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1.
Blood Adv ; 3(20): 3052-3061, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648336

RESUMO

Fms-like tyrosine kinase 3 (Flt3) is expressed on progenitor cells and acute myeloid leukemia (AML) blasts. Fms-like tyrosine kinase 3 ligand (Flt3L) is detectable during homeostasis and increases in hypoplasia due to genetic defects or treatment with cytoreductive agents. Conversely, Flt3+ AML is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering complete remission (CR) but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the bone marrow. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 140 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib or placebo. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney UP < .0001). Day 26 Flt3L was also associated with survival; Flt3L ≤291 pg/mL was associated with inferior event-free survival (EFS), and Flt3L >1185 pg/mL was associated with higher overall survival (OS; P = .0119). The separation of EFS and OS curves increased when minimal residual disease (MRD) status was combined with Flt3L measurement, and Flt3L retained a near-significant association with survival after adjusting for MRD in a proportional hazards model. Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML illustrates the potential value of monitoring Flt3L to identify relapse. Measurement of Flt3L is a noninvasive test with the potential to inform clinical decisions in patients with AML.

2.
Cell Rep ; 23(12): 3658-3672.e6, 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29925006

RESUMO

The IRF8-dependent subset of classical dendritic cells (cDCs), termed cDC1, is important for cross-priming cytotoxic T cell responses against pathogens and tumors. Culture of hematopoietic progenitors with DC growth factor FLT3 ligand (FLT3L) yields very few cDC1s (in humans) or only immature "cDC1-like" cells (in the mouse). We report that OP9 stromal cells expressing the Notch ligand Delta-like 1 (OP9-DL1) optimize FLT3L-driven development of cDC1s from murine immortalized progenitors and primary bone marrow cells. Co-culture with OP9-DL1 induced IRF8-dependent cDC1s with a phenotype (CD103+ Dec205+ CD8α+) and expression profile resembling primary splenic cDC1s. OP9-DL1-induced cDC1s showed preferential migration toward CCR7 ligands in vitro and superior T cell cross-priming and antitumor vaccination in vivo. Co-culture with OP9-DL1 also greatly increased the yield of IRF8-dependent CD141+ cDC1s from human bone marrow progenitors cultured with FLT3L. Thus, Notch signaling optimizes cDC generation in vitro and yields authentic cDC1s for functional studies and translational applications.

3.
Nat Commun ; 9(1): 1239, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29588478

RESUMO

Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide.

4.
Semin Cell Dev Biol ; 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29452225

RESUMO

The critical functions of dendritic cells (DCs) in immunity and tolerance have been demonstrated in many animal models but their non-redundant roles in humans are more difficult to probe. Human primary immunodeficiency (PID), resulting from single gene mutations, may result in DC deficiency or dysfunction. This relatively recent recognition illuminates the in vivo role of human DCs and the pathophysiology of the associated clinical syndromes. In this review, the development and function of DCs as established in murine models and human in vitro systems, discussed. This forms the basis of predicting the effects of DC deficiency in vivo and understanding the consequences of specific mutations on DC development and function. DC deficiency syndromes are associated with heterozygous GATA2 mutation, bi-allelic and heterozygous IRF8 mutation and heterozygous IKZF1 mutation. The intricate involvement of DCs in the balance between immunity and tolerance is leading to increased recognition of their involvement in a number of other immunodeficiencies and autoimmune conditions. Owing to the precise control of transcription factor gene expression by super-enhancer elements, phenotypic anomalies are relatively commonly caused by heterozygous mutations.

5.
Immunology ; 154(1): 3-20, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29313948

RESUMO

Dendritic cells (DC) are a class of bone-marrow-derived cells arising from lympho-myeloid haematopoiesis that form an essential interface between the innate sensing of pathogens and the activation of adaptive immunity. This task requires a wide range of mechanisms and responses, which are divided between three major DC subsets: plasmacytoid DC (pDC), myeloid/conventional DC1 (cDC1) and myeloid/conventional DC2 (cDC2). Each DC subset develops under the control of a specific repertoire of transcription factors involving differential levels of IRF8 and IRF4 in collaboration with PU.1, ID2, E2-2, ZEB2, KLF4, IKZF1 and BATF3. DC haematopoiesis is conserved between mammalian species and is distinct from monocyte development. Although monocytes can differentiate into DC, especially during inflammation, most quiescent tissues contain significant resident populations of DC lineage cells. An extended range of surface markers facilitates the identification of specific DC subsets although it remains difficult to dissociate cDC2 from monocyte-derived DC in some settings. Recent studies based on an increasing level of resolution of phenotype and gene expression have identified pre-DC in human blood and heterogeneity among cDC2. These advances facilitate the integration of mouse and human immunology, support efforts to unravel human DC function in vivo and continue to present new translational opportunities to medicine.


