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OBJECTIVES: Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections in patients with Neuromyelitis optica spectrum disorder (NMOSD) remain unclear. The objective of this study was to investigate CMV and EBV infections in patients with NMOSD. METHODS: Serum immunoglobin (Ig) G antibodies against CMV and EBV were measured in patients with NMOSD and healthy controls (HCs), including anti-CMV, anti-EBV nuclear antigen-1 (EBNA-1), anti-EBV virus capsid antigen (VCA), and anti-EBV early antigen (EA) IgGs. The immune status ratio (ISR) was used to evaluate the serum anti-CMV and anti-EBV IgG levels and ISR â§1.10 was defined as seropositivity. RESULTS: In total, 238 serum samples were collected from 94 patients with NMOSD and 144 HCs, and no significant difference of sex and age between NMOSD and HCs. Comparing to the HCs, patients with NMOSD exhibited significantly higher serum anti-CMV IgG level. In contrast, the serum anti-EBNA1 IgG level was significantly lower in patients with NMOSD than in HCs. The serum anti-VCA and anti-EA IgG levels did not differ between the two groups, but the anti-EA seropositivity was significantly higher in NMOSD group than that in HC group. We did not find associations between serum anti-CMV or anti-EBV IgG levels and NMOSD disease stage, immunotherapy, or disability score. CONCLUSIONS: Our findings indicated that increased CMV infection and EBV recent infection, as well as reduced EBV latency infection were associated with the risk of NMOSD. Prospective cohort studies are needed to verify our findings and clarify the correlation between CMV and EBV infections and clinical characteristics of NMOSD.
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Platinum (II) drugs, including cisplatin, carboplatin, and oxaliplatin, have achieved significant clinical success in cancer treatment. However, their clinical application has been greatly hindered by various adverse factors such as non-specific activation and drug resistance. Compared with Pt(II) drugs, the axial ligands within Pt(IV) compounds can improve the pharmacokinetic properties, selectivity, and biological activity, implementing alternative cytotoxic mechanisms beyond DNA cross-linking and partially overcoming drug resistance. The controlled conversion of Pt(IV) prodrugs into Pt(II) agents at the tumor site has been extensively explored internationally. In this review, Pt(IV) prodrug modification strategies are first summarized, next the development of the predominant external and internal photosensitizers is listed. Finally, three representative photoreduction mechanisms and strategies for developing corresponding Pt(IV) prodrugs are discussed. This work provides constructive instruction for the subsequent molecular design of Pt(IV) prodrugs.
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Aquaporin 4-immunoglobulin G (AQP4-IgG) specifically targets aquaporin 4 in approximately 80% of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases. NMOSD is presently categorized as anti-AQP4-antibody (Ab) positive or negative based on AQP4-Ab presence. The association between antibody titers and patient prognosis remains unclear. Therefore, the present study explores the correlation between severe attacks and serum AQP4 Ab titers in patients with neuromyelitis optica spectrum disorder. Data were gathered retrospectively from 546 patients with NMOSD between September 1, 2009, and December 1, 2021. Patients were categorized based on their AQP4-Ab titers: AQP4 titer ≥ 1:320 were classified as the high-titer group, AQP4 (+ +), and AQP4 titer of ≤ 1:100 were classified as the low-titer group, AQP4 ( +). Clinical characteristics and prognoses between the two groups were compared. Patients with AQP4 ( +) exhibited few severe optic neuritis (SON) attacks (false discovery rate [FDR] corrected p < 0.001), a reduced percentage experiencing SON attacks, and a lower incidence of visual disability than patients with AQP4 (+ +). Patients with AQP4 (+ +) and AQP4 ( +) NMOSD exhibited significant difference in annual recurrence rate (ARR) (FDR-corrected p < 0.001). The lower AQP4 Ab titer group demonstrated reduced susceptibility to severe relapse with conventional immunosuppressive agents and rituximab (RTX) than the higher titer group. No significant differences in sex, age at onset, coexisting connective tissue diseases, motor disability, or mortality rates were observed between the two groups. Higher AQP4 Ab titers correlated with increased disease severity and visual disability in patients with NMOSD.
