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1.
Immunity ; 53(2): 353-370.e8, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32735845

RESUMEN

The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.


Asunto(s)
Antígenos CD34/metabolismo , Células Dendríticas/citología , Hematopoyesis/fisiología , Factores Reguladores del Interferón/metabolismo , Animales , Antígenos CD1/metabolismo , Línea Celular , Linaje de la Célula/inmunología , Células Dendríticas/inmunología , Glicoproteínas/metabolismo , Células Madre Hematopoyéticas/citología , Humanos , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Ratones , Receptores Inmunológicos/metabolismo
2.
Blood ; 140(17): 1875-1890, 2022 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-35839448

RESUMEN

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.


Asunto(s)
Proteína de la Leucemia Mieloide-Linfoide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Epigénesis Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Genes Reguladores , Cromatina
3.
Immunity ; 41(3): 465-477, 2014 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-25200712

RESUMEN

Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system.


Asunto(s)
Receptores de Lipopolisacáridos/metabolismo , Macrófagos/inmunología , Piel/inmunología , Animales , Antígeno CD11b/biosíntesis , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Movimiento Celular/inmunología , Células Cultivadas , Células Dendríticas/inmunología , Femenino , Humanos , Memoria Inmunológica/inmunología , Ratones , Ratones Transgénicos , Receptores de IgG/biosíntesis , Piel/citología , Linfocitos T/inmunología
4.
Blood ; 130(2): 167-175, 2017 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-28512190

RESUMEN

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. BRAFV600E mutation is the most common mutation in both conditions and also occurs in the hematopoietic neoplasm hairy cell leukemia (HCL). It is not known if adult LCH or ECD arises from hematopoietic stem cells (HSCs), nor which potential blood borne precursors lead to the formation of histiocytic lesions. In this study, BRAFV600E allele-specific polymerase chain reaction was used to map the neoplastic clone in 20 adults with LCH, ECD, and HCL. BRAFV600E was tracked to classical monocytes, nonclassical monocytes, and CD1c+ myeloid dendritic cells (DCs) in the blood, and mutations were observed in HSCs and myeloid progenitors in the bone marrow of 4 patients. The pattern of involvement of peripheral blood myeloid cells was indistinguishable between LCH and ECD, although the histiocytic disorders were distinct to HCL. As reported in children, detection of BRAFV600E in peripheral blood of adults was a marker of active multisystem LCH. The healthy counterparts of myeloid cells affected by BRAF mutation had a range of differentiation potentials depending on exogenous signals. CD1c+ DCs acquired high langerin and CD1a with granulocyte-macrophage colony-stimulating factor and transforming growth factor ß alone, whereas CD14+ classical monocytes required additional notch ligation. Both classical and nonclassical monocytes, but not CD1c+ DCs, made foamy macrophages easily in vitro with macrophage colony-stimulating factor and human serum. These studies are consistent with a hematopoietic origin and >1 immediate cellular precursor in both LCH and ECD.


Asunto(s)
Células de la Médula Ósea/patología , Enfermedad de Erdheim-Chester/diagnóstico , Células Madre Hematopoyéticas/patología , Histiocitosis de Células de Langerhans/diagnóstico , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Alelos , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos CD1/genética , Antígenos CD1/inmunología , Células de la Médula Ósea/inmunología , Diferenciación Celular , Células Dendríticas/inmunología , Células Dendríticas/patología , Diagnóstico Diferencial , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/inmunología , Enfermedad de Erdheim-Chester/patología , Femenino , Células Espumosas/inmunología , Células Espumosas/patología , Expresión Génica , Glicoproteínas/genética , Glicoproteínas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Células Madre Hematopoyéticas/inmunología , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/inmunología , Histiocitosis de Células de Langerhans/patología , Humanos , Inmunofenotipificación , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/inmunología , Masculino , Lectinas de Unión a Manosa/genética , Lectinas de Unión a Manosa/inmunología , Monocitos/inmunología , Monocitos/patología , Mutación , Proteínas Proto-Oncogénicas B-raf/inmunología , Receptores Notch/genética , Receptores Notch/inmunología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología
6.
J Allergy Clin Immunol ; 141(6): 2234-2248, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29128673

RESUMEN

BACKGROUND: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. OBJECTIVE: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. METHODS: Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. RESULTS: Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. CONCLUSIONS: This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation.


