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Cell Death & Disease May 2024Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression....
Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression. Mesangial cells (MCs) are intrinsic cells in the kidney that can regulate capillary blood flow, phagocytose apoptotic cells, and secrete vasoactive substances and growth factors. Previous studies have shown that various types of inflammatory cells can activate MCs for hyperproliferation, leading to disruption of the filtration barrier and impairment of renal function in LN. Here, we characterized the heterogeneity of kidney cells of LN mice by single-nucleus RNA sequencing (snRNA-seq) and revealed the interaction between macrophages and MCs through the CXC motif chemokine ligand 12 (CXCL12)/dipeptidyl peptidase 4 (DPP4) axis. In culture, macrophages modulated the proliferation and migration of MCs through this ligand-receptor interaction. In LN mice, treatment with linagliptin, a DPP4 inhibitor, effectively inhibited MC proliferation and reduced urinary protein levels. Together, our findings indicated that targeting the CXCL12/DPP4 axis with linagliptin treatment may serve as a novel strategy for the treatment of LN via the CXCL12/DPP4 axis.
Topics: Lupus Nephritis; Animals; Dipeptidyl Peptidase 4; Chemokine CXCL12; Mesangial Cells; Mice; Macrophages; Cell Proliferation; Humans; Female; Cell Movement; Cell Communication; Linagliptin; Signal Transduction; Dipeptidyl-Peptidase IV Inhibitors; Mice, Inbred C57BL
PubMed: 38762508
DOI: 10.1038/s41419-024-06708-4 -
Biochemical and Biophysical Research... May 2024The contributions of anti-Topoisomerase 1 (Top1) autoantibodies to the pathophysiology of diffuse cutaneous systemic sclerosis (dcSSc), the most aggressive scleroderma...
The contributions of anti-Topoisomerase 1 (Top1) autoantibodies to the pathophysiology of diffuse cutaneous systemic sclerosis (dcSSc), the most aggressive scleroderma subtype, are unknown. Top1 catalyzes DNA relaxation and unwinding in cell nuclei, a site previously considered inaccessible to antibodies. The discovery of autoantibodies in systemic lupus erythematosus that penetrate nuclei and inhibit DNA repair raised the possibility that nuclear-penetrating autoantibodies contribute to mechanisms of autoimmunity. Here we show that an anti-Top1 autoantibody produced by a single B cell clone from a patient with dcSSc penetrates live cells and localizes into nuclei. Functionally, the autoantibody inhibits formation of the Top1 cleavage complex necessary for DNA nicking, which distinguishes it from cytotoxic camptothecin Top1 inhibitors used in cancer therapy that trap the cleavage complex rather than preventing its formation. Discovery of a patient-derived cell-penetrating scleroderma anti-Top1 autoantibody that inhibits Top1 cleavage complex formation supports the hypothesis that anti-Top1 autoantibodies contribute to cellular dysfunction in dcSSc and offers a valuable antibody reagent resource for future studies on anti-Top1 autoantibody contributions to scleroderma pathophysiology.
PubMed: 38759301
DOI: 10.1016/j.bbrc.2024.150123 -
Northern Clinics of Istanbul 2024Biomarkers using routine laboratory tests accurately presenting systemic lupus erythematosus (SLE) disease activity may have important practical values in clinical...
OBJECTIVE
Biomarkers using routine laboratory tests accurately presenting systemic lupus erythematosus (SLE) disease activity may have important practical values in clinical settings. The primary purpose of this study was to investigate neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII; neutrophil X platelet/lymphocyte) as potential biomarkers of disease activity in cases with SLE.
METHODS
In this case-control observational study, cases with SLE and demographically similar healthy controls were included. For clinical evaluation demographic features, disease duration and drugs were recorded. SLE clinical disease activity was assessed with SLEDAI scores. For laboratory assessments; erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and C3-C4 levels and anti-dsDNA positivity were recorded. Based on the simultaneous complete blood count (CBC) of the participants NLR, PLR and SII were calculated. The correlation between clinical and laboratory data was analyzed.
RESULTS
68 cases with SLE (64 women, 8 men) and 69 controls (65 women, 4 men) were included in this investigation. The demographic features of the cases and controls were similar. ESR, CRP, NLR, PLR and SII scores were statistically higher in cases with SLE than controls (p<0.000). Statistically significant positive correlations between SLEDAI and NLR, PLR and SII scores were demonstrated (p=0.01, r=0.505; 0.414; 0.698, respectively). We determined a cut-off value of SII as 681,3 presenting 77% sensitivity and 76% specificity to discriminate no-mild disease activity and moderate-higher SLE disease activity status. The SII cut-off value was determined as 681,3 presenting 77% sensitivity and 76% specificity (p<0.000, and AUC=0.930).
