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1.
Nat Commun ; 14(1): 1394, 2023 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-36914633

RESUMEN

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.


Asunto(s)
Anticuerpos Biespecíficos , Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Receptor ErbB-2/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico
2.
Lancet Planet Health ; 7(1): e33-e44, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36608946

RESUMEN

BACKGROUND: Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus. METHODS: We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PM2·5, PM10, O3, NO2, SO2, CO, and Pb from the US Environmental Protection Agency spanning the years of both cohorts, and matched values and concentrations to each illness for each participant. We investigated the associations between regional air pollutant concentrations and respiratory illnesses and asthma exacerbations, pulmonary function, and upper airway transcriptional signatures by use of a combination of generalised additive models, case crossover analyses, and generalised linear mixed-effects models. FINDINGS: Of the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PM2·5 and O3 concentrations, were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection. Moreover, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM2·5 with increased epithelial induction of tissue kallikreins, mucus hypersecretion, and barrier functions and O3 with increased type-2 inflammation. INTERPRETATION: Our findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Asma , Humanos , Masculino , Niño , Femenino , Adolescente , Estados Unidos/epidemiología , Contaminantes Atmosféricos/análisis , Estudios Retrospectivos , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Asma/epidemiología , Material Particulado/análisis
4.
Sci Rep ; 11(1): 16460, 2021 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-34385543

RESUMEN

This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell activation and function in patients with relapsed/refractory (RR) multiple myeloma (MM). Immunologic changes in peripheral blood and bone marrow of patients treated with durvalumab as monotherapy or in combination with pomalidomide with/without dexamethasone were characterized by assessing subsets of immune cells and gene signatures to understand the immunomodulatory effect of the treatment. Soluble PD-L1 levels were elevated at screening in patients with RRMM but did not correlate with response to durvalumab combination therapy. Immune cell subsets were increased in peripheral blood during treatment with durvalumab and pomalidomide, and combination therapy induced significant gene expression changes in the MM tumor microenvironment versus durvalumab alone. Estimation of cell populations based on RNA sequencing data revealed increased monocytes, neutrophils, and natural killer cells with the combination therapy, but not with durvalumab alone. Additionally, multiplex immunofluorescence of bone marrow demonstrated that immune populations were different in responders versus nonresponders to durvalumab plus pomalidomide with dexamethasone therapy. Overall, durvalumab effectively blocked soluble PD-L1; however, durvalumab monotherapy was not associated with immunologic changes, which were observed with combination therapy.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Quimioterapia Combinada , Regulación Neoplásica de la Expresión Génica , Humanos , Interferón gamma/metabolismo , Mieloma Múltiple/patología , Receptores de Antígenos de Linfocitos T/genética , Análisis de Secuencia de ARN , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Microambiente Tumoral
5.
Nat Commun ; 12(1): 4385, 2021 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-34282143

RESUMEN

As the capacity for generating large-scale molecular profiling data continues to grow, the ability to extract meaningful biological knowledge from it remains a limitation. Here, we describe the development of a new fixed repertoire of transcriptional modules, BloodGen3, that is designed to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome data. The construction of this repertoire is based on co-clustering patterns observed across sixteen immunological and physiological states encompassing 985 blood transcriptome profiles. Interpretation is supported by customized resources, including module-level analysis workflows, fingerprint grid plot visualizations, interactive web applications and an extensive annotation framework comprising functional profiling reports and reference transcriptional profiles. Taken together, this well-characterized and well-supported transcriptional module repertoire can be employed for the interpretation and benchmarking of blood transcriptome profiles within and across patient cohorts. Blood transcriptome fingerprints for the 16 reference cohorts can be accessed interactively via:  https://drinchai.shinyapps.io/BloodGen3Module/ .