Asunto(s)
Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Factores Reguladores del Interferón/genética , Células Dendríticas/patología , Humanos , Masculino , Monocitos/patología , Mutación
7.
J Immunol ; 196(5): 2085-94, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26829983

RESUMEN

Germinal centers (GCs) are microanatomical structures critical for the development of high-affinity Abs and B cell memory. They are organized into two zones, light and dark, with coordinated roles, controlled by local signaling. The innate lectin-like transcript 1 (LLT1) is known to be expressed on B cells, but its functional role in the GC reaction has not been explored. In this study, we report high expression of LLT1 on GC-associated B cells, early plasmablasts, and GC-derived lymphomas. LLT1 expression was readily induced via BCR, CD40, and CpG stimulation on B cells. Unexpectedly, we found high expression of the LLT1 ligand, CD161, on follicular dendritic cells. Triggering of LLT1 supported B cell activation, CD83 upregulation, and CXCR4 downregulation. Overall, these data suggest that LLT1-CD161 interactions play a novel and important role in B cell maturation within the GC in humans.


Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Lectinas Tipo C/inmunología , Activación de Linfocitos/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Receptores CXCR4/inmunología , Receptores de Superficie Celular/inmunología , Linfocitos B/metabolismo , Separación Celular , Regulación hacia Abajo , Citometría de Flujo , Humanos , Inmunohistoquímica , Lectinas Tipo C/biosíntesis , Subfamilia B de Receptores Similares a Lectina de Células NK/biosíntesis , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CXCR4/biosíntesis , Receptores de Superficie Celular/biosíntesis
8.
Blood ; 125(3): 470-3, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25352125

RESUMEN

Langerhans cells (LCs) are self-renewing in the steady state but repopulated by myeloid precursors after injury. Human monocytes give rise to langerin-positive cells in vitro, suggesting a potential precursor role. However, differentiation experiments with human lineage-negative cells and CD34(+) progenitors suggest that there is an alternative monocyte-independent pathway of LC differentiation. Recent data in mice also show long-term repopulation of the LC compartment with alternative myeloid precursors. Here we show that, although monocytes are able to express langerin, when cultured with soluble ligands granulocyte macrophage colony-stimulating factor (GM-CSF), transforming growth factor ß (TGFß), and bone morphogenetic protein 7 (BMP7), CD1c(+) dendritic cells (DCs) become much more LC-like with high langerin, Birbeck granules, EpCAM, and E-cadherin expression under the same conditions. These data highlight a new potential precursor function of CD1c(+) DCs and demonstrate an alternative pathway of LC differentiation that may have relevance in vivo.


Asunto(s)
Antígenos CD1/metabolismo , Células Sanguíneas/citología , Diferenciación Celular , Células Dendríticas/citología , Glicoproteínas/metabolismo , Células de Langerhans/citología , Monocitos/citología , Antígenos CD/metabolismo , Células Sanguíneas/inmunología , Células Sanguíneas/metabolismo , Proteína Morfogenética Ósea 7/metabolismo , Cadherinas/metabolismo , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Células de Langerhans/inmunología , Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Unión a Manosa/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
10.
Curr Opin Hematol ; 23(1): 28-35, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26554892

RESUMEN

PURPOSE OF REVIEW: This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions. RECENT FINDINGS: Langerhans cells originate prenatally and may endure throughout life, independently of bone marrow-derived precursors. Fate-mapping experiments have recently resolved the relative contribution of primitive yolk sac and fetal liver hematopoiesis to the initial formation of Langerhans cells. In postnatal life, local self-renewal restores Langerhans cell numbers following chronic or low-grade inflammatory insults. However, severe inflammation recruits de-novo bone marrow-derived precursors in two waves; a transient population of classical monocytes followed by uncharacterized myeloid precursors that form a stable self-renewing Langerhans cell network as inflammation subsides. Human CD1c⁺ dendritic cells have Langerhans cell potential in vitro, raising the possibility that dendritic cell progenitors provide the second wave. Langerhans cell development depends upon transforming growth factor beta receptor signaling with distinct pathways active during differentiation and homeostasis. Langerhans cell survival is mediated by multiple pathways including mechanistic target of rapamycin and extracellular signal-regulated kinase signaling, mechanisms that become highly relevant in Langerhans cell neoplasia. SUMMARY: The study of Langerhans cells continues to provide novel and unexpected insights into the origin and regulation of myeloid cell populations. The melding of macrophage and dendritic cell biology, shaped by a unique habitat, is a special feature of Langerhans cells.