Subject(s)
Aquaporin 4 , Autoantibodies , Neuromyelitis Optica , Humans , Neuromyelitis Optica/blood , Neuromyelitis Optica/immunology , Aquaporin 4/immunology , Aquaporin 4/blood , Female , Male , Adult , Middle Aged , Autoantibodies/blood , Retrospective Studies , Young Adult , Severity of Illness Index , Aged , AdolescentABSTRACT
BACKGROUND: Dysregulation of the immune system and N6-methyladenosine (m6A) contribute to immune therapy resistance and cancer progression in urothelial carcinoma (UC). This study aims to identify immune-related molecules, that are m6A-modified, and that are associated with tumor progression, poor prognosis, and immunotherapy response. METHODS: We identified prognostic immune genes (PIGs) using Cox analysis and random survival forest variable hunting algorithm (RSF-VH) on immune genes retrieved from the Immunology Database and Analysis Portal database (ImmPort). The RM2Target database and MeRIP-seq analysis, combined with a hypergeometric test, assessed m6A methylation in these PIGs. We analyzed the correlation between the immune pattern and prognosis, as well as their association with clinical factors in multiple datasets. Moreover, we explored the interplay between immune patterns, tumor immune cell infiltration, and m6A regulators. RESULTS: 28 PIGs were identified, of which the 10 most significant were termed methylated prognostic immune genes (MPIGs). These MPIGs were used to create an immune pattern score. Kaplan-Meier and Cox analyses indicated this pattern as an independent risk factor for UC. We observed significant associations between the immune pattern, tumor progression, and immune cell infiltration. Differential expression analysis showed correlations with m6A regulators expression. This immune pattern proved effective in predicting immunotherapy response in UC in real-world settings. CONCLUSION: The study identified a m6A-modified immune pattern in UC, offering prognostic and therapeutic response predictions. This emphasizes that immune genes may influence tumor immune status and progression through m6A modifications.
Subject(s)
Adenosine , Immunotherapy , Humans , Adenosine/analogs & derivatives , Prognosis , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/therapy , Gene Expression Regulation, Neoplastic , Biomarkers, Tumor/genetics , Carcinoma, Transitional Cell/immunology , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/mortality , Carcinoma, Transitional Cell/pathology , Carcinoma, Transitional Cell/therapyABSTRACT
The roles of Aß low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of SplitCre labeled mouse Aß-LTMRs in this regard. Genetic ablation of SplitCre-Aß-LTMRs increased mechanical nociception but not thermosensation in both acute and chronic inflammatory pain conditions, indicating a modality-specific role in gating mechanical nociception. Local optogenetic activation of SplitCre-Aß-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a model, in which Aß-LTMRs play distinctive local and global roles in transmitting or alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a strategy of global activation plus local inhibition of Aß-LTMRs for treating mechanical hyperalgesia.
Subject(s)
Chronic Pain , Hyperalgesia , Mice , Animals , Hyperalgesia/genetics , Nociception , Mechanoreceptors/physiology , Inflammation/geneticsABSTRACT
We compared the prognosis of Tibetan and Han Chinese patients with neuromyelitis optica spectrum disorder (NMOSD). The Expanded Disability Status Scale (EDSS) score at each attack, response to immunosuppressive therapy, risk of first relapse, severe attack, visual disability, motor disability, and total risk of disability were compared between Tibetan and Han Chinese patients. Tibetan patients showed higher EDSS during acute attacks. Annualized relapse rate did not differ between groups. Risk of severe attack, visual disability, and total risk of disability were higher in Tibetan patients. Tibetan patients with NMOSD have a higher risk of poor prognosis than Han Chinese patients.
Subject(s)
Disabled Persons , Motor Disorders , Neuromyelitis Optica , Humans , Neuromyelitis Optica/diagnosis , Neuromyelitis Optica/drug therapy , Tibet/epidemiology , Retrospective Studies , Prognosis , RecurrenceABSTRACT
In the published publication [...].
ABSTRACT
BACKGROUND AND PURPOSE: The association between onset age and sex with relapse risk in neuromyelitis optica spectrum disorder (NMOSD) remains inconclusive. We aimed to describe the clinical features of patients with NMOSD in different age groups and sexes and to analyse relapse characteristics pre- and post-immunosuppressive therapy (IST). METHODS: Patients with NMOSD were retrospectively reviewed from our clinical centre's database. Demographic and clinical data, attack presentation, and disease course pre- and post-IST were investigated. We also analysed the effect of onset age on the annualized relapse rate and relapse risk according to sex and IST status. Interactions on the additive scale between onset age and sex were analysed. A restricted cubic spline was used to analyse potential nonlinear correlations. Longitudinal changes in the Expanded Disability Status Scale score across NMOSD attacks were analysed using linear mixed-effect models. RESULTS: In total, 533 patients experienced 1394 attacks pre-IST and 753 relapses post-IST. Older age at onset was correlated with more myelitis attacks but fewer optic neuritis attacks, with no sex-related differences in attack presentation. Pre-IST, relapse risk increased with age at onset in women, while a U-shaped correlation between onset age and relapse risk was found in men. Post-IST, an inverted U-shaped association between the predicted relapse risk and onset age was observed in women. Conversely, a negative correlation between the predicted relapse risk and onset age was found in men. Overall, a higher ratio of myelitis attacks was found post-IST. CONCLUSIONS: Patients of different onset ages and sexes had different relapse patterns before and after IST.
