-
Frontiers in Immunology 2024This study aimed to demonstrate the potential of activated leukocyte cell adhesion molecule (ALCAM), hemopexin (HPX), and peroxiredoxin 6 (PRDX6) as urine biomarkers for...
Longitudinal assessment of urinary ALCAM, HPX, and PRDX6 in Korean patients with systemic lupus erythematosus: implications for disease activity monitoring and treatment response.
INTRODUCTION
This study aimed to demonstrate the potential of activated leukocyte cell adhesion molecule (ALCAM), hemopexin (HPX), and peroxiredoxin 6 (PRDX6) as urine biomarkers for systemic lupus erythematosus (SLE).
METHODS
Urine samples were collected from 138 Korean patients with SLE from the Ajou Lupus Cohort and 39 healthy controls (HC). The concentrations of urine biomarkers were analyzed using enzyme-linked immunosorbent assay kits specific for ALCAM, HPX, and PRDX6, respectively. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic utility, and Pearson's correlation analysis was conducted to assess the relationships between the disease activity and urine biomarkers.
RESULTS
Patients with SLE and patients with lupus nephritis (LN) showed significantly elevated ALCAM, HPX, and PRDX6 levels compared with HCs. ALCAM, HPX, and PRDX6 showed significant diagnostic values, especially for lupus nephritis (LN), with areas under the receiver operating characteristic curve for LN was 0.850 for ALCAM (95% CI, 0.778-0.921), 0.781 for HPX (95% CI, 0.695-0.867), and 0.714 for PRDX6 (95% CI, 0.617-0.812). Correlation analysis revealed that all proteins were significantly associated with anti-double stranded DNA antibody (ALCAM, r = 0.350, p < 0.001; HPX, r = 0.346, p < 0.001; PRDX6, r = 0.191, p = 0.026) and SLEDAI (ALCAM, r = 0.526, p < 0.001; HPX, r = 0.479, p < 0.001; PRDX6, r = 0.262, p = 0.002). Results from the follow-up of the three biomarker levels in these patients revealed a significant decrease, showing a positive correlation with changes in SLEDAI-2k scores (ALCAM, r = 0.502, p < 0.001; HPX, r = 0.475, p < 0.001; PRDX6, r = 0.245, p = 0.026), indicating their potential as indicators for tracking disease activity.
DISCUSSIONS
Urinary ALCAM, HPX, and PRDX6 levels have diagnostic value and reflect disease activity in Korean patients with SLE, emphasizing their potential for non-invasive monitoring and treatment response evaluation.
Topics: Humans; Female; Male; Biomarkers; Adult; Lupus Erythematosus, Systemic; Republic of Korea; Peroxiredoxin VI; Middle Aged; Fetal Proteins; Longitudinal Studies; Severity of Illness Index; Young Adult; Antigens, CD; ROC Curve; Cell Adhesion Molecules, Neuronal; Case-Control Studies; Lupus Nephritis; Activated-Leukocyte Cell Adhesion Molecule
PubMed: 38915417
DOI: 10.3389/fimmu.2024.1369385 -
BMC Infectious Diseases Jun 2024The pathogenesis of hypertension (HTN) in people living with HIV/AIDS (PLHIV) is complex and remains not fully understood. Chronic immune activation (IA) is postulated...
BACKGROUND
The pathogenesis of hypertension (HTN) in people living with HIV/AIDS (PLHIV) is complex and remains not fully understood. Chronic immune activation (IA) is postulated to be one of the culprits. This notion is derived from studies in HIV-uninfected populations and/or animals while data on HTN and how it relates to IA in PLHIV remains scarce. We determined the relationship between HTN and IA among antiretroviral therapy (ART) naïve PLHIV.
METHODS
We analysed baseline data of 365 out of 430 clinical trial participants whose main aim was to investigate the effect of low-dose aspirin on HIV disease progression in PLHIV starting ART. Soluble CD14 (sCD14), T cells co-expressing CD38 and HLA-DR, and PD-1 were the IA and exhaustion markers, respectively studied and were analysed by flow cytometry. Mann-Whitney U-test was used for comparison of the markers by HTN status. A robust Poisson regression model was used to determine the predictors for HTN.
RESULTS
A quarter of the 365 were hypertensive (25.3%, 95% CI 20.9-29.8%), and, had higher median (IQR) body mass index (kg/m) (23.4 (19.6, 28.0) versus 21.9 (19.3, 25.1)) and lower median (IQR) estimated glomerular filtration rate (mL/min/1.73m) (101.2 (79.4, 126.9) versus 113.6 (92.7, 138.8)) than normotensive participants (p < 0.05). Participants with HTN had higher median frequencies of all markers of IA and exhaustion but lower sCD14 (p > 0.05). None of these markers significantly predicted the occurrence of HTN.