Asunto(s)
Diferenciación Celular , Homeostasis , Células de Langerhans/citología , Células de Langerhans/fisiología , Animales , Linaje de la Célula , Autorrenovación de las Células , Feto , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/metabolismo , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Células de Langerhans/patología , Hígado/citología , Hígado/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Monocitos/citología , Monocitos/metabolismo , Células Madre/citología , Células Madre/metabolismo , Saco Vitelino/citología
11.
Blood ; 123(6): 863-74, 2014 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-24345756

RESUMEN

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.


Asunto(s)
Linfocitos B/patología , Células Dendríticas/patología , Factor de Transcripción GATA2/genética , Células Asesinas Naturales/patología , Monocitos/patología , Mutación/genética , Síndromes Mielodisplásicos/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Evolución Clonal , Estudios Transversales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/genética , Linaje , Pronóstico , Adulto Joven , Tirosina Quinasa 3 Similar a fms/metabolismo
12.
Arthritis Rheumatol ; 76(1): 141-145, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37561109

RESUMEN

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.


Asunto(s)
Enfermedad de Erdheim-Chester , Humanos , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/patología , Estudio de Asociación del Genoma Completo , Genómica , Células Germinativas/patología
13.
Histopathology ; 63(6): 788-801, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24117687

RESUMEN

AIMS: To reassess the prognostic validity of immunohistochemical markers and algorithms identified in the CHOP era in immunochemotherapy-treated diffuse large B cell lymphoma patients. METHODS AND RESULTS: The prognostic significance of immunohistochemical markers (CD10, Bcl-6, Bcl-2, MUM1, Ki-67, CD5, GCET1, FoxP1, LMO2) and algorithms (Hans, Hans*, Muris, Choi, Choi*, Nyman, Visco-Young, Tally) was assessed using clinical diagnostic blocks taken from an unselected, population-based cohort of 190 patients treated with R-CHOP. Dichotomizing expression, low CD10 (<10%), low LMO2 (<70%) or high Bcl-2 (≥80%) predicted shorter overall survival (OS; P = 0.033, P = 0.010 and P = 0.008, respectively). High Bcl-2 (≥80%), low Bcl-6 (<60%), low GCET1 (<20%) or low LMO2 (<70%) predicted shorter progression-free survival (PFS; P = 0.001, P = 0.048, P = 0.045 and P = 0.002, respectively). The Hans, Hans* and Muris classifiers predicted OS (P = 0.022, P = 0.037 and P = 0.011) and PFS (P = 0.021, P = 0.020 and P = 0.004). The Choi, Choi* and Tally were associated with PFS (P = 0.049, P = 0.009 and P = 0.023). In multivariate analysis, the International Prognostic Index (IPI) was the only independent predictor of outcome (OS; HR: 2.60, P < 0.001 and PFS; HR: 2.91, P < 0.001). CONCLUSIONS: Results highlight the controversy surrounding immunohistochemistry-based algorithms in the R-CHOP era. The need for more robust markers, applicable to the clinic, for incorporation into improved prognostic systems is emphasized.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Inmunoterapia , Linfoma de Células B Grandes Difuso/terapia , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Biomarcadores de Tumor/metabolismo , Estudios de Cohortes , Terapia Combinada , Ciclofosfamida/administración & dosificación , Proteínas de Unión al ADN/metabolismo , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Proteínas con Dominio LIM/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Neprilisina/metabolismo , Prednisona/administración & dosificación , Pronóstico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6 , Rituximab , Serpinas/metabolismo , Vincristina/administración & dosificación , Adulto Joven
14.
Life Sci Alliance ; 6(11)2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37652671

