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BACKGROUND: Spermatogenesis is a highly regulated and complex process in which DNA methylation plays a crucial role. This study aimed to explore the differential methylation profiles in sperm DNA between patients with asthenospermia (AS) and healthy controls (HCs), those with oligoasthenospermia (OAS) and HCs, and patients with AS and those with OAS. RESULTS: Semen samples and clinical data were collected from five patients with AS, five patients with OAS, and six age-matched HCs. Reduced representation bisulfite sequencing (RRBS) was performed to identify differentially methylated regions (DMRs) in sperm cells among the different types of patients and HCs. A total of 6520, 28,019, and 16,432 DMRs were detected between AS and HC, OAS and HC, and AS and OAS groups, respectively. These DMRs were predominantly located within gene bodies and mapped to 2868, 9296, and 9090 genes in the respective groups. Of note, 12, 9, and 8 DMRs in each group were closely associated with spermatogenesis and male infertility. Furthermore, BDNF, SMARCB1, PIK3CA, and DDX27; RBMX and SPATA17; ASZ1, CDH1, and CHDH were identified as strong differentially methylated candidate genes in each group, respectively. Meanwhile, the GO analysis of DMR-associated genes in the AS vs. HC groups revealed that protein binding, cytoplasm, and transcription (DNA-templated) were the most enriched terms in the biological process (BP), cellular component (CC), and molecular function (MF), respectively. Likewise, in both the OAS vs. HC and AS vs. OAS groups, GO analysis revealed protein binding, nucleus, and transcription (DNA-templated) as the most enriched terms in BP, CC, and MF, respectively. Finally, the KEGG analysis of DMR-annotated genes and these genes at promoters suggested that metabolic pathways were the most significantly associated across all three groups. CONCLUSIONS: The current study results revealed distinctive sperm DNA methylation patterns in the AS vs. HC and OAS vs. HC groups, particularly between patients with AS and those with OAS. The identification of key genes associated with spermatogenesis and male infertility in addition to the differentially enriched metabolic pathways may contribute to uncovering the potential pathogenesis in different types of abnormal sperm parameters.
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Astenozoospermia , Metilación de ADN , Oligospermia , Humanos , Masculino , Astenozoospermia/genética , Adulto , Oligospermia/genética , Espermatozoides/metabolismo , Espermatogénesis/genética , Estudios de Casos y Controles , Epigénesis GenéticaRESUMEN
At the end of 2022, a huge tide of SARS-CoV-2 infection mainly Omicron BA.4/5 developed in China. Multiple myeloma (MM) patients suffered cancer deterioration and mortality from COVID-19, yet profound analyses of Omicron variants-induced immunity function are scarce. We presented a longitudinal study in 218 MM patients and 73 healthy controls (HCs), reporting the prognostic factors and dynamic humoral and cellular immune responses. Neutralizing antibody and interferon γ ELISpot assay of SARS-CoV-2 was tested at three time points: 2-4, 8-10, and 14-16 weeks after infections. Our data showed older age, active MM, relapsed/refractory MM (R/RMM), immunotherapy, comorbidity, and non-vaccination were risk factors associated with hospitalization. Severe humoral immunity impairment within 2-4 weeks was especially seen in patients with unvaccinated, older age, immunotherapy, R/RMM and comorbidities, while T-cell response was relatively intact. Although antibodies of Omicron variants reached positive levels in MM patients at 8-10 weeks, half lost effective antibody protection at 14-16 weeks. However, most seronegative patients (76.2% at 2-4 weeks, 83.3% at 8-10 weeks) could develop effective T-cell response. Notably, the inactivated wild-type vaccinated patients exhibited weaker humoral and cellular immunity only at 2-4 weeks, escalating to similar levels as those in HCs later. Our findings indicate impairment of humoral immunity at acute-phase after infection is the major factor correlated with hospitalization. One-month suspension of immune therapy is suggested to prevent serious infection. These results confirm the value of inactivated vaccine, but indicate the need for additional booster at 14-16 weeks after infection for high-risk MM population.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Inmunidad Humoral , Mieloma Múltiple , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/virología , COVID-19/epidemiología , Mieloma Múltiple/inmunología , SARS-CoV-2/inmunología , Masculino , Persona de Mediana Edad , Femenino , Inmunidad Humoral/inmunología , Anciano , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Pronóstico , Estudios Longitudinales , China/epidemiología , Adulto , Anciano de 80 o más Años , Inmunidad CelularRESUMEN