Asunto(s)
Análisis Químico de la Sangre , Sangre , Perfilación de la Expresión Génica/métodos , Transcriptoma , Bacterias , Sangre/inmunología , Análisis Químico de la Sangre/métodos , Análisis por Conglomerados , Biología Computacional/métodos , Redes Reguladoras de Genes , Humanos
6.
JCI Insight ; 4(23)2019 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-31671072

RESUMEN

At diagnosis, most people with type 1 diabetes (T1D) produce measurable levels of endogenous insulin, but the rate at which insulin secretion declines is heterogeneous. To explain this heterogeneity, we sought to identify a composite signature predictive of insulin secretion, using a collaborative assay evaluation and analysis pipeline that incorporated multiple cellular and serum measures reflecting ß cell health and immune system activity. The ability to predict decline in insulin secretion would be useful for patient stratification for clinical trial enrollment or therapeutic selection. Analytes from 12 qualified assays were measured in shared samples from subjects newly diagnosed with T1D. We developed a computational tool (DIFAcTO, Data Integration Flexible to Account for different Types of data and Outcomes) to identify a composite panel associated with decline in insulin secretion over 2 years following diagnosis. DIFAcTO uses multiple filtering steps to reduce data dimensionality, incorporates error estimation techniques including cross-validation and sensitivity analysis, and is flexible to assay type, clinical outcome, and disease setting. Using this novel analytical tool, we identified a panel of immune markers that, in combination, are highly associated with loss of insulin secretion. The methods used here represent a potentially novel process for identifying combined immune signatures that predict outcomes relevant for complex and heterogeneous diseases like T1D.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , Progresión de la Enfermedad , Secreción de Insulina/fisiología , Adolescente , Adulto , Niño , Biología Computacional , Femenino , Humanos , Hipoglucemiantes/farmacología , Inmunoterapia/métodos , Células Secretoras de Insulina/metabolismo , Masculino , Adulto Joven
7.
Nat Immunol ; 20(5): 637-651, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30962590

RESUMEN

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.


Asunto(s)
Asma/inmunología , Redes Reguladoras de Genes/inmunología , Transcriptoma/inmunología , Virosis/inmunología , Adolescente , Asma/genética , Asma/virología , Estudios de Casos y Controles , Niño , Resfriado Común/genética , Resfriado Común/inmunología , Resfriado Común/virología , Femenino , Humanos , Estudios Longitudinales , Masculino , Estudios Prospectivos , Transducción de Señal/genética , Transducción de Señal/inmunología , Virosis/genética , Virosis/virología
8.
Diabetes ; 68(6): 1240-1250, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30894366

RESUMEN

Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell-mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.


Asunto(s)
Linfocitos B/inmunología , Diabetes Mellitus Tipo 1/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Enfermedades Asintomáticas , Autoanticuerpos/inmunología , Subgrupos de Linfocitos B/inmunología , Linfocitos B/efectos de los fármacos , Niño , Progresión de la Enfermedad , Femenino , Humanos , Memoria Inmunológica/inmunología , Interleucina-2/farmacología , Masculino , Fenotipo , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Interleucina-21/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Adulto Joven
9.
Science ; 363(6423)2019 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-30630901

RESUMEN

Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6Chi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.


Asunto(s)
Anemia/fisiopatología , Síndrome de Activación Macrofágica/fisiopatología , Glicoproteínas de Membrana/fisiología , Fagocitos/citología , Transducción de Señal , Receptor Toll-Like 7/fisiología , Receptor Toll-Like 9/fisiología , Animales , Diferenciación Celular , Células Cultivadas , Proteínas de Unión al ADN/fisiología , Inflamación/fisiopatología , Factores Reguladores del Interferón/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , Factor 88 de Diferenciación Mieloide/fisiología , Plasmodium yoelii , Bazo/citología , Trombocitopenia/fisiopatología , Transcriptoma
10.
Front Immunol ; 9: 1408, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29988522