RESUMEN

Pathogenic mitochondrial DNA (mtDNA) single-nucleotide variants are a common cause of adult mitochondrial disease. Levels of some variants decrease with age in blood. Given differing division rates, longevity, and energetic requirements within haematopoietic lineages, we hypothesised that cell-type-specific metabolic requirements drive this decline. We coupled cell-sorting with mtDNA sequencing to investigate mtDNA variant levels within progenitor, myeloid, and lymphoid lineages from 26 individuals harbouring one of two pathogenic mtDNA variants (m.3243A>G and m.8344A>G). For both variants, cells of the T cell lineage show an enhanced decline. High-throughput single-cell analysis revealed that decline is driven by increasing proportions of cells that have cleared the variant, following a hierarchy that follows the current orthodoxy of T cell differentiation and maturation. Furthermore, patients with pathogenic mtDNA variants have a lower proportion of T cells than controls, indicating a key role for mitochondrial function in T cell homeostasis. This work identifies the ability of T cell subtypes to selectively purify their mitochondrial genomes, and identifies pathogenic mtDNA variants as a new means to track blood cell differentiation status.


Asunto(s)
ADN Mitocondrial , Mitocondrias , Adulto , Humanos , ADN Mitocondrial/genética , Diferenciación Celular/genética , Mitocondrias/genética , Activación de Linfocitos , Linaje de la Célula
15.
Blood Adv ; 7(10): 2171-2176, 2023 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-36112425

RESUMEN

Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 patients with high-risk disease were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals of 3 to 6 years, and 10 patients, also given inhibitors, were analyzed more than 2 years after diagnosis. In contrast to the patients responding to salvage chemotherapy who completely cleared BRAFV600E within 6 months, children who received inhibitors maintained high BRAFV600E alleles in their blood. At diagnosis, mutation was detected predominantly in monocytes and myeloid dendritic cells. With time, mutation switched to the T-cell compartment, which accounted for most of the mutational burden in peripheral blood mononuclear cells, more than 2 years from diagnosis (median, 85.4%; range, 44.5%-100%). The highest level of mutation occurred in naïve CD4+ T cells (median, 51.2%; range, 3.8%-93.5%). This study reveals an unexpected lineage switch of BRAFV600E mutation in high-risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.


Asunto(s)
Células Dendríticas , Histiocitosis de Células de Langerhans , Monocitos , Linfocitos T , Humanos , Células Dendríticas/patología , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Leucocitos Mononucleares , Monocitos/patología , Mutación , Masculino , Femenino , Lactante , Preescolar , Linfocitos T/patología , Linaje de la Célula/genética
16.
Qual Prim Care ; 20(6): 435-42, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23540823

RESUMEN

BACKGROUND: This paper considers the role of teaching primary care trusts (tPCTs) at the turn of the century. A retrospective evaluation of a complex intervention is used. The evaluation has three perspectives. These are (1) a commentary on tPCTs in health policy in England, (2) the authors' reflections as senior members of a tPCT in Northern England and (3) a look-back exercise with tPCT members. RESULTS: It outlines the achievements and reflects on the experience of the tPCT and its relationship with its stakeholders. The resultant themes and challenges experienced by the tPCT members working at their organisational boundaries with their stakeholder both provide organisational developmental insight for the emergent primary care commissioning groups (Health and Social Care Bill 2011) and highlight the continuing need for organisational cultural change within general practice. CONCLUSION: Quality criteria for acceptability, accessibility, appropriateness, equity, clinical effectiveness and cost-effectiveness can only be truly addressed by a learning organisation approach. This was one of the original remits for tPCTs.


Asunto(s)
Atención Primaria de Salud/organización & administración , Mejoramiento de la Calidad/organización & administración , Medicina Estatal/organización & administración , Análisis Costo-Beneficio , Inglaterra , Política de Salud , Accesibilidad a los Servicios de Salud/organización & administración , Humanos , Atención Primaria de Salud/economía , Atención Primaria de Salud/normas , Estudios Retrospectivos , Medicina Estatal/normas
17.
Sci Immunol ; 7(78): eadd3330, 2022 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-36525505

RESUMEN

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.