Viral communities exist in a variety of ecosystems and play significant roles in mediating biogeochemical processes, whereas viruses inhabiting strongly alkaline geochemical systems remain underexplored. In this study, the viral diversity, potential functionalities, and virus-host interactions in a strongly alkaline environment (pH = 10.4-12.4) exposed to the leachates derived from the serpentinization-like reactions of smelting slags were investigated. The viral populations (e.g., Herelleviridae, Queuovirinae, and Inoviridae) were closely associated with the dominating prokaryotic hosts (e.g., Meiothermus, Trueperaceae, and Serpentinomonas) in this ultrabasic environment. Auxiliary metabolic genes (AMGs) suggested that viruses may enhance hosts' fitness by facilitating cofactor biosynthesis, hydrogen metabolism, and carbon cycling. To evaluate the activity of synthesis of essential cofactor vitamin B9 by the viruses, a viral folA (vfolA) gene encoding dihydrofolate reductase (DHFR) was introduced into a thymidine-auxotrophic strain Escherichia coli MG1655 ΔfolA mutant, which restored the growth of the latter in the absence of thymidine. Notably, the homologs of the validated vDHFR were globally distributed in the viromes across various ecosystems. The present study sheds new light on the unique viral communities in hyperalkaline ecosystems and their potential beneficial impacts on the coexisting microbial consortia by supplying essential cofactors. IMPORTANCE: This study presents a comprehensive investigation into the diversity, potential functionalities, and virus-microbe interactions in an artificially induced strongly alkaline environment. Functional validation of the detected viral folA genes encoding dihydrofolate reductase substantiated the synthesis of essential cofactors by viruses, which may be ubiquitous, considering the broad distribution of the viral genes associated with folate cycling.
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There is a paucity of data on hybrid immunity (vaccination plus breakthrough infection [BI]), especially cell-mediated responses to Omicron among immunosuppressed patients. We aim to investigate humoral and cellular responses to Omicron BA.4/5 among people living with HIV (PLWH) with/without BIs, the most prevalent variant of concern after the reopening of China. Based on our previous study, we enrolled 77 PLWH with baseline immune status of severe acute respiratory syndrome coronavirus 2 specific antibodies after inactivated vaccination. "Correlates of protection," including serological immunoassays, T cell phenotypes and memory B cells (MBC) were determined in PLWH without and with BI, together with 16 PLWH with reinfections. Higher inhibition rate of neutralizing antibodies (NAb) against BA.4/5 was elicited among PLWH with BI than those without. Omicron-reactive IL4+ CD8+ T cells were significantly elevated in PLWH experienced postvaccine infection contrasting with those did not. NAb towards wild type at baseline was associated with prolonged negative conversion time for PLWH whereas intermediate MBCs serve as protecting effectors. We uncovered that hybrid immunity intensified more protection on BA.4/5 than vaccination did. Strengthened surveillance on immunological parameters and timely clinical intervention on PLWH deficient in protection would reduce the severity and mortality in the context of coexistence with new Omicron subvariants.
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Infección Irruptiva , Linfocitos T CD8-positivos , Humanos , Estudios de Seguimiento , Anticuerpos Neutralizantes , Anticuerpos Antivirales , InmunidadRESUMEN
OBJECTIVE: The current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred. METHOD: A cross-sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared. RESULT: Patients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO. CONCLUSION: This present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis.