CONCLUSION
CBC indices were shown to be higher in cases with SLE than healthy controls in our study. By presenting a strong correlation with disease activity and discriminating ability of disease status, SII might serve as a biomarker supporting clinical evaluation in SLE.
PubMed: 38757099
DOI: 10.14744/nci.2023.90132 -
Mediterranean Journal of Rheumatology Mar 2024Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules responsible for signal transduction of multiple cytokines and... (Review)
Review
Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules responsible for signal transduction of multiple cytokines and growth factors in different cell types, involved in the maintenance of immune tolerance. Thus, the dysregulation of this pathway plays a crucial role in the pathogenesis of multiple autoimmune, inflammatory, and allergic diseases and is an attractive treatment target. JAK inhibitors (JAKinibs) have been approved in the treatment of multiple autoimmune diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (SPA). In SLE, there is a plethora of ongoing trials evaluating their efficacy, with tofacitinib, baricitinib and deucravacitinib showing promising results, without major safety concerns. In this review, we will discuss the rationale of targeting JAKinibs in SLE and summarize the clinical data of efficacy and safety of JAKinibs in SLE patients.
PubMed: 38756931
DOI: 10.31138/mjr.231123.jia -
Frontiers in Immunology 2024Impaired metabolism is recognized as an important contributor to pathogenicity of T cells in (SLE). Over the last two decades, we have acquired significant knowledge... (Review)
Review
Impaired metabolism is recognized as an important contributor to pathogenicity of T cells in (SLE). Over the last two decades, we have acquired significant knowledge about the signaling and transcriptomic programs related to metabolic rewiring in healthy and SLE T cells. However, our understanding of metabolic network activity derives largely from studying metabolic pathways in isolation. Here, we argue that enzymatic activities are necessarily coupled through mass and energy balance constraints with in-built network-wide dependencies and compensation mechanisms. Therefore, metabolic rewiring of T cells in SLE must be understood in the context of the entire network, including changes in metabolic demands such as shifts in biomass composition and cytokine secretion rates as well as changes in uptake/excretion rates of multiple nutrients and waste products. As a way forward, we suggest cell physiology experiments and integration of orthogonal metabolic measurements through computational modeling towards a comprehensive understanding of T cell metabolism in lupus.
Topics: Lupus Erythematosus, Systemic; Humans; T-Lymphocytes; Metabolic Networks and Pathways; Energy Metabolism; Animals; Signal Transduction; Cytokines
PubMed: 38756769
DOI: 10.3389/fimmu.2024.1371708 -
BMC Rheumatology May 2024Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease, carries high risk of organ damage and burden to healthcare systems. SLE disease...
BACKGROUND
Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease, carries high risk of organ damage and burden to healthcare systems. SLE disease modification aims to reduce disease activity with minimal treatment toxicity and preventing or minimizing organ damage development. This real-world study utilizing healthcare administrative claims data assessed organ damage development, associated costs and healthcare resource utilization (HCRU) in patients with SLE in Germany.
METHODS
Claims data from January 1, 2007, to December 31, 2017, were obtained from the Betriebskrankenkassen German Sickness Fund Database. Adults (> 18 years) with a confirmed SLE diagnosis between January 1, 2009, and December 31, 2014, (inclusion period) were included. The index date was calculated based on the first recorded SLE diagnosis during this period. Patients were propensity score-matched (1:3) to a comparator cohort without SLE by age, sex, and comorbidities (Charlson comorbidity index). Organ damage was identified using an algorithm developed based on conditions described in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), using ICD-10-GM diagnostic codes, healthcare procedures, and/or treatments.
RESULTS
2121 patients with SLE and 6308 comparator patients were included (mean follow-up time: 6.4 years). Organ damage prevalence increased from 60.5% at baseline to 83.0% during 6 years of follow-up in all patients with SLE, while 17.0% of patients with SLE did not develop organ damage. Patients with newly confirmed SLE diagnosis without organ damage at baseline were nearly twice as likely to develop organ damage within 5 years versus the comparator cohort (52.0% vs. 27.0%). Total annual costs per patient-year for patients with SLE with organ damage were more than double those of patients with SLE without organ damage; both the number of inpatient admissions and length of stay were higher.