RESUMEN

Understanding the peanut-specific CD4 T cell responses in peanut-allergic (PA) subjects should provide new insights into the development of innovative immunotherapies for the treatment of peanut allergy. Although peanut-specific CD4 T cells have a TH2 profile in PA subjects, the immunogenicity of different Ara h components in eliciting specific CD4 T cell responses and the heterogeneity of these Ara h-reactive TH2 cells remains unclear. In this study, we investigated Ara h 1, 2, 3, 6, and 8-specific T cell responses in PA and sensitized non-peanut-allergic (sNPA) subjects, using the CD154 upregulation assay and the class II tetramer technology. In the PA group, T cells directed against Ara h 1, 2, 3, and 6 have a heterogeneous TH2 phenotype characterized by differential expression of CRTH2, CD27, and CCR6. Reactivity toward these different components was also distinct for each PA subject. Two dominant Ara h 2 epitopes associated with DR1501 and DR0901 were also identified. Frequencies of Ara h-specific T cell responses were also linked to the peanut specific-IgE level. Conversely, low peanut-IgE level in sNPA subjects was associated with a weak or an absence of the allergen-specific T cell reactivity. Ara h 8-specific T cell reactivity was weak in both PA and sNPA subjects. Thus, peanut-IgE level was associated with a heterogeneous Ara h (but not Ara h 8)-specific T cell reactivity only in PA patients. This suggests an important immunogenicity of each Ara h 1, 2, 3, and 6 in inducing peanut allergy. Targeting Ara h 1-, 2-, 3-, and 6-specific effector-TH2 cells can be the future way to treat peanut allergy.

11.
J Allergy Clin Immunol ; 142(6): 1856-1866, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29518416

RESUMEN

BACKGROUND: Childhood asthma in inner-city populations is a major public health burden, and understanding early-life immune mechanisms that promote asthma onset is key to disease prevention. Children with asthma demonstrate a high prevalence of aeroallergen sensitization and TH2-type inflammation; however, the early-life immune events that lead to TH2 skewing and disease development are unknown. OBJECTIVE: We sought to use RNA sequencing of PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma. METHODS: In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years. RESULTS: PBMCs from the cases showed higher levels of expression of natural killer (NK) cell-related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell-like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules, including the key TH2-type cytokines IL9, IL13, and CCL17, as well as a dendritic cell-like gene network, including upregulation of CD1 lipid antigen presentation molecules. The NK cell-like response was reproducible in an independent group of children with later-onset allergic sensitization and asthma and was found to be specific to only those children with both aeroallergen sensitization and asthma. CONCLUSION: These findings provide important mechanistic insight into an early-life immune pathway involved in TH2 polarization, leading to the development of allergic asthma.


Asunto(s)
Alérgenos/inmunología , Antígenos Dermatofagoides/inmunología , Asma/inmunología , Cucarachas/inmunología , Células Asesinas Naturales/inmunología , Animales , Asma/genética , Niño , Preescolar , Femenino , Expresión Génica , Humanos , Inmunoglobulina E/inmunología , Lactante , Recién Nacido , Masculino , Análisis de Secuencia de ARN
12.
J Allergy Clin Immunol ; 142(2): 451-459, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29106997

RESUMEN

BACKGROUND: Respiratory viral infection in early childhood, including that from respiratory syncytial virus (RSV), has been previously associated with the development of asthma. OBJECTIVE: We aimed to determine whether ex vivo RSV infection of bronchial epithelial cells (BECs) from children with asthma would induce specific gene expression patterns and whether such patterns were associated with lung function among BEC donors. METHODS: Primary BECs from carefully characterized children with asthma (n = 18) and matched healthy children without asthma (n = 8) were differentiated at an air-liquid interface for 21 days. Air-liquid interface cultures were infected with RSV for 96 hours and RNA was subsequently isolated from BECs. In each case, we analyzed gene expression using RNA sequencing and assessed differences between conditions by linear modeling of the data. BEC donors completed spirometry to measure lung function. RESULTS: RSV infection of BECs from subjects with asthma, compared with uninfected BECs from subjects with asthma, led to a significant increase in expression of 6199 genes. There was significantly greater expression of 195 genes in BECs from children with asthma and airway obstruction (FEV1/forced vital capacity < 0.85 and FEV1 < 100% predicted) than in BECs from children with asthma without obstruction, or in BECs from healthy children. These specific genes were found to be highly enriched for viral response genes induced in parallel with types I and III interferons. CONCLUSIONS: BECs from children with asthma and with obstructive physiology exhibit greater expression of types I and III interferons and interferon-stimulated genes than do cells from children with normal lung function, and expression of interferon-associated genes correlates with the degree of airway obstruction. These findings suggest that an exaggerated interferon response to viral infection by airway epithelial cells may be a mechanism leading to lung function decline in a subset of children with asthma.