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COVID-19 , Enfermedad Crítica , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Humanos , COVID-19/inmunología , COVID-19/mortalidad , COVID-19/epidemiología , Masculino , Femenino , China/epidemiología , SARS-CoV-2/inmunología , Persona de Mediana Edad , Estudios Transversales , Adulto , Anciano , Anticuerpos Antivirales/sangre , Citocinas/sangre , Citocinas/inmunología , Inflamación/inmunologíaRESUMEN
Various isomers have been developed to regulate the morphology and reduce defects in state-of-the-art perovskite solar cells. To insight the structure-function-effect correlations for the isomerization of thiourea derivatives on the performance of the perovskite solar cells (PSCs), we developed two thiourea derivatives [(3,5-dichlorophenyl)amino]thiourea (AT) and N-(3,5-dichlorophenyl)hydrazinecarbothioamide (HB). Supported by experimental and calculated results, it was found that AT can bind with undercoordinated Pb2+ defect through synergistic interaction between N1 and C=S group with a defect formation energy of 1.818 eV, which is much higher than that from the synergistic interaction between two -NH- groups in HB and perovskite (1.015 eV). Moreover, the stronger interaction between AT and Pb2+ regulates the crystallization process of perovskite film to obtain a high-quality perovskite film with high crystallinity, large grain size, and low defect density. Consequently, the AT-treated FACsPbI3 device engenders an efficiency of 25.71% (certified as 24.66%), which is greatly higher than control (23.74%) and HB-treated FACsPbI3 devices (25.05%). The resultant device exhibits a remarkable stability for maintaining 91.0% and 95.2% of its initial efficiency after aging 2000 h in air condition or tracking at maximum power point for 1000 h, respectively.
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Systemic sclerosis (SSc) is a systemic autoimmune disorder that leads to vasculopathy and tissue fibrosis. A lack of reliable biomarkers has been a challenge for clinical diagnosis of the disease. We employed a protein array-based approach to identify and validate SSc-specific autoantibodies. Phase I involved profiled autoimmunity using human proteome microarray (HuProt arrays) with 90 serum samples: 40 patients with SSc, 30 patients diagnosed with autoimmune diseases, and 20 healthy subjects. In Phase II, we constructed a focused array with candidates identified antigens and used this to profile a much larger cohort comprised of serum samples. Finally, we used a western blot analysis to validate the serum of validated proteins with high signal values. Bioinformatics analysis allowed us to identify 113 candidate autoantigens that were significantly associated with SSc. This two-phase strategy allowed us to identify and validate anti-small nuclear ribonucleoprotein polypeptide A (SNRPA) as a novel SSc-specific serological biomarker. The observed positive rate of anti-SNRPA antibody in patients with SSc was 11.25%, which was significantly higher than that of any disease control group (3.33%) or healthy controls (1%). In conclusion, anti-SNRPA autoantibody serves as a novel biomarker for SSc diagnosis and may be promising for clinical applications.
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Enfermedades Autoinmunes , Esclerodermia Sistémica , Humanos , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/metabolismo , Autoanticuerpos , Biomarcadores/metabolismo , Autoinmunidad , PéptidosRESUMEN
Understanding autoimmunity to endogenous proteins is crucial in diagnosing and treating autoimmune diseases. In this work, we developed a user-friendly AAgAtlas portal (http://biokb.ncpsb.org.cn/aagatlas_portal/index.php#), which can be used to search for 8045 non-redundant autoantigens (AAgs) and 47 post-translationally modified AAgs against 1073 human diseases that are prioritized by a credential score developed by multisource evidence. Using AAgAtlas, the immunogenic properties of human AAgs was systematically elucidated according to their genetic, biophysical, cytological, expression profile, and evolutionary characteristics. The results indicated that human AAgs are evolutionally conserved in protein sequence and enriched in three hydrophilic and polar amino acid residues (K, D, and E) that are located at the protein surface. AAgs are enriched in proteins that are involved in nucleic acid binding, transferase, and the cytoskeleton. Genome, transcriptome, and proteome analyses further indicated that AAb production is associated with gene variance and abnormal protein expression related to the pathological activities of different tumors. Collectively, our data outlines the hallmarks of human AAgs that facilitate the understanding of humoral autoimmunity and the identification of biomarkers of human diseases.
