (233 patients). By applying a least absolute shrinkage and selection operator (LASSO) regression approach combined with multivariate logistic regression analysis to build a nomogram for prediction of PLN that was then assessed by receiver operating characteristic (ROC) curves, calibration curves, and clinical decision curves (DCA) in both the training and validation cohorts. The area under the ROC curve (AUC) of the model in the training cohort was 0.921 (95% confidence interval (CI): 0.895-0.946), the AUC of internal validation in the training cohort was 0.909 and the AUC of external validation was 0.848 (95% CI: 0.796-0.900). The nomogram showed good performance as evaluated using calibration and DCA curves. Taken together, our results indicate that our nomogram that comprises 12 significantly relevant variables could be clinically valuable to prognosticate on the risk of PLN in SLE, so as to improve patient prognoses.

Regulation of macrophage polarization by targeted metabolic reprogramming for the treatment of lupus nephritis.

Lupus nephritis (LN) is a severe and common manifestation of systemic lupus erythematosus (SLE) that is frequently identified with a poor prognosis. Macrophages play an important role in its pathogenesis. Different macrophage subtypes have different effects on lupus-affected kidneys. Based on their origin, macrophages can be divided into monocyte-derived macrophages (MoMacs) and tissue-resident macrophages (TrMacs). During nephritis, TrMacs develop a hybrid pro-inflammatory and anti-inflammatory functional phenotype, as they do not secrete arginase or nitric oxide (NO) when stimulated by cytokines. The infiltration of these mixed-phenotype macrophages is related to the continuous damage caused by immune complexes and exposure to circulating inflammatory mediators, which is an indication of the failure to resolve inflammation. On the other hand, MoMacs differentiate into M1 or M2 cells under cytokine stimulation. M1 macrophages are pro-inflammatory and secrete pro-inflammatory cytokines, while the M2 main phenotype is essentially anti-inflammatory and promotes tissue repair. Conversely, MoMacs undergo differentiation into M1 or M2 cells in response to cytokine stimulation. M1 macrophages are considered pro-inflammatory cells and secrete pro-inflammatory mediators, whereas the M2 main phenotype is primarily anti-inflammatory and promotes tissue repair. Moreover, based on cytokine expression, M2 macrophages can be further divided into M2a, M2b, and M2c phenotypes. M2a and M2c have anti-inflammatory effects and participate in tissue repair, while M2b cells have immunoregulatory and pro-inflammatory properties. Further, memory macrophages also have a role in the advancement of LN. Studies have demonstrated that the polarization of macrophages is controlled by multiple metabolic pathways, such as glycolysis, the pentose phosphate pathway, fatty acid oxidation, sphingolipid metabolism, the tricarboxylic acid cycle, and arginine metabolism. The changes in these metabolic pathways can be regulated by substances such as fish oil, polyenylphosphatidylcholine, taurine, fumaric acid, metformin, and salbutamol, which inhibit M1 polarization of macrophages and promote M2 polarization, thereby alleviating LN.

Unraveling Complexity: A Case of Possible Overlapping Between Mixed Connective Tissue Disease and Systemic Lupus Erythematosus With Renal Involvement.

Autoimmune diseases, a term encompassing conditions where the immune system targets its own cells, consist of various pathologies, two of which are systemic lupus erythematosus (SLE) and mixed connective tissue disorder (MCTD). We present the unique case of an anti-ribonucleoprotein (RNP)-positive patient exhibiting renal pathology consistent with lupus nephritis and an additional collapsing variant of focal segmental glomerulonephropathy, who initially presented to the emergency department with signs and symptoms of pneumonia and portal vein thrombosis that were subsequently treated. Conflicting accounts of her autoimmune history led to an extensive workup during her stay, which yielded a tentative diagnosis of SLE vs. MCTD during her current hospitalization for pneumonia. The diagnostic labs revealed conflicting serological markers, with delayed anti-Smith positive results favoring lupus due to its high specificity. A subsequent renal biopsy showed complex renal involvement, suggesting SLE, despite initial positive anti-RNP antibodies known to be protective against renal pathology and classic for MCTD. Complicating matters further, the renal biopsy findings extended beyond common SLE pathology, including additional focal segmental glomerulonephritis (FSGS) involvement. Despite this uncertainty, the patient was treated as if solely having SLE, and immunosuppressives that could have been utilized for the possible MCTD component were avoided due to minimal signs of inflammation/immune response and normal kidney function. This case highlights the difficulty in accurately classifying lupus and MCTD, emphasizing the need for precise diagnosis for tailored patient care. Ongoing research is crucial to refine diagnostic criteria and improve patient outcomes.

Peripheral blood cells RNA-seq identifies differentially expressed gene network linked to lymphocyte subsets alterations and active lupus nephritis associated with declines in renal function.