Asunto(s)
Histiocitosis de Células de Langerhans , Neoplasias , Humanos , Linaje de la Célula , Histiocitosis de Células de Langerhans/metabolismo , Histiocitosis de Células de Langerhans/patología , Diferenciación Celular , Monocitos/metabolismo
18.
J Invest Dermatol ; 141(1): 84-94.e6, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32522485

RESUMEN

Langerhans cells (LCs) in the skin are a first line of defense against pathogens but also play an essential role in skin homeostasis. Their exclusive expression of the C-type lectin receptor Langerin makes them prominent candidates for immunotherapy. For vaccine testing, an easily accessible cell platform would be desirable as an alternative to the time-consuming purification of LCs from human skin. Here, we present such a model and demonstrate that monocytes in the presence of GM-CSF, TGF-ß1, and the Notch ligand DLL4 differentiate within 3 days into CD1a+Langerin+cells containing Birbeck granules. RNA sequencing of these monocyte-derived LCs (moLCs) confirmed gene expression of LC-related molecules, pattern recognition receptors, and enhanced expression of genes involved in the antigen-presenting machinery. On the protein level, moLCs showed low expression of costimulatory molecules but prominent expression of C-type lectin receptors. MoLCs can be matured, secrete IL-12p70 and TNF-α, and stimulate proliferation and cytokine production in allogeneic CD4+ and CD8+ T cells. In regard to vaccine testing, a recently characterized glycomimetic Langerin ligand conjugated to liposomes demonstrated specific and fast internalization into moLCs. Hence, these short-term in vitro‒generated moLCs represent an interesting tool to screen LC-based vaccines in the future.


Asunto(s)
Células Dendríticas/inmunología , Células de Langerhans/inmunología , Activación de Linfocitos/inmunología , Monocitos/inmunología , Piel/inmunología , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/patología , Humanos , Células de Langerhans/patología , Fenotipo , Piel/patología
19.
Blood Adv ; 4(1): 87-99, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31899802

RESUMEN

Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder that is characterized by the inflammatory lesions with pathogenic CD1a+CD207+ dendritic cells (DCs). BRAFV600E and other somatic activating MAPK gene mutations have been identified in differentiating bone marrow and blood myeloid cells, but the origin of the LCH lesion CD1a+CD207+ DCs and mechanisms of lesion formation remain incompletely defined. To identify candidate LCH CD1a+CD207+ DC precursor populations, gene-expression profiles of LCH lesion CD1a+CD207+ DCs were first compared with established gene signatures from human myeloid cell subpopulations. Interestingly, the CD1c+ myeloid DC (mDC) gene signature was most enriched in the LCH CD1a+CD207+ DC transcriptome. Additionally, the BRAFV600E allele was not only localized to CD1a+CD207- DCs and CD1a+CD207+ DCs, but it was also identified in CD1c+ mDCs in LCH lesions. Transcriptomes of CD1a+CD207- DCs were nearly indistinguishable from CD1a+CD207+ DCs (both CD1a+CD207low and CD1a+CD207high subpopulations). Transcription profiles of LCH lesion CD1a+CD207+ DCs and peripheral blood CD1c+ mDCs from healthy donors were compared to identify potential LCH DC-specific biomarkers: HLA-DQB2 expression was significantly increased in LCH lesion CD1a+CD207+ DCs compared with circulating CD1c+ mDCs from healthy donors. HLA-DQB2 antigen was identified on LCH lesion CD1a+CD207- DCs and CD1a+CD207+ DCs as well as on CD1c+(CD1a+CD207-) mDCs, but it was not identified in any other lesion myeloid subpopulations. HLA-DQB2 expression was specific to peripheral blood of patients with BRAFV600E+ peripheral blood mononuclear cells, and HLA-DQB2+CD1c+ blood cells were highly enriched for the BRAFV600E in these patients. These data support a model in which blood CD1c+HLA-DQB2+ mDCs with activated ERK migrate to lesion sites where they differentiate into pathogenic CD1a+CD207+ DCs.


Asunto(s)
Histiocitosis de Células de Langerhans , Leucocitos Mononucleares , Antígenos CD/genética , Antígenos CD1/genética , Biomarcadores , Células Dendríticas , Glicoproteínas , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/genética , Humanos , Lectinas Tipo C/genética , Lectinas de Unión a Manosa/genética , Células Mieloides
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