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Autoantígenos , Enfermedades Autoinmunes , Humanos , Autoantígenos/genética , Autoanticuerpos , Enfermedades Autoinmunes/genética , Autoinmunidad , Secuencia de AminoácidosRESUMEN
Behçet's disease (BD) is a multisystemic chronic vasculitis. Sustained and enhanced immune responses were reportedly associated with active BD. Although genetic polymorphisms increase development risk, genetic factors alone cannot account for BD development, suggesting the involvement of exogenous factors. Also, how various infectious agents promote BD in high-risk populations is not fully understood. In this review, we summarized the current findings on the associations of infectious agents with BD pathogenesis. The review also highlights the potential microbial risk factors and their pathogenic role in BD progression. Interactions between genetic and infectious risk factors was also discussed. Furthermore, evidence implied that after the eradication of infectious agents, BD symptoms and recurrence decreased, thus highlighting that combined use of antibiotics may be an effective therapy for BD. Finally, we summarized the main limitation of the current related studies, providing valuable insights and a basis for future studies on BD pathogenic factors.
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Síndrome de Behçet , Vasculitis , Humanos , Vasculitis/complicaciones , Factores de RiesgoRESUMEN
Neuro-Behçet's disease (NBD) contributes to poor prognosis in BD patients which lacks reliable laboratory biomarkers in assessing intrathecal injury. This study aimed to determine the diagnostic value of myelin basic protein (MBP), an indicator of central nervous system (CNS) myelin damage, in NBD patients and disease controls. Paired samples of cerebrospinal fluid (CSF) and serum MBP were measured using ELISA, while IgG and Alb were routinely examined before the MBP index was developed. CSF and serum MBP in NBD were significantly higher than in NIND, which could distinguish NBD from NIND with a specificity exceeding 90%, moreover, they could also be excellent discriminators for acute NBD and chronic progressive ones. We found positive linkage between MBP index and IgG index. Serial MBP monitoring confirmed serum MBP's sensitive response to disease recurrences and drug effects, whereas MBP index suggests relapses prior to clinical symptoms. MBP has high diagnostic yield for NBD with demyelination and identifies CNS pathogenic processes before imaging or clinical diagnosis.
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Síndrome de Behçet , Proteína Básica de Mielina , Humanos , Síndrome de Behçet/sangre , Síndrome de Behçet/diagnóstico , Biomarcadores/sangre , Biomarcadores/metabolismo , Sistema Nervioso Central/metabolismo , Inmunoglobulina G , Proteína Básica de Mielina/sangre , Proteína Básica de Mielina/metabolismoRESUMEN
Relapsing polychondritis (RP) is a rare inflammatory disease with significant individual heterogeneity that involves systemic organs. The diagnosis of RP mainly depends on the clinical manifestations; currently, there are no molecular biomarkers routinely evaluated in clinical practice. Biomarkers have diagnostic or monitoring values and can predict response to treatment or the disease course. Over the years, many biomarkers have been proposed to facilitate diagnosis and prognosis. Unfortunately, ideal biomarkers to diagnose RP have not yet been discovered. Most of the molecular biomarkers in RP are immunological biomarkers, with autoantibodies and proteins related to cartilage damage in the blood being the most common. Alterations in some genes (HLA typing and UBA1 somatic mutation) were detected in patients with RP, which could serve as a potential biomarker for the diagnosis of RP. Moreover, proinflammatory cytokines and lymphocyte levels, and certain laboratory tests, have certain values of RP diagnosis and disease activity assessment but lack specificity and sensitivity. This review describes the different types of biomarkers and their clinical correlation with respect to the diagnosis of RP and disease activity. Research on biomarkers and disease pathology is ongoing to identify the ideal biomarkers that are sensitive and specific for RP.