Subject(s)
Myelitis , Neuromyelitis Optica , Male , Humans , Female , Neuromyelitis Optica/drug therapy , Neuromyelitis Optica/epidemiology , Retrospective Studies , Aquaporin 4 , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , RecurrenceABSTRACT
Skin employs interdependent cellular networks to facilitate barrier integrity and host immunity through ill-defined mechanisms. This study demonstrates that manipulation of itch-sensing neurons bearing the Mas-related G protein-coupled receptor A3 (MrgprA3) drives IL-17+ γδ T cell expansion, epidermal thickening, and resistance to the human pathogen Schistosoma mansoni through mechanisms that require myeloid antigen presenting cells (APC). Activated MrgprA3 neurons instruct myeloid APCs to downregulate interleukin 33 (IL-33) and up-regulate TNFα partially through the neuropeptide calcitonin gene related peptide (CGRP). Strikingly, cell-intrinsic deletion of IL-33 in myeloid APC basally alters chromatin accessibility at inflammatory cytokine loci and promotes IL-17/23-dependent epidermal thickening, keratinocyte hyperplasia, and resistance to helminth infection. Our findings reveal a previously undescribed mechanism of intercellular cross-talk wherein "itch" neuron activation reshapes myeloid cytokine expression patterns to alter skin composition for cutaneous immunity against invasive pathogens.
ABSTRACT
CD36, a multifunctional glycoprotein, has been shown to play critical roles in tumor initiation, progression, metastasis, immune response, and drug resistance. CD36 serves as a receptor for a wide range of ligands, including lipid-related ligands (e.g., long-chain fatty acid (LCFA), oxidized low-density lipoprotein (oxLDL), and oxidized phospholipids), as well as protein-related ligands (e.g., thrombospondins, amyloid proteins, collagens I and IV). CD36 is overexpressed in various cancers and may act as an independent prognostic marker. While it was initially identified as a mediator of anti-angiogenesis through its interaction with thrombospondin-1 (TSP1), recent research has highlighted its role in promoting tumor growth, metastasis, drug resistance, and immune suppression. The varied impact of CD36 on cancer is likely ligand-dependent. Therefore, we focus specifically on the ligand-dependent role of CD36 in cancer to provide a critical review of recent advances, perspectives, and challenges.
Subject(s)
Neoplasms , Humans , Ligands , Neoplasms/drug therapy , CD36 Antigens/metabolism , Drug Resistance , Immunity , Lipoproteins, LDL/metabolismABSTRACT
BACKGROUND: Low anterior resection syndrome (LARS) is a series of bowel dysfunction symptoms, including altered bowel frequency, irregular bowel rhythms, fecal incontinence, and constipation. LARS occurs in 80% of patients undergoing sphincter-preserving surgery, affecting patients' quality of life along with social avoidance. Different measurements and treatments have been raised to deal with LARS, but no systematic standard has been developed. OBJECTIVE AND METHODS: To promote the standardization of clinical trials and clinical management of LARS, this review summarizes the latest findings up until 2023 regarding the diagnostic criteria, assessment protocols, and treatment modalities for postoperative LARS in rectal cancer. RESULTS: The diagnostic criteria for LARS need to be updated to the definition proposed by the LARS International Collaborative Group, replacing the current application of the LARS score. In both clinical trials and clinical treatment, the severity of LARS should be assessed using at least one symptom assessment questionnaire, the LARS score or MSKCC BFI, and at least one scale related to quality of life. Anorectal manometry, fecoflowmetry, endoscopic ultrasonography, and pelvic floor muscle strength testing are recommended to be adopted only in clinical trials. After analysis of the latest literature on LARS treatment, a stepwise classification model is established for the standardized clinical management of LARS. Patients with minor LARS can start with first-line treatment, including management of self-behavior with an emphasis on diet modification and medication. Lamosetron, colesevelam hydrochloride, and loperamide are common antidiarrheal agents. Second-line management indicates multi-mode pelvic floor rehabilitation and transanal irrigation. Patients with major LARS should select single or several treatments in second-line management. Refractory LARS can choose antegrade enema, neuromodulation, or colostomy. CONCLUSIONS: In clinical trials of LARS treatment between 2020 and 2022, the eligibility criteria and evaluation system have been variable. Therefore, it is urgent to create a standard for the diagnosis, assessment, and treatment of LARS. Failure to set placebos and differentiate subgroups are limitations of many current LARS studies. Randomized controlled trials comparing diverse therapies and long-term outcomes are absent, as well. Moreover, a new scale needs to be developed to incorporate the patient's perspective and facilitate outpatient follow-up. Though the establishment of a stepwise classification model for LARS treatment here is indispensable, the refinement of the guidelines may be improved by more standardized studies.