CONCLUSIONS
The application of a recently developed algorithm allowed us to use claims data to elucidate SLE organ damage, and its associated high clinical and economic burden, in a large, representative sample in Germany. To our knowledge, this is the first European analysis of its kind involving a broad cohort of patients with SLE treated in the routine care setting.
PubMed: 38755673
DOI: 10.1186/s41927-024-00387-6 -
Lupus Science & Medicine May 2024Trauma history is associated with SLE onset and worse patient-reported outcomes; perceived stress is associated with greater SLE disease activity. Stress perceptions...
OBJECTIVE
Trauma history is associated with SLE onset and worse patient-reported outcomes; perceived stress is associated with greater SLE disease activity. Stress perceptions vary in response to life events and may be influenced by psychosocial factors. In an SLE cohort, we examined whether stressful events associated with perceived stress, whether psychosocial factors affected perceived stress, and whether these relationships varied by prior trauma exposure.
METHODS
This is a cross-sectional analysis of data from the California Lupus Epidemiology Study, an adult SLE cohort. Multivariable linear regression analyses controlling for age, gender, educational attainment, income, SLE damage, comorbid conditions, glucocorticoids ≥7.5 mg/day and depression examined associations of recent stressful events (Life Events Inventory) and positive (resilience, self-efficacy, emotional support) and negative (social isolation) psychosocial factors with perceived stress. Analyses were stratified by lifetime trauma history (Brief Trauma Questionnaire (BTQ)) and by adverse childhood experiences (ACEs) in a subset.
RESULTS
Among 242 individuals with SLE, a greater number of recent stressful events was associated with greater perceived stress (beta (95% CI)=0.20 (0.07 to 0.33), p=0.003). Positive psychosocial factor score representing resilience, self-efficacy and emotional support was associated with lower perceived stress when accounting for number of stressful events (-0.67 (-0.94 to -0.40), p<0.0001); social isolation was associated with higher stress (0.20 (0.14 to 0.25), p<0.0001). In analyses stratified by BTQ trauma and ACEs, associations of psychosocial factors and perceived stress were similar between groups. However, the number of recent stressful events was significantly associated with perceived stress only for people with BTQ trauma (0.17 (0.05 to 0.29), p=0.0077) and ACEs (0.37 (0.15 to 0.58), p=0.0011).
CONCLUSION
Enhancing positive and lessening negative psychosocial factors may mitigate deleterious perceived stress, which may improve outcomes in SLE, even among individuals with a history of prior trauma who may be more vulnerable to recent stressful events.
Topics: Humans; Female; Lupus Erythematosus, Systemic; Male; Adult; Stress, Psychological; Cross-Sectional Studies; Middle Aged; Self Efficacy; Social Support; Resilience, Psychological; California; Life Change Events; Adverse Childhood Experiences; Surveys and Questionnaires; Social Isolation; Depression
PubMed: 38754905
DOI: 10.1136/lupus-2023-001060 -
PloS One 2024The objective of this study was to evaluate the relationship between the platelet-to-lymphocyte ratio (PLR) and systemic lupus erythematosus (SLE). Additionally, the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The objective of this study was to evaluate the relationship between the platelet-to-lymphocyte ratio (PLR) and systemic lupus erythematosus (SLE). Additionally, the study aimed to establish an association between PLR and SLE disease activity, specifically lupus nephritis (LN).
METHODS
We conducted a comprehensive search across Medline, Embase, and Cochrane databases to identify relevant articles. Subsequently, we performed meta-analyses to compare PLR between SLE patients and controls, as well as active and inactive SLE cases, along with LN and non-LN groups. Furthermore, a meta-analysis was conducted on correlation coefficients between PLR and various parameters in SLE patients, including the SLE Disease Activity Index (SLEDAI), C3, C4, anti-dsDNA, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).
RESULTS
In total, fifteen studies comprising 1,522 SLE patients and 1,424 controls were eligible for inclusion. The meta-analysis demonstrated a significant elevation of PLR in the SLE group compared to the control group (Standardized Mean Difference [SMD] = 0.604, 95% Confidence Interval [CI] = 0.299-0.909, p < 0.001). Upon stratification by ethnicity, an elevated PLR was observed in the SLE group among both Asian and Arab populations. Subgroup analysis based on sample size revealed consistently higher PLR in both small (n < 200) and large sample (n ≥ 200) SLE groups. Moreover, when considering disease activity, there was a noteworthy trend of increased PLR in the active disease group compared to the inactive group (SMD = 0.553, 95% CI = 0.000-1.106, p = 0.050). However, the meta-analysis did not demonstrate a significant distinction in PLR between the LN and non-LN groups. Notably, a positive association was established between PLR and SLEDAI (correlation coefficient = 0.325, 95% CI = 0.176-0.459, p < 0.001). Furthermore, PLR exhibited positive correlations with ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels.