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Policondritis Recurrente , Humanos , Policondritis Recurrente/diagnóstico , Policondritis Recurrente/tratamiento farmacológico , Policondritis Recurrente/patología , Autoanticuerpos , Citocinas , Biomarcadores , PronósticoRESUMEN
This study aimed to investigate the immunogenicity to SARS-CoV-2 and evasive subvariants BA.4/5 in people living with HIV (PLWH) following a third booster shot of inactivated SARS-CoV-2 vaccine. We conducted a cross-sectional study in 318 PLWH and 241 healthy controls (HC) using SARS-CoV-2 immunoassays. Vaccine-induced immunological responses were compared before and after the third dose. Serum levels of IgG anti-RBD and inhibition rate of NAb were significantly elevated at the "post-third dose" sampling time compared with the pre-third dose in PLWH, but were relatively decreased in contrast with those of HCs. Induced humoral and cellular responses attenuated over time after triple-dose vaccination. The neutralizing capacity against BA.4/5 was also intensified but remained below the positive inhibition threshold. Seropositivity of SARS-CoV-2-specific antibodies in PLWH was prominently lower than that in HC. We also identified age, CD4 cell counts, time after the last vaccination, and WHO staging type of PLWH as independent factors associated with the seropositivity of antibodies. PLWH receiving booster shot of inactivated vaccines generate higher antibody responses than the second dose, but lower than that in HCs. Decreased anti-BA.4/5 responses than that of WT impede the protective effect of the third dose on Omicron prevalence.
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COVID-19 , Infecciones por VIH , Humanos , Vacunas contra la COVID-19 , Estudios Transversales , COVID-19/prevención & control , SARS-CoV-2 , Anticuerpos Antivirales , Vacunas de Productos Inactivados , Anticuerpos NeutralizantesRESUMEN
Herein, we report a Pt-decorated Ti3C2Tx/TiO2gas sensor for the enhanced NH3sensing response at room temperature. Firstly, the TiO2nanosheets (NSs) arein situgrown onto the two-dimensional (2D) Ti3C2Txby hydrothermal treatment. Similar to Ti3C2Txsensor, the Ti3C2Tx/TiO2sensor has a positive resistance variation upon exposure to NH3, but with slight enhancement in response. However, after the loading of Pt nanoparticles (NPs), the Pt-Ti3C2Tx/TiO2sensor shows a negative response with significantly improved NH3sensing performance. The shift in response direction indicates that the dominant sensing mechanism has changed under the sensitization effect of Pt NPs. At room temperature, the response of Pt-Ti3C2Tx/TiO2gas sensor to 100 ppm NH3is about 45.5%, which is 13.8- and 10.8- times higher than those of Ti3C2Txand Ti3C2Tx/TiO2gas sensors, respectively. The experimental detection limit of the Pt-Ti3C2Tx/TiO2gas sensor to detect NH3is 10 ppm, and the corresponding response is 10.0%. In addition, the Pt-Ti3C2Tx/TiO2gas sensor shows the fast response/recovery speed (23/34 s to 100 ppm NH3), high selectivity and good stability. Considering both the response value and the response direction, the corresponding gas-sensing mechanism is also deeply discussed. This work is expected to shed a new light on the development of noble metals decorated MXene-metal oxide gas sensors.