Asunto(s)
Asma/inmunología , Interferón Tipo I/metabolismo , Interferón gamma/metabolismo , Pulmón/fisiología , Mucosa Respiratoria/fisiología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Adolescente , Asma/complicaciones , Células Cultivadas , Niño , Femenino , Humanos , Inmunidad Innata , Interferón Tipo I/genética , Interferón gamma/genética , Masculino , Infecciones por Virus Sincitial Respiratorio/complicaciones , Análisis de Secuencia de ARN , Espirometría , Transcriptoma
13.
Sci Transl Med ; 9(401)2017 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-28768806

RESUMEN

Allergen-specific type 2 helper T (TH2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease-causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic TH2 cell types. We have described a subset of human memory TH2 cells confined to atopic individuals that includes all allergen-specific TH2 cells. These cells are terminally differentiated CD4+ T cells (CD27- and CD45RB-) characterized by coexpression of CRTH2, CD49d, and CD161 and exhibit numerous functional attributes distinct from conventional TH2 cells. Hence, we have denoted these cells with this stable allergic disease-related phenotype as the TH2A cell subset. Transcriptome analysis further revealed a distinct pathway in the initiation of pathogenic responses to allergen, and elimination of these cells is indicative of clinical responses induced by immunotherapy. Together, these findings identify a human TH2 cell signature in allergic diseases that could be used for response-monitoring and designing appropriate immunomodulatory strategies.


Asunto(s)
Hipersensibilidad/inmunología , Células Th2/inmunología , Adolescente , Adulto , Alérgenos/inmunología , Arachis/inmunología , Niño , Preescolar , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Hipersensibilidad/genética , Inmunoterapia , Fenotipo , Subgrupos de Linfocitos T/inmunología , Adulto Joven
14.
Rheumatology (Oxford) ; 56(3): 477-487, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28031441

RESUMEN

Objective: LN is a severe complication of SLE. Non-invasive biomarkers are needed for identifying patients at risk of a renal flare, for differentiating proliferative from non-proliferative forms and for assessing prognoses for LN. Methods: We assessed the link between blood transcriptional signatures and LN using blood samples from patients with biopsy-proven LN, extra-renal SLE flares or quiescent SLE. Healthy controls, and control patients with glomerular diseases or bacterial sepsis were included. Modular repertoire analyses from microarray data were confirmed by PCR. Results: A modular neutrophil signature (upregulation of module M5.15) was present in 65% of SLE patients and was strongly associated with LN. M5.15 activity was stronger in LN than in extra-renal flares (88 vs 17%). M5.15 was neither correlated to IFN modules, nor to SLEDAI or anti-dsDNA antibodies, but moderately to CS dose. M5.15 activity was associated with severity of LN, was stronger when proliferative, and decreased in patients responding to treatment. M5.15 activation was not caused by higher CS dose because it correlated only moderately to neutrophil count and was also observed among quiescent patients. Among quiescent patients, those with a past history of LN had higher M5.15 activity (50 vs 8%). M5.15 activation was present in patients with bacterial sepsis or ANCA-associated vasculitis, but not in patients with other glomerular diseases. Overall, M5.15 activation was associated with past, present or future flares of LN. Conclusion: Modular neutrophil signature could be a biomarker for stratifying LN risk and for monitoring its response to treatment. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00920114.