CONCLUSION
Studied markers of IA and exhaustion were higher in PLHIV with HTN than those without but were unpredictive of HTN. Larger multicentre studies with a wider range of markers are needed to confirm the role of IA in HIV-associated HTN.
Topics: Humans; Male; HIV Infections; Female; Adult; Hypertension; Middle Aged; Lipopolysaccharide Receptors; Biomarkers
PubMed: 38914935
DOI: 10.1186/s12879-024-09548-x -
Scientific Reports Jun 2024Circulating leukocytes enter tissue either through endothelial junctions (paracellular) or via a pore through the body of endothelial cells (transcellular). We have...
Circulating leukocytes enter tissue either through endothelial junctions (paracellular) or via a pore through the body of endothelial cells (transcellular). We have previously shown that genetically replacing VE-cadherin with a VE-cadherin-α-catenin (VEC-αC) fusion construct-which binds constitutively to actin-obstructs junctions, and blocks leukocyte extravasation in lung, skin and postcapillary venules of cremaster muscle. However, neutrophil recruitment into the inflamed peritoneal cavity was unimpaired. Investigating reasons for this, here, we visualized neutrophil diapedesis by 3D intravital video microscopy in the cremaster muscle and omentum, the major site of neutrophil recruitment into the peritoneal cavity. We found that 80% of neutrophil-extravasation occurred through HEVs in the omentum, which was unimpaired by VEC-αC. In addition, in larger venules (60-85 µm) of both tissues, less than 15% of neutrophils extravasated transcellularly in WT mice. However, in VEC-α-C mice, transcellular diapedesis increased severalfold in the omentum, but not in the cremaster. In line with this, omental venules expressed higher levels of ICAM-1 and atypical chemokine receptor 1. Furthermore, only in the omentum, VEC-αC expression caused reduced elongation of venular endothelium in flow-direction, suggesting different biomechanical properties. Collectively, VEC-αC does not inhibit paracellular transmigration in all types of venules and can modulate the diapedesis route.
Topics: Animals; Neutrophils; Mice; Transendothelial and Transepithelial Migration; Omentum; Cadherins; Venules; Intercellular Adhesion Molecule-1; Endothelial Cells; Antigens, CD; Neutrophil Infiltration; Mice, Inbred C57BL; Transcellular Cell Migration
PubMed: 38914623
DOI: 10.1038/s41598-024-65173-3 -
Nature Communications Jun 2024Broadly neutralizing antibodies (bNAbs) are promising candidates for the treatment and prevention of HIV-1 infections. Despite their critical importance, automatic...
Broadly neutralizing antibodies (bNAbs) are promising candidates for the treatment and prevention of HIV-1 infections. Despite their critical importance, automatic detection of HIV-1 bNAbs from immune repertoires is still lacking. Here, we develop a straightforward computational method for the Rapid Automatic Identification of bNAbs (RAIN) based on machine learning methods. In contrast to other approaches, which use one-hot encoding amino acid sequences or structural alignment for prediction, RAIN uses a combination of selected sequence-based features for the accurate prediction of HIV-1 bNAbs. We demonstrate the performance of our approach on non-biased, experimentally obtained and sequenced BCR repertoires from HIV-1 immune donors. RAIN processing leads to the successful identification of distinct HIV-1 bNAbs targeting the CD4-binding site of the envelope glycoprotein. In addition, we validate the identified bNAbs using an in vitro neutralization assay and we solve the structure of one of them in complex with the soluble native-like heterotrimeric envelope glycoprotein by single-particle cryo-electron microscopy (cryo-EM). Overall, we propose a method to facilitate and accelerate HIV-1 bNAbs discovery from non-selected immune repertoires.
Topics: HIV-1; Humans; Machine Learning; HIV Antibodies; Cryoelectron Microscopy; Antibodies, Neutralizing; HIV Infections; CD4 Antigens; Amino Acid Sequence; HIV Envelope Protein gp120
PubMed: 38914562
DOI: 10.1038/s41467-024-49676-1 -
Nature Communications Jun 2024Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC)...
Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.
Topics: Animals; Skin Neoplasms; Carcinoma, Squamous Cell; Mice; Humans; B7-H1 Antigen; Immune Checkpoint Inhibitors; Male; Immunotherapy; Epithelial-Mesenchymal Transition; Cell Plasticity; Cell Line, Tumor; Programmed Cell Death 1 Receptor; CTLA-4 Antigen; Receptors, Virus; B7-1 Antigen; Receptors, Immunologic
PubMed: 38914547
DOI: 10.1038/s41467-024-49718-8 -
Investigative Ophthalmology & Visual... Jun 2024The aim of this study was to elucidate the role of Sema4D in the pathogenesis of senescence-associated choroidal neovascularization (CNV) and to explore its underlying...