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OBJECTIVE: The current study evaluated the diagnostic performance of serum (1,3)-beta-D Glucan (BDG) in differentiating PJP from P. jirovecii-colonization in HIV-uninfected patients with P. jirovecii PCR-positive results. METHODS: This was a single-center retrospective study between 2019 and 2021. The diagnosis of PJP was based on the following criteria: detection of P. jirovecii in sputum or BAL specimen by qPCR or microscopy; Meet at least two of the three criteria: (1) have respiratory symptoms of cough and/or dyspnea, hypoxia; (2) typical radiological picture findings; (3) receiving a complete PJP treatment. After exclusion, the participants were divided into derivation and validation cohorts. The derivation cohort defined the cut-off value of serum BDG. Then, it was verified using the validation cohort. RESULTS: Two hundred and thirteen HIV-uninfected patients were enrolled, with 159 PJP and 54 P. jirovecii-colonized patients. BDG had outstanding specificity, LR, and PPV for PJP in both the derivation (90.00%, 8.900, and 96.43%) and the validation (91.67%, 9.176, and 96.30%) cohorts at ≥ 117.7 pg/mL. However, it had lower sensitivity and NPV in the derivation cohort (89.01% and 72.97%), which was even lower in the validation cohort (76.47% and 57.89%). Of note, BDG ≥ 117.7 pg/mL has insufficient diagnostic efficacy for PJP in patients with lung cancer, interstitial lung disease (ILD) and nephrotic syndrome. And although lymphocytes, B cells, and CD4+ T cells in PJP patients were significantly lower than those in P. jirovecii-colonized patients, the number and proportion of peripheral blood lymphocytes did not affect the diagnostic efficacy of serum BDG. CONCLUSIONS: Serum BDG ≥ 117.7 pg/mL could effectively distinguish P. jirovecii-colonization from infection in qPCR-positive HIV-uninfected patients with infectious diseases, solid tumors (excluding lung cancer), autoimmune or inflammatory disorders, and hematological malignancies. Of note, for patients with lung cancer, ILD, and nephrotic diseases, PJP should be cautiously excluded at BDG < 117.7 pg/mL.
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Infecciones por VIH , Enfermedades Pulmonares Intersticiales , Neoplasias Pulmonares , Pneumocystis carinii , Neumonía por Pneumocystis , beta-Glucanos , Humanos , Neumonía por Pneumocystis/diagnóstico , Pneumocystis carinii/genética , Glucanos , Estudios Retrospectivos , Infecciones por VIH/complicacionesRESUMEN
To identify novel autoantibodies of Takayasu arteritis (TAK) using HuProt array-based approach, a two-phase approach was adopted. In Phase I, serum samples collected from 40 TAK patients, 15 autoimmune disease patients, and 20 healthy subjects were screened to identify TAK-specific autoantibodies using human protein (HuProt) arrays. In phase II, the identified candidate autoantibodies were validated with TAK-focused arrays using an additional cohort comprised of 109 TAK patients, 110 autoimmune disease patients, and 96 healthy subjects. Subsequently, the TAK-specific autoantibodies validated in phase II were further confirmed using western blot analysis. We identified and validated eight autoantibodies as potential TAK-specific diagnostic biomarkers, including anti-SPATA7, -QDPR, -SLC25A2, -PRH2, -DIXDC1, -IL17RB, -ZFAND4, and -NOLC1 antibodies, with AUC of 0.803, 0.801, 0.780, 0.696, 0.695, 0.678, 0.635, and 0.613, respectively. SPATA7 could distinguish TAK from healthy and disease controls with 73.4% sensitivity at 85.4% specificity, while QDPR showed 71.6% sensitivity at 86.4% specificity. SLC25A22 showed the highest sensitivity of 80.7%, but at lower specificity of 67.0%. In addition, PRH2, IL17RB, and NOLC1 showed good specificities of 88.3%, 85.9%, and 86.9%, respectively, but at lower sensitivities (<50%). Finally, DIXDC1 and ZFAND4 showed moderate performance as compared with the other autoantibodies. Using a decision tree model, we could reach a specificity of 94.2% with AUC of 0.843, a significantly improved performance as compared with that by each individual biomarker. The performances of three autoantibodies, namely anti-SPATA7, -QDPR, and -PRH2, were successfully confirmed with western blot analysis. Using this two-phase strategy, we identified and validated eight novel autoantibodies as TAK-specific biomarker candidates, three of which could be readily adopted in a clinical setting.