Background: The aim of this study was to investigate whether quantitative changes in lymphocyte subsets and gene expression in peripheral blood (PB) cells are related to the clinical manifestations and pathogenesis of lupus nephritis (LN). Methods: We enrolled 95 pediatric-onset SLE patients with renal involvement who presented with 450 clinical episodes suspicious for LN flare. Percentages of lymphocyte subsets at each episode were determined. We stratified 55 of 95 patients as high or low subset group according to the median percentage of each lymphocyte subset and the association with changes in the eGFR (ΔeGFR) were analyzed. Peripheral blood bulk RNA-seq to identify differentially expressed genes (DEGs) in 9 active LN vs. 9 inactive LN patients and the DEG-derived network was constructed by Ingenuity Pathway Analysis (IPA). Results: The mean ΔeGFR of low NK-low memory CD4+ T-high naive CD4+ T group (31.01 mL/min/1.73 m2) was significantly greater than that of high NK-high memory CD4+ T-low naive CD4+ T group (11.83 mL/min/1.73 m2; P = 0.0175). Kaplan-Meier analysis showed that the median time for ΔeGFR decline to mean ΔeGFR is approximately 10 years for high NK-high memory CD4+ T-low naive CD4+ T group and approximately 5 years for low NK-low memory CD4+ T-high naive CD4+ T group (log-rank test P = 0.0294). Conclusions: Our study highlighted important connections between DEG-derived network, lymphocyte subset composition, and disease status of LN and GN. A novel scoring system based on lymphocyte subset proportions effectively stratified patients into groups with differential risks for declining renal function.

SLE: a cognitive step forward-a synthesis of rethinking theories, causality, and ignored DNA structures.

Systemic lupus erythematosus (SLE) is classified by instinctual classification criteria. A valid proclamation is that these formally accepted SLE classification criteria legitimate the syndrome as being difficult to explain and therefore enigmatic. SLE involves scientific problems linked to etiological factors and criteria. Our insufficient understanding of the clinical condition uniformly denoted SLE depends on the still open question of whether SLE is, according to classification criteria, a well-defined one disease entity or represents a variety of overlapping indistinct syndromes. Without rational hypotheses, these problems harm clear definition(s) of the syndrome. Why SLE is not anchored in logic, consequent, downstream interdependent and interactive inflammatory networks may rely on ignored predictive causality principles. Authoritative classification criteria do not reflect consequent causality criteria and do not unify characterization principles such as diagnostic criteria. We need now to reconcile legendary scientific achievements to concretize the delimitation of what SLE really is. Not all classified SLE syndromes are "genuine SLE"; many are theoretically "SLE-like non-SLE" syndromes. In this study, progressive theories imply imperative challenges to reconsider the fundamental impact of "the causality principle". This may offer us logic classification and diagnostic criteria aimed at identifying concise SLE syndromes as research objects. Can a systems science approach solve this problem?

Exostosin-1/exostosin-2 expression and favorable kidney outcomes in lupus nephritis: a retrospective cohort study.

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

Cordyceps protein alleviates renal injury by inhibiting T cell infiltration and Th1 cell differentiation in lupus nephritis mice.

BACKGROUND: T cell infiltration and differentiation play a central part in the development of lupus nephritis (LN). Our prior research has indicated that protein, the primary active component of cordyceps (WCP), a traditional Chinese medicine, possesses properties that can enhance renal fibrosis and provide kidney protection. Nonetheless, the connection between WCP and T cell infiltration and differentiation in LN remains poorly understood. OBJECTIVE: The objective of this research was to assess the immunomodulatory impacts of WCP in LN mice and elucidate the underlying mechanism through in vivo and in vitro investigations. METHODS: To investigate the impact and mechanism of WCP in MRL/lpr lupus-prone mice, WCP (1.5 g/kg/d), Bailing capsules (BC, 0.75 g/kg/d), and saline in equivalent quantities were administered to the mice over a period of 8 weeks. The therapeutic effects, T cell infiltration and differentiation of WCP on MRL/lpr mice were verified through ELISA, Hematoxylin-eosin (H&E), Periodic Acid Schiff (PAS) staining, immunofluorescence, Luminex analysis and flow cytometry. The mechanism by which WCP alleviates LN was investigated using tissues of mice, T cells and Mouse Podocyte Clone-5 (MPC-5) cells by transcriptomics, Western blot (WB), and Real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We found that WCP improved LN in MRL/lpr mice by reducing urinary protein, creatinine, and serum auto antibodies, increasing complement 3 (C3) level, improving renal immunopathology and downregulating serum cytokines, including IFN-γ, IL-12, and RANTES. Notably, the infiltration of CD4+ and CD8+ T cells in the kidney was reduced by WCP. Similarly, the cell transwell co-culturation study showed that the WCP treated MPC-5 cells were weaker in inducing T cell migration. Consistent with this finding, our observations revealed that WCP could inhibit T cell-related chemokine expression in kidney and MPC-5 cells, as well as reduce the levels of TLR4, MYD88, phosphorylated-p38, phosphorylated-ERK, and phosphorylated-JNK. On the other hand, WCP was found to greatly inhibit the Th1 cells differentiation in vivo and in vitro. Cytokine-receptor induced Th1 cell differentiation pathway and PI3K-AKT pathway were the most enriched pathways based on differentially expressed genes (DEGs) enrichment analysis among different cell groups. Results from RT-qPCR and WB showed that WCP notably reduced the levels of IL-12, p-STAT4, IFN-γ, p-STAT1, p-PI3K, and p-AKT in T cells. CONCLUSION: WCP demonstrated positive immunomodulatory effects on LN disease, by decreasing the T cells infiltration through TLR4/MYD88/MAPK signaling pathway and inhibiting Th1 cells differentiation via IL-12-STAT4 and IFN-γ-STAT1 pathways, in addition to the PI3K-AKT pathway.