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Amino acid binding proteins (AABPs) undergo significant conformational closure in the periplasmic space of Gram-negative bacteria, tightly binding specific amino acid substrates and then initiating transmembrane transport of nutrients. Nevertheless, the possible closure mechanisms after substrate binding, especially long-range signaling, remain unknown. Taking three typical AABPs-glutamine binding protein (GlnBP), histidine binding protein (HisJ) and lysine/arginine/ornithine binding protein (LAOBP) in Escherichia coli (E. coli)-as research subjects, a series of theoretical studies including sequence alignment, Gaussian network model (GNM), anisotropic network model (ANM), conventional molecular dynamics (cMD) and neural relational inference molecular dynamics (NRI-MD) simulations were carried out. Sequence alignment showed that GlnBP, HisJ and LAOBP have high structural similarity. According to the results of the GNM and ANM, AABPs' Index Finger and Thumb domains exhibit closed motion tendencies that contribute to substrate capture and stable binding. Based on cMD trajectories, the Index Finger domain, especially the I-Loop region, exhibits high molecular flexibility, with residues 11 and 117 both being potentially key residues for receptor-ligand recognition and initiation of receptor allostery. Finally, the signaling pathway of AABPs' conformational closure was revealed by NRI-MD training and trajectory reconstruction. This work not only provides a complete picture of AABPs' recognition mechanism and possible conformational closure, but also aids subsequent structure-based design of small-molecule oncology drugs.
Subject(s)
Amino Acids , Escherichia coli , Humans , Escherichia coli/genetics , Escherichia coli/chemistry , Protein Binding , Protein Conformation , Molecular Dynamics Simulation , Lysine , LigandsABSTRACT
Pain and itch coding mechanisms in polymodal sensory neurons remain elusive. MrgprD+ neurons represent a major polymodal population and mediate both mechanical pain and nonhistaminergic itch. Here, we show that chemogenetic activation of MrgprD+ neurons elicited both pain- and itch-related behavior in a dose-dependent manner, revealing an unanticipated compatibility between pain and itch in polymodal neurons. While VGlut2-dependent glutamate release is required for both pain and itch transmission from MrgprD+ neurons, the neuropeptide neuromedin B (NMB) is selectively required for itch signaling. Electrophysiological recordings further demonstrated that glutamate synergizes with NMB to excite NMB-sensitive postsynaptic neurons. Ablation of these spinal neurons selectively abolished itch signals from MrgprD+ neurons, without affecting pain signals, suggesting a dedicated itch-processing central circuit. These findings reveal distinct neurotransmitters and neural circuit requirements for pain and itch signaling from MrgprD+ polymodal sensory neurons, providing new insights on coding and processing of pain and itch.