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Autoanticuerpos/sangre , Arteritis de Takayasu/sangre , Adulto , Autoantígenos/inmunología , Biomarcadores/sangre , Proteínas de Unión al ADN/inmunología , Árboles de Decisión , Dihidropteridina Reductasa/inmunología , Femenino , Humanos , Masculino , Análisis por Matrices de Proteínas , Proteínas Salivales Ricas en Prolina/inmunología , Arteritis de Takayasu/inmunología , Adulto JovenRESUMEN
OBJECTIVES: An immunoglobulin G4 (IgG4) level above 1350 mg/L is one of the comprehensive criteria for the diagnosis of IgG4-related disease (IgG4-RD). The purpose of this study was to evaluate the differences in IgG4 levels determined using reagents from two main manufacturers and their concordance with clinical diagnosis. METHODS: IgG4 levels were measured in 309 patients, including 146, 40, 42, 41, and 40 patients with untreated IgG4-RD, pancreatic cancer, primary Sjogren syndrome, systemic lupus erythematosus, and idiopathic retroperitoneal fibrosis, respectively, and 141 healthy controls. The results obtained using the Binding Site and Siemens reagents were compared in patients with IgG4-RD. RESULTS: The serum IgG4 level measured using the Siemens reagent was almost two times that measured using the Binding Site reagent. The rate of IgG4-negative patients, which was 19.9% based on measurement using the Binding Site reagent, was only 4.8% based on measurement using the Siemens reagent (p < .001). CONCLUSIONS: There were significant differences in serum IgG4 levels based on commonly used reagents from different manufacturers. The IgG4 cut-off level of 1350 mg/L was not suitable for all detection reagents. Clinicians and patients should be cognizant of these differences associated with the specific detection reagents when evaluating the test results.
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Enfermedad Relacionada con Inmunoglobulina G4 , Fibrosis Retroperitoneal , Humanos , Inmunoglobulina G , Fibrosis Retroperitoneal/diagnósticoRESUMEN
BACKGROUND: The pathogenesis of immunoglobulin G4-related disease (IgG4-RD) remains unclear. IgG4-RD often mimics other diseases, including pancreatic cancer (PC) and Sjogren's syndrome (SS), which may easily lead to misdiagnosis. This study was performed to explore the metabolite changes and potential biomarkers of IgG4-RD and other misdiagnosed diseases. METHODS: Untargeted liquid chromatography-tandem mass spectrometry metabolomics profiling of plasma samples from a cohort comprising healthy controls (HCs) and patients with IgG4-RD (n = 87), PC (n = 33), and SS (n = 31) was performed. A random forest machine learning model was used to verify the relevance of the identified metabolites in the diagnosis of different diseases and the prediction of disease prognosis. RESULTS: The ATP-binding cassette transporter pathway was found to be most closely related to IgG4-RD, which was significantly up-regulated in the IgG4-RD group than in all the matched groups. Five metabolites were proved to be valuable biomarkers for IgG4-RD. Caftaric acid, maltotetraose, D-glutamic acid, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphoserine, and hydroxyproline were useful in distinguishing between IgG4-RD, PC, SS, and HC [area under the curve (AUC) = 1]. A combination of phenylalanine betaine, 1-(1z-hexadecenyl)-sn-glycero-3-phosphocholine, Pi 40:8, uracil, and N1-methyl-2-pyridone-5-carboxamide showed a moderate value in predicting relapse in patients with IgG4-RD (AUC = 0.8). CONCLUSIONS: Our findings revealed the metabolite changes of IgG4-RD and provide new insights for deepening our understanding of IgG4-RD despite the lack of validation in external cohorts. Metabolomic biomarkers have significance in the clinical diagnosis and disease prognosis of IgG4-RD.