Asunto(s)
Fallo Renal Crónico/genética , Nefritis Lúpica/genética , Síndrome Nefrótico/genética , Neutrófilos/metabolismo , ARN Mensajero/metabolismo , Transcriptoma , Corticoesteroides/uso terapéutico , Adulto , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Antinucleares/inmunología , Estudios de Casos y Controles , ADN/inmunología , Progresión de la Enfermedad , Femenino , Glomerulonefritis/genética , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/inmunología , Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Masculino , Síndrome Nefrótico/etiología , Síndrome Nefrótico/inmunología , Reacción en Cadena de la Polimerasa , Pronóstico , Sepsis/genética , Sepsis/inmunología , Índice de Severidad de la Enfermedad , Regulación hacia Arriba
15.
Sci Transl Med ; 8(356): 356ra119, 2016 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-27629486

RESUMEN

Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6-specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3. An important determinant of enhanced IL-6 responsiveness in T1D is IL-6 receptor surface expression, which correlated with phospho-STAT3 levels. Further, reduced expression of the IL-6R sheddase ADAM17 in T cells from patients indicated a mechanistic link to enhanced IL-6 responses in T1D. IL-6-induced STAT3 phosphorylation was inversely correlated with time from diagnosis, suggesting that dysregulation of IL-6 signaling may be a marker of early disease. Finally, whole-transcriptome analysis of IL-6-stimulated CD4(+) T cells from patients revealed previously unreported IL-6 targets involved in T cell migration and inflammation, including lymph node homing markers CCR7 and L-selectin. In summary, our study demonstrates enhanced T cell responses to IL-6 in T1D due, in part, to an increase in IL-6R surface expression. Dysregulated IL-6 responsiveness may contribute to diabetes through multiple mechanisms including altered T cell trafficking and indicates that individuals with T1D may benefit from IL-6-targeted therapeutic intervention such as the one that is being currently tested (NCT02293837).


Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Interleucina-6/inmunología , Receptores de Interleucina-6/metabolismo , Linfocitos T/inmunología , Adulto , Autoinmunidad , Estudios de Casos y Controles , Movimiento Celular/genética , Movimiento Celular/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología , Linfocitos T/metabolismo , Investigación Biomédica Traslacional , Adulto Joven
16.
Sci Rep ; 6: 31291, 2016 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-27506615

RESUMEN

Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.


Asunto(s)
Inflamación/sangre , Malaria Falciparum/sangre , Malaria Falciparum/inmunología , Transcriptoma , Adolescente , Citocinas/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Malí , Países Bajos , Plasmodium falciparum , Reacción en Cadena de la Polimerasa , Prueba de Estudio Conceptual , Estudios Prospectivos , Análisis de Secuencia de ARN , Adulto Joven
18.
Am J Gastroenterol ; 111(6): 852-63, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27002799

RESUMEN

OBJECTIVES: The objective of this study was to determine the relationship of serum vitamin D deficiency (VDD) to histologic features of non-alcoholic fatty liver disease (NAFLD), and associated demographic, clinical, laboratory, and transcriptomic data in the well-characterized Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) cohort. METHODS: Serum vitamin D 25(OH)D (VD) was quantified by liquid chromatography-tandem mass spectrometry in 190 adults (>18 years) with biopsy-proven NAFLD. Subjects were categorized according to their level of VD as either sufficient (>30 ng/ml), insufficient (≥20≤30 ng/ml), or deficient (VDD; <20 ng/ml). Multivariable logistic regression was used to investigate the association of VDD and the presence of definite NASH and individual histological features of NAFLD after adjusting for age, sex, race, body mass index, alanine aminotransferase, and diabetes status. Hepatic transcriptomic data was compared between VDD and non-VDD subjects. RESULTS: VDD was present in 55% of subjects and was independently associated with definitive NASH (odds ratio (OR) 3.15, 95% confidence interval (CI), 1.62-6.15, P=0.001), increased lobular inflammation (OR=1.98, 95% CI, 1.08-3.61, P=0.026), more ballooning (OR=2.38, 95% CI, 1.32-4.30, P=0.004), and the presence of fibrosis (OR=2.32, 95% CI, 1.13-4.77, P=0.022). There was a significant inverse relationship between lower levels of serum resistin and increased VD level category (P=0.013). The KRT10, SEMA3B, SNORD3C, ARSD, and IGKV4-1 genes were differentially expressed (false discovery rate <0.05) between VDD and non-VDD subjects. Gene ontology and pathway analysis suggest activation of the mitogen-activated protein kinase and nuclear factor-κB pathways in VDD NAFLD subjects. CONCLUSIONS: VDD is prevalent among US adult NAFLD patients and is independently associated with a definitive diagnosis of NASH and increased histological severity. Novel associations in proinflammatory pathways were identified, which suggest the mechanism for VDD in the pathogenesis of NASH and support dietary and/or lifestyle modifications to increase vitamin D levels in these patients.


