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1.
Front Immunol ; 15: 1437224, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39211051

RESUMO

IL-32 expression is important for pathogen clearance but detrimental in chronic inflammation, autoimmunity, and cancer. T cells are major IL-32 producers in these diseases and key mediators of pathogen and tumor elimination but also autoimmune destruction. However, their contribution to IL-32 biology during immune responses is hardly understood due to several isoforms with divergent inflammatory properties. Here, we identified IL-32ß as the predominant isoform in various T cell subsets of healthy individuals and breast cancer patients with the highest levels detected in intratumoral regulatory T cells. We show that IL-32ß is induced by IL-2 but IL-32ß release requires T Cell Receptor rather than IL2R stimulation. Using inhibitors of protein secretion pathways and serial (ultra)centrifugation of T cell supernatants, we demonstrate that T cells actively secrete IL-32ß unconventionally, as a free protein and, to a minor degree, through exosomes. Thus, our data identify activated T cells as major IL-32ß secretors in health and cancer.


Assuntos
Neoplasias da Mama , Interleucina-2 , Interleucinas , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Humanos , Interleucinas/metabolismo , Interleucina-2/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Feminino , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
2.
Cell Stem Cell ; 30(5): 706-721.e8, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37098346

RESUMO

Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.


Assuntos
Leucemia Mieloide Aguda , Multiômica , Humanos , Leucemia Mieloide Aguda/genética , Diferenciação Celular , Células-Tronco Neoplásicas/metabolismo
3.
J Clin Med ; 10(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33918081

RESUMO

Serological testing is crucial in detection of previous infection and in monitoring convalescent and vaccine-induced immunity. During the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) pandemic, numerous assay platforms have been developed and marketed for clinical use. Several studies recently compared clinical performance of a limited number of serological tests, but broad comparative evaluation is currently missing. Within this study, a panel of 161 sera from SARS-CoV-2 infected, seasonal CoV-infected and SARS-CoV-2 naïve subjects was enrolled to evaluate 16 ELISA/ECLIA-based and 16 LFA-based tests. Specificities of all ELISA/ECLIA-based assays were acceptable and generally in agreement with the providers' specifications, but sensitivities were lower as specified. Results of the LFAs were less accurate as compared to the ELISAs, albeit with some exceptions. We found a sporadic unequal immune response for different antigens and thus recommend the use of a nucleocapsid protein (N)- and spike protein (S)-based test combination when maximal sensitivity is necessary. Finally, the quality of the immune response in terms of neutralization should be tested using S-based IgG tests.

4.
Infection ; 49(1): 75-82, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32827125

RESUMO

OBJECTIVE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges national health systems and the global economy. Monitoring of infection rates and seroprevalence can guide public health measures to combat the pandemic. This depends on reliable tests on active and former infections. Here, we set out to develop and validate a specific and sensitive enzyme linked immunosorbent assay (ELISA) for detection of anti-SARS-CoV-2 antibody levels. METHODS: In our ELISA, we used SARS-CoV-2 receptor-binding domain (RBD) and a stabilized version of the spike (S) ectodomain as antigens. We assessed sera from patients infected with seasonal coronaviruses, SARS-CoV-2 and controls. We determined and monitored IgM-, IgA- and IgG-antibody responses towards these antigens. In addition, for a panel of 22 sera, virus neutralization and ELISA parameters were measured and correlated. RESULTS: The RBD-based ELISA detected SARS-CoV-2-directed antibodies, did not cross-react with seasonal coronavirus antibodies and correlated with virus neutralization (R2 = 0.89). Seroconversion started at 5 days after symptom onset and led to robust antibody levels at 10 days after symptom onset. We demonstrate high specificity (99.3%; N = 1000) and sensitivity (92% for IgA, 96% for IgG and 98% for IgM; > 10 days after PCR-proven infection; N = 53) in serum. CONCLUSIONS: With the described RBD-based ELISA protocol, we provide a reliable test for seroepidemiological surveys. Due to high specificity and strong correlation with virus neutralization, the RBD ELISA holds great potential to become a preferred tool to assess thresholds of protective immunity after infection and vaccination.


Assuntos
Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , COVID-19/diagnóstico , Ensaio de Imunoadsorção Enzimática/normas , Testes de Neutralização/normas , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Neutralizantes/sangue , Antígenos Virais/química , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Estudos Transversais , Humanos , Soros Imunes/química , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Domínios Proteicos , Sensibilidade e Especificidade , Glicoproteína da Espícula de Coronavírus/química
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