PURPOSE
The aim of this study was to elucidate the role of Sema4D in the pathogenesis of senescence-associated choroidal neovascularization (CNV) and to explore its underlying mechanisms.
METHODS
In this study, we utilized a model of laser-induced CNV in both young (3 months old) and old (18 months old) mice, including those with or without Sema4D knockout. The expression and localization of Sema4D in CNV were assessed using PCR, Western blot, and immunostaining. Subsequently, the morphological and imaging examinations were used to evaluate the size of CNV and vascular leakage. Finally, the expression of M2 markers, senescence-related markers, and molecules involved in the RhoA/ROCK pathway was detected.
RESULTS
We found that Sema4D was predominantly expressed in macrophages within CNV lesions, and both the mRNA and protein levels of Sema4D progressively increased following laser photocoagulation, a trend more pronounced in old mice. Moreover, Sema4D knockout markedly inhibited M2 polarization in senescent macrophages and reduced the size and leakage of CNV, particularly in aged mice. Mechanistically, aging was found to upregulate RhoA/ROCK signaling, and knockout of Sema4D effectively suppressed the activation of this pathway, with more significant effects observed in aged mice.
CONCLUSIONS
Our findings revealed that the deletion of Sema4D markedly inhibited M2 macrophage polarization through the suppression of the RhoA/ROCK pathway, ultimately leading to the attenuation of senescence-associated CNV. These data indicate that targeting Sema4D could offer a promising approach for gene editing therapy in patients with neovascular age-related macular degeneration.
Topics: Animals; Choroidal Neovascularization; Mice; Macrophages; rho-Associated Kinases; Mice, Knockout; Semaphorins; Disease Models, Animal; Signal Transduction; Mice, Inbred C57BL; rhoA GTP-Binding Protein; Antigens, CD; Blotting, Western; Male; Fluorescein Angiography
PubMed: 38913005
DOI: 10.1167/iovs.65.6.34 -
Frontiers in Immunology 2024The study aimed to analyze the efficacy and safety of PD-1 inhibitors plus chemotherapy with or without endostatin for stage IV lung squamous cell carcinoma (LUSC).
BACKGROUD
The study aimed to analyze the efficacy and safety of PD-1 inhibitors plus chemotherapy with or without endostatin for stage IV lung squamous cell carcinoma (LUSC).
METHODS
A total of 219 patients with stage IV LUSC were included. 120 received PD-1 inhibitors plus chemotherapy with or without endostatin (IC ± A), of which 39 received endostatin (IC+A) and 81 did not receive endostatin (IC-A). 99 received chemotherapy with or without endostatin (C ± A). Endpoints included overall survival (OS), progression-free survival (PFS), adverse events (AEs), and immune-related adverse events (irAEs).
RESULTS
The median PFS in the IC ± A group versus the C ± A group was 8 and 4 months (P < 0.001), and the median OS was 17 and 9 months (P < 0.001). There was no significant difference in any grade AEs between the IC ± A and C ± A groups (P > 0.05). The median PFS in the IC+A group versus the IC-A group was 11 and 7 months (P = 0.024), and the median OS was 34 and 15 months (P = 0.01). There was no significant difference between the IC+A group and the IC-A group for all grade AEs and irAEs (P > 0.05). The subgroup analysis showed that patients with LIPI = 0 had significant OS and PFS benefits in IC+A group, while for patients with LIPI = 1-2, there was no significant difference in OS and PFS benefits between the IC+A group and IC-A group.
CONCLUSIONS
PD-1 inhibitors plus chemotherapy with endostatin might be first-line treatment for patients with stage IV LUSC.
Topics: Humans; Endostatins; Male; Female; Lung Neoplasms; Middle Aged; Retrospective Studies; Aged; Immune Checkpoint Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Staging; Carcinoma, Squamous Cell; Adult; Programmed Cell Death 1 Receptor; Treatment Outcome
PubMed: 38911862
DOI: 10.3389/fimmu.2024.1413204 -
Frontiers in Immunology 2024To investigate the treatment response and toxicity of the combination of induction chemotherapy (IC) and PD-1 inhibitor in locally advanced nasopharyngeal carcinoma...
PURPOSE
To investigate the treatment response and toxicity of the combination of induction chemotherapy (IC) and PD-1 inhibitor in locally advanced nasopharyngeal carcinoma (LANPC).
METHODS
Patients with stage III-IVA NPC who received IC or IC + PD-1 inhibitor were included. The chi-square test and multivariate logistic regression analysis were used for statistical analysis.