Subject(s)
Pruritus , Sensory Receptor Cells , Humans , Sensory Receptor Cells/physiology , Pain , Signal Transduction/physiology , GlutamatesABSTRACT
BACKGROUND: Immune therapy is widely used in treating clear cell renal cell carcinoma (ccRCC), yet identifying patient subgroups that are expected to response remains challenging. As complement system can mediate immune effects, including the progression of tumors, a correlation between complement system and immune therapy may exist. METHODS: Based on 11 complement system associated genes (CSAGs) identified from The Cancer Genome Atlas (TCGA), we performed unsupervised clustering and classified the tumors into two different complement system (CS) patterns. The clinical significance, tumor microenvironment (TME), functional enrichment, and immune infiltration were further analyzed. A novel scoring system named CSscore was developed based on the expression levels of the 11 CSAGs. RESULTS: Two distinct CS patterns were identified, classified as Cluster1 and Cluster2, and Cluster1 showed poor clinical outcome. Further analysis of functional enrichment, immune cell infiltration, and genetic variation revealed that Cluster1 had high infiltration of TME immune cells, but also exhibited high immune escape. The novel prognostic model, CSscore could act as an independent prognostic factor and effectively predict patients' prognosis and distinguish the therapeutic efficacy of different immune treatment strategies. The pan-cancer analysis of the CSscore indicates its potential to be further generalized to other types of cancer. CONCLUSIONS: Two distinct CS patterns were identified and were further analyzed in terms of infiltration of TME immune cells and immune escape, providing potential explanations for the impact on prognosis of ccRCC. Our CSscore prognostic model may offer a novel perspective in the management of ccRCC patients, and potentially other types of cancer as well.
Subject(s)
Carcinoma, Renal Cell , Carcinoma , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/genetics , Clinical Relevance , Cluster Analysis , Tumor Microenvironment/genetics , Kidney Neoplasms/geneticsABSTRACT
BACKGROUND: Renal cell carcinoma (RCC) is characterized by a high rate of distant metastasis, which leads to poor prognosis in patients with advanced RCC. PUS10 has been recognized as a member of the pseudouridine synthase family, and recently other functions beyond the synthesis of the RNA modification have been uncovered. However, little is known about its role in diseases such as cancer. METHODS: RT-qPCR, western blot and immunohistochemistry were used to measure the expression of PUS10 in RCC tissues. Transwell assay, wound healing assay, and in vivo metastasis model were conducted to determine the function of PUS10 in RCC progression. MicroRNA sequencing and GEO database were used to screen for the downstream microRNAs of PUS10. RNA immunoprecipitation, dual luciferase reporter assay, immunostaining, and rescue experiments were employed to establish the PUS10/miR-194-5p/nuclear distribution protein C(NUDC)/Cofilin1 axis in RCC migration. Chromatin immunoprecipitation and dual luciferase reporter assay were used to verify its upstream transcriptional regulator. RESULTS: The expression of PUS10 was significantly decreased in RCC tissues, and low expression predicted poor prognosis. In vitro and in vivo experiments showed that PUS10 suppressed RCC migration, which, however, was independent of its classical pseudouridine catalytic function. Mechanically, PUS10 promoted the maturation of miR-194-5p, which sequentially inhibited RCC migration via disrupting NUDC-dependent cytoskeleton. Furthermore, hypoxia and HIF-1 A were found involved in the downregulation of PUS10. CONCLUSION: We unraveled PUS10 restrained RCC migration via the PUS10/miR-194-5p/NUDC/Cofilin1 pathway, which independent of its classical catalytic function. Furthermore, a linkage between the critical tumor microenvironment hallmark with malfunction of the forementioned metastasis inhibition mechanism was presented, as demonstrated by repressed expression of PUS10 due to hypoxia and HIF-1A.
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The roles of Aß low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of SplitCre labeled Aß-LTMRs in this regard. Genetic ablation of SplitCre-Aß-LTMRs increased mechanical pain but not thermosensation in both acute and chronic inflammatory pain conditions, indicating their modality-specific role in gating mechanical pain transmission. Local optogenetic activation of SplitCre-Aß-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a new model, in which Aß-LTMRs play distinctive local and global roles in transmitting and alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a new strategy of global activation plus local inhibition of Aß-LTMRs for treating mechanical hyperalgesia.
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OBJECTIVE: To investigate the correlation among body mass index at onset, clinical features, and prognosis in patients with neuromyelitis optica spectrum disorder. METHOD: This retrospective cohort studied patients with neuromyelitis optica spectrum disorder from January 2015 to January 2022, grouping them by body mass index at onset. Demographics and clinical records were reviewed. Anderson-Gill, Kaplan-Meier, and Cox models evaluated the body mass index's effect on relapse risk and long-term outcomes. RESULTS: Of 246 patients with 799 neuromyelitis optica spectrum disorder attacks study, 36 patients had low, 133 had normal, 77 had high body mass index, with a mean onset age of 40 ± 13 years, and the population was 88% female. The medium follow-up time was 49 months; AQP4-IgG was found in 193 (78%) patients. Onset and relapse of area postrema syndrome were less frequent in patients with a normal body mass index. The annual relapse rate after immunosuppressive therapy was significantly lower in patients with a low body mass index. In the multivariable analysis, statistical correlation still existed between body mass index at onset and risk of relapse (HR = 1.03, 95% CI: 1.03-1.03, P < 0.001), risk of severe attack (HR = 0.92, 95% CI: 0.86-0.98, P = 0.013), risk of visual disability (HR = 0.9, 95% CI: 0.81-1, P = 0.047), and overall risk of disability (HR = 0.89, 95% CI: 0.82-0.98, P = 0.015) after adjusting various variables. INTERPRETATION: Lower body mass index at onset was associated with less frequent relapse but poor prognosis.