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Enfermedad Relacionada con Inmunoglobulina G4 , Neoplasias Pancreáticas , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/metabolismo , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Pronóstico , Biomarcadores , Neoplasias Pancreáticas/diagnósticoRESUMEN
Innate lymphoid cells (ILCs), a novel group of innate immune cells, play a key role in the early immune response via rapidly reacting to signals expressed by tissue-resident cells. ILCs contribute to some autoimmune diseases. We aim to investigate the proportions of circulating ILC subgroups in patients with primary biliary cholangitis (PBC). Overall, 48 patients with PBC and 24 healthy controls (HCs) were enrolled. Circulating ILCs and cytokine production were detected by flow cytometry. The proportions of total ILCs, ILC precursors (ILCPs) and ILCP/ILC2 ratio increased and that of ILC2s decreased in patients with PBC. ILC2 proportion was negatively correlated with gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The proportion of ILCPs and ILCP/ILC2 ratio were positively correlated with alkaline phosphatase, GGT, ALT and AST. ILC2 proportion was significantly decreased in the ursodeoxycholic acid (UDCA) -non-responder group compared with the UDCA-responder group, whereas the proportion of ILCPs and ILCP/ILC2 were ratio significantly increased. The proportions of CD38+ ILC2s, CD38+ ILCPs, CD45RO+ ILC2s and CD45RO+ ILCPs were significantly higher in patients with PBC than in HCs. Levels of IL-17A producing ILCs were higher in patients with PBC than in HCs. PBC is accompanied by alterations in circulating ILCs. The proportions of ILC2s, ILCPs, and ILCP/ILC2 ratio were associated with the PBC disease activity. The proportions of ILCPs and ILCP/ILC2 ratio may reflect the UDCA treatment failure in patients with PBC. ILC2s and ILCPs from patients with PBC get activated, these cells may be involved in the pathogenesis of PBC.
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Inmunidad Innata , Cirrosis Hepática Biliar , Citometría de Flujo , Humanos , Cirrosis Hepática Biliar/tratamiento farmacológico , LinfocitosRESUMEN
BACKGROUND: Primary biliary cholangitis (PBC) is an autoimmune disease. CD8 + T cell (CTLs) cytotoxicity played a crucial rule in of PBC with unclear detailed pathogenesis. AIMS: The role of the programmed death-1 (PD-1) pathway in CD8 + T cell cytotoxicity in patients with PBC was determined. METHODS: We recruited 69 patients with PBC and 57 healthy controls (HCs). PD-1 pathway in peripheral CD8 + T cells and related cytokines were detected, and gene expression levels were detected. Immunofluorescence staining of PD-1/PD-L1 was performed on liver tissue. PD-1 ± CTLs were cocultured with human intrahepatic biliary epithelial cells (HiBECs) to measure CTL cytotoxicity, proliferation and cytokine levels and HiBEC apoptosis. The upstream signaling pathway of PD-1 was detected. RESULTS: PBC patients exhibited Tbet gene upregulation and PD-1 downregulation in CTLs, with PD-1 expression reduced in CTLs and PD-L1 reduced in the liver portal region relative to HCs. Higher plasma IL-10, interferon-γ and transforming growth factor-ß concentrations were observed in the PBC group than the HC group. In CTL and HiBEC coculture experiment, compared with PD-1- CTLs, PD-1 + CTLs exhibited weaker cytotoxicity, less proliferation and lower cytokine production. When the system was blocked by anti-PD-1 antibodies, these effects were antagonized. CONCLUSIONS: PD-1 expression in CD8 + T cells decreased, and PD-1 pathway-related cytokines changed in patients with PBC. PD-1/PD-L1 pathway silencing increased CD8 + T cell proliferation, related cytokine production and CTL cytotoxic effects on HiBECs in coculture experiment. The PD-1/PD-L1 pathway might represent an important pathway in the immunological mechanism underlying PBC.
Asunto(s)
Antígeno B7-H1 , Cirrosis Hepática Biliar , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos , Citocinas/metabolismo , Regulación hacia Abajo , Humanos , Cirrosis Hepática Biliar/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.