RESULTS
A total of 225 patients were identified, including 193 (85.8%) and 32 (14.2%) who received IC alone and IC + PD-1 inhibitor, respectively. The addition of PD-1 inhibitor to IC significantly improved the tumor response than those treated with IC alone. The complete response (CR), partial response, stable disease, and progressive disease rates of 4.7% vs. 31.3%, 69.4% vs. 62.5%, 24.9% vs. 6.3%, and 1.0% vs. 0% in patients receiving IC alone and IC + PD-1 inhibitor, respectively (P<0.001). The results of the multivariate logistic regression showed that receiving PD-1 inhibitor was an independent predictor influencing the CR rate of patients (odds ratio 9.814, P<0.001). The most common toxicity by using IC and PD-1 inhibitor was hematological toxicity. In terms of non-hematological toxicity, 7 (21.9%) patients experienced thyroid dysfunction and all of them were hyperthyroidism. No grade 5 toxicities were found. In those who received IC and PD-1 inhibitor, the one-year locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 100%, 96.9%, 96.9%, and 100%, respectively.
CONCLUSION
The addition of PD-1 inhibitor to IC has promise as an effective treatment approach for LANPC. More studies are expected to provide further insights into the optimal use of this treatment strategy, paving the way for more personalized and effective treatment options for patients with LANPC.
Topics: Humans; Male; Female; Nasopharyngeal Carcinoma; Middle Aged; Induction Chemotherapy; Adult; Nasopharyngeal Neoplasms; Aged; Immune Checkpoint Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Programmed Cell Death 1 Receptor; Treatment Outcome; Neoplasm Staging; Young Adult; Retrospective Studies
PubMed: 38911859
DOI: 10.3389/fimmu.2024.1415246 -
Frontiers in Immunology 2024Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a... (Review)
Review
Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a small subset of patients and relapse can occur in patients who initially respond to the treatment. Recent breakthroughs in this field have identified innate immune checkpoints harnessed by cancer cells to escape immunosurveillance from innate immunity. MHC1 appears to be such a molecule expressed on cancer cells which can transmit a negative signal to innate immune cells through interaction with leukocyte immunoglobulin like receptor B1 (LILRB1). The review aims to summarize the current understanding of MHC1/LILRB1 axis on mediating cancer immune evasion with an emphasis on the therapeutic potential to block this axis for cancer therapy. Nevertheless, one should note that this field is still in its infancy and more studies are warranted to further verify the effectiveness and safety in clinical as well as the potential to combine with existing immune checkpoints.
Topics: Humans; Leukocyte Immunoglobulin-like Receptor B1; Neoplasms; Immunity, Innate; Animals; Immune Checkpoint Inhibitors; Tumor Escape; Histocompatibility Antigens Class I; Immunotherapy; Signal Transduction; Antigens, CD
PubMed: 38911856
DOI: 10.3389/fimmu.2024.1421092 -
Frontiers in Immunology 2024Programmed cell death protein-1 (PD-1) maintains peripheral immune tolerance by preventing T cell continuous activation. Aiming to understand the extent of PD-1...
OBJECTIVES
Programmed cell death protein-1 (PD-1) maintains peripheral immune tolerance by preventing T cell continuous activation. Aiming to understand the extent of PD-1 expression in inflammatory arthritis beyond its involvement with T cells, we assess its presence on various circulating single cells.
METHODS
Mass cytometry analysis of patients with active seropositive/seronegative rheumatoid (RA; n=9/8) and psoriatic (PsA; n=9) arthritis versus healthy controls (HC; n=13), re-evaluating patients after 3 months of anti-rheumatic treatment.
RESULTS
PD-1 was expressed in all leukocyte subpopulations, with the highest PD-1 cell frequencies in eosinophils (59-73%) and T cells (50-60%), and the lowest in natural-killer cells (1-3%). PD-1 cell frequencies and PD-1 median expression were comparable between patient subgroups and HC, in the majority of cell subsets. Exceptions included increases in certain T cell/B cell subsets of seropositive RA and specific monocyte subsets and dendritic cells of PsA; an expanded PD-1CD4CD45RACD27CD28 T subset, denoting exhausted T cells, was common across patient subgroups. Strikingly, significant inverse correlations between individual biomarkers of systemic inflammation (ESR and/or serum CRP) and PD-1 cell frequencies and/or median expression were evident in several innate and adaptive immunity cell subsets of RA and PsA patients. Furthermore, all inverse correlations noted in individuals with active arthritis were no longer discernible in those who attained remission/low disease activity post-treatment.
CONCLUSION
PD-1 expression may be insufficient, relative to the magnitude of the concomitant systemic inflammatory response on distinct leukocyte subsets, varying between RA and PsA. Our results point to the potential therapeutic benefits of pharmacological PD-1 activation, to rebalance the autoimmune response and reduce inflammation.
Topics: Humans; Programmed Cell Death 1 Receptor; Male; Female; Middle Aged; Single-Cell Analysis; Arthritis, Rheumatoid; Arthritis, Psoriatic; Proteomics; Aged; Adult; Autoimmunity; Biomarkers
PubMed: 38911848
DOI: 10.3389/fimmu.2024.1403680