Subject(s)
Neuromyelitis Optica , Humans , Female , Adult , Middle Aged , Male , Neuromyelitis Optica/drug therapy , Body Mass Index , Retrospective Studies , Aquaporin 4 , Prognosis , RecurrenceABSTRACT
BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorders (NMOSD) is widely recognized as a CNS demyelinating disease associated with AQP4-IgG (T cell-dependent antibody), and its trigger is still unclear. In addition, although the treatment of NMOSD currently can rely on traditional immunosuppressive and modulating agents, effective methods to predict the efficacy of these therapeutics are lacking. METHODS: In this study, high-throughput T-cell receptor (TCR) sequencing was performed on peripheral blood from 151 pretreatment patients with AQP4-IgG+ NMOSD and 151 healthy individuals. We compared the TCR repertoire of those with NMOSD with that of healthy individuals and identified TCR clones that were significantly enriched in NMOSD. In addition, we treated 28 patients with AQP4-IgG+ NMOSD with immunosuppressants and followed up for 6 months to compare changes in NMOSD-specific TCRs (NMOSD-TCRs) before and after treatment. Moreover, we analyzed transcriptome and single-cell B-cell receptor (BCR) data from public databases and performed T-cell activation experiments using antigenic epitopes of cytomegalovirus (CMV) to further explore the triggers of AQP4-IgG+ NMOSD. RESULTS: Compared with healthy controls, patients with AQP4-IgG+ NMOSD had significantly reduced diversity and shorter CDR3 length of TCRß repertoire. Furthermore, we identified 597 NMOSD-TCRs with a high sequence similarity that have the potential to be used in the diagnosis and prognosis of NMOSD. The characterization of NMOSD-TCRs and pathology-associated clonotype annotation indicated that the occurrence of AQP4-IgG+ NMOSD may be associated with CMV infection, which was further corroborated by transcriptome and single-cell BCR analysis results from public databases and T-cell activation experiments. DISCUSSION: Our findings suggest that the occurrence of AQP4-IgG+ NMOSD may be associated with CMV infection. In conclusion, our study provides new clues to uncover the causative factors of AQP4-IgG+ NMOSD and provides a theoretical foundation for treating and monitoring the disease.
Subject(s)
Cytomegalovirus Infections , Neuromyelitis Optica , Humans , Neuromyelitis Optica/complications , Aquaporin 4 , Autoantibodies , Immunoglobulin GABSTRACT
Background and objectives: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system characterized by simultaneous or consecutive episodes of acute optic neuritis and transverse myelitis. Attacks of NMOSD can result in the accrual of severe visual disability over time. This study aimed to develop and validate prognostic models for visual disability risk within 1, 3, and 5 years. Methods: Medical records of NMOSD patients were retrospectively analyzed. The least absolute shrinkage and selection operator (LASSO) regression algorithm and univariate and multivariate Cox regression analyses were performed to select predictors of visual disability. Two models predicting the probability of visual disability in 1, 3, and 5 years were developed based on different selections and displayed as nomograms. Risk scores were calculated for every patient, and a cut-off point was obtained to recognize patients at high risk. Results: In total, 161 (25.2%) patients developed visual disabilities during the follow-up period. Four visual disability-related factors were selected using LASSO regression: optic neuritis (ON) onset, higher annual relapse rate (ARR) before maintenance therapy, no maintenance immune suppression therapy (IST), and initial severe attack. Three additional predictors were determined using multivariate Cox regression: male sex, age at first onset, and positive AQP4-IgG serology. Discrimination and calibration were satisfied, with concordance indexes (C-index) close to 0.9 in both models. Decision curve analysis showed good clinical usefulness in both models, and Kaplan-Meier curves showed satisfactory discrimination between patients with high risk and low risk by the cut-off points. Conclusion: This study reported predictors of visual disability and generated nomograms. High-risk patients need more active treatment and management to avoid unfavorable outcomes.