Asunto(s)
Sistema de Señalización de MAP Quinasas , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/metabolismo , Biomarcadores/metabolismo , Cromatografía Liquida , Citocinas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Luz Solar , Espectrometría de Masas en Tándem , Deficiencia de Vitamina D/sangre
19.
J Immunol ; 196(5): 2051-2062, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26826243

RESUMEN

Innate lymphoid cells (ILC) are a heterogeneous group of cellular subsets that produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of Ag. In this study, we define distinct patterns of surface marker and cytokine expression among the ILC subsets that may further delineate their migration and function. Most notably, we found that the subset previously defined as group 1 ILC (ILC1) contains CD4(+) CD8(-), CD4(-) CD8(+), and CD4(-) CD8(-) populations. Although all ILC1 subsets shared characteristics with Th1 cells, CD4(+) ILC1 also demonstrated significant phenotypic and functional heterogeneity. We also show that the frequencies of CD4(+) ILC1 and NKp44(+) group 3 ILC, but not CD4(-) ILC1 or group 2 ILC, are increased in the peripheral blood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular pathology, as well as immune dysregulation. Furthermore, we demonstrate that CD4(+) and CD4(-) ILC1 are functionally divergent based on their IL-6Rα expression and that the frequency of IL-6Rα expression on ILC is altered in SSc. The distinct phenotypic and functional features of CD4(+) and CD4(-) ILC1 suggest that they may have differing roles in the pathogenesis of immune-mediated diseases, such as SSc.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Esclerodermia Sistémica/inmunología , Subgrupos de Linfocitos T/inmunología , Separación Celular , Citometría de Flujo , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos
20.
J Transl Med ; 13: 196, 2015 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-26088622

RESUMEN

BACKGROUND: Systems immunology approaches have proven invaluable in translational research settings. The current rate at which large-scale datasets are generated presents unique challenges and opportunities. Mining aggregates of these datasets could accelerate the pace of discovery, but new solutions are needed to integrate the heterogeneous data types with the contextual information that is necessary for interpretation. In addition, enabling tools and technologies facilitating investigators' interaction with large-scale datasets must be developed in order to promote insight and foster knowledge discovery. METHODS: State of the art application programming was employed to develop an interactive web application for browsing and visualizing large and complex datasets. A collection of human immune transcriptome datasets were loaded alongside contextual information about the samples. RESULTS: We provide a resource enabling interactive query and navigation of transcriptome datasets relevant to human immunology research. Detailed information about studies and samples are displayed dynamically; if desired the associated data can be downloaded. Custom interactive visualizations of the data can be shared via email or social media. This application can be used to browse context-rich systems-scale data within and across systems immunology studies. This resource is publicly available online at [Gene Expression Browser Landing Page ( https://gxb.benaroyaresearch.org/dm3/landing.gsp )]. The source code is also available openly [Gene Expression Browser Source Code ( https://github.com/BenaroyaResearch/gxbrowser )]. CONCLUSIONS: We have developed a data browsing and visualization application capable of navigating increasingly large and complex datasets generated in the context of immunological studies. This intuitive tool ensures that, whether taken individually or as a whole, such datasets generated at great effort and expense remain interpretable and a ready source of insight for years to come.


Asunto(s)
Sistema Inmunológico/fisiología , Internet , Estadística como Asunto , Biología de Sistemas , Interpretación Estadística de Datos , Bases de Datos como Asunto , Humanos , Interfaz Usuario-Computador
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