CONCLUSIONS
The outcomes of this meta-analysis underscored the elevated PLR in SLE patients, suggesting its potential as a biomarker for gauging systemic inflammation in SLE. Additionally, PLR exhibited correlations with SLEDAI, as well as with key indicators such as ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels.
Topics: Humans; Lupus Erythematosus, Systemic; Biomarkers; Lymphocytes; Blood Platelets; Inflammation; Blood Sedimentation; Platelet Count; C-Reactive Protein; Lupus Nephritis; Lymphocyte Count
PubMed: 38753735
DOI: 10.1371/journal.pone.0303665 -
Pediatric Quality & Safety 2024Patients with rheumatic diseases are at a high risk of invasive pneumococcal disease due to immunosuppression. We conducted a quality improvement project, and the first...
BACKGROUND
Patients with rheumatic diseases are at a high risk of invasive pneumococcal disease due to immunosuppression. We conducted a quality improvement project, and the first aim was to increase the percentage of patients with systemic lupus erythematosus and mixed connective tissue disease that is up to date on pneumococcal vaccinations from 9.6% to 80% within one year. Subsequently, the second aim was to increase the percentage of patients on immunosuppression with systemic lupus erythematosus, mixed connective tissue disease, juvenile dermatomyositis and systemic vasculitis that is up to date on pneumococcal vaccinations from 62.6% to 80% within one year.
METHODS
Two process measures were up-to-date vaccination status on (1) 13-valent pneumococcal conjugated vaccine (PCV13) and (2) 23-valent pneumococcal polysaccharide vaccine (PPSV23). Our outcome measure was being fully up to date on both pneumococcal vaccinations. Interventions included an immunization algorithm, reporting of eligible patients, education, reminders, and pre-visit planning.
RESULTS
There were shifts in the centerline for all quality measures in both phases of this project. The combined pneumococcal vaccination rate for Phase 1 increased from 9.6% to 91.1%, and this centerline was sustained. Pneumococcal vaccination rates also significantly increased for Phase 2: 68.8% to 93.4% for PCV13, 65.2% to 88.5% for PPSV23, and 62.6% to 86.5% for the combined pneumococcal vaccination rate.
CONCLUSIONS
Quality improvement methodology significantly increased and sustained pneumococcal vaccination rates in our high-risk, immunosuppressed patients. We continue to prioritize this important initiative to mitigate the risk of invasive pneumococcal disease.
PubMed: 38751894
DOI: 10.1097/pq9.0000000000000725 -
Kidney Diseases (Basel, Switzerland) Apr 2024Chimeric antigen receptor (CAR)-T cell therapy represents a significant advancement in the field of immunotherapy, providing targeted eradication of abnormal cells... (Review)
Review
BACKGROUND
Chimeric antigen receptor (CAR)-T cell therapy represents a significant advancement in the field of immunotherapy, providing targeted eradication of abnormal cells through the recognition between CAR and target antigens. This approach has garnered considerable attention due to its promising results in the clinical treatment of hematological malignancies and autoimmune diseases. As the focus shifts toward exploring novel targets and expanding the application of CAR-T cell therapy to solid tumors, including renal malignancies, researchers are pushing the boundaries of this innovative treatment. However, it is crucial to address the observed comorbidities associated with CAR-T cell therapy, particularly nephrotoxicity, due to the superseding release of cytokines and impairment of normal tissue.
SUMMARY
Our review discusses the research strategies and nephrotoxicity related to CAR-T cell therapy in various kidney-related diseases and provides insights into enhancing investigation and optimization.
KEY MESSAGES
CAR-T cell therapy has captured the attention of researchers and clinicians in the treatment of renal malignancies, multiple myeloma, systemic lupus erythematosus, and acquired immunodeficiency syndrome, which may lead to potential nephrotoxicity as they involve primary or secondary kidney complications. Understanding and summarizing the current research progress of CAR-T cell therapies can provide valuable insights into novel targets and combinations to optimize research models and enhance their clinical value.
PubMed: 38751795
DOI: 10.1159/000536194