Assuntos
Células Dendríticas/imunologia , Imunidade , Biomarcadores/metabolismo , Comunicação Celular , Diferenciação Celular , Células Dendríticas/classificação , Células Dendríticas/metabolismo , Humanos , Imunofenotipagem , Fenótipo , Transdução de Sinais
7.
Blood ; 131(8): 917-931, 2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29279357

RESUMO

The primary immunodeficiencies (PIDs), rare inherited diseases characterized by severe dysfunction of immunity, have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in childhood. Controversy exists regarding optimal timing and use of Allo-HSCT in adults, due to lack of experience and previous poor outcomes. Twenty-nine consecutive adult patients, with a mean age at transplant of 24 years (range, 17-50 years), underwent Allo-HSCT. Reduced-intensity conditioning (RIC) included fludarabine (Flu)/melphalan/alemtuzumab (n = 20), Flu/busulfan (Bu)/alemtuzumab (n = 8), and Flu/Bu/antithymocyte globulin (n = 1). Stem cell donors were matched unrelated donors or mismatched unrelated donors (n = 18) and matched related donors (n = 11). Overall survival (OS), event-free survival, transplant-related mortality (TRM), acute and chronic graft-versus-host disease incidence and severity, time to engraftment, lineage-specific chimerism, immune reconstitution, and discontinuation of immunoglobulin replacement therapy were recorded. OS at 3 years for the whole cohort was 85.2%. The rarer PID patients without chronic granulomatous disease (CGD) achieved an OS at 3 years of 88.9% (n = 18), compared with 81.8% for CGD patients (n = 11). TRM was low with only 4 deaths observed at a median follow-up of 3.5 years. There were no cases of early or late rejection. In all surviving patients, either stable mixed chimerism or full donor chimerism were observed. At last follow-up, 87% of the surviving patients had no evidence of persistent or recurrent infections. Allo-HSCT is safe and effective in young adult patients with severe PID and should be considered the treatment of choice where an appropriate donor is available.

9.
J Allergy Clin Immunol ; 141(6): 2234-2248, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29128673

RESUMO

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.

10.
Nature ; 546(7660): 662-666, 2017 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-28614294

RESUMO

During gestation the developing human fetus is exposed to a diverse range of potentially immune-stimulatory molecules including semi-allogeneic antigens from maternal cells, substances from ingested amniotic fluid, food antigens, and microbes. Yet the capacity of the fetal immune system, including antigen-presenting cells, to detect and respond to such stimuli remains unclear. In particular, dendritic cells, which are crucial for effective immunity and tolerance, remain poorly characterized in the developing fetus. Here we show that subsets of antigen-presenting cells can be identified in fetal tissues and are related to adult populations of antigen-presenting cells. Similar to adult dendritic cells, fetal dendritic cells migrate to lymph nodes and respond to toll-like receptor ligation; however, they differ markedly in their response to allogeneic antigens, strongly promoting regulatory T-cell induction and inhibiting T-cell tumour-necrosis factor-α production through arginase-2 activity. Our results reveal a previously unappreciated role of dendritic cells within the developing fetus and indicate that they mediate homeostatic immune-suppressive responses during gestation.


Assuntos
Arginase/metabolismo , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Feto/imunologia , Tolerância Imunológica , Linfócitos T/imunologia , Adulto , Movimento Celular , Proliferação de Células , Citocinas/biossíntese , Citocinas/imunologia , Feto/citologia , Feto/enzimologia , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Receptores Toll-Like/imunologia
11.
J Exp Med ; 214(7): 1913-1923, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28606987

RESUMO

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.


Assuntos
Células da Medula Óssea/imunologia , Diferenciação Celular/imunologia , Inflamação/imunologia , Monócitos/imunologia , Animais , Sobrevivência Celular/imunologia , Células Cultivadas , Deutério/metabolismo , Endotoxemia/sangue , Endotoxemia/imunologia , Citometria de Fluxo , Homeostase/imunologia , Humanos , Inflamação/sangue , Marcação por Isótopo/métodos , Camundongos , Fatores de Tempo
12.
Blood ; 130(2): 167-175, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28512190

RESUMO

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.


Assuntos
Células da Medula Óssea/patologia , Doença de Erdheim-Chester/diagnóstico , Células-Tronco Hematopoéticas/patologia , Histiocitose de Células de Langerhans/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Alelos , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD1/genética , Antígenos CD1/imunologia , Células da Medula Óssea/imunologia , Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/patologia , Diagnóstico Diferencial , Doença de Erdheim-Chester/genética , Doença de Erdheim-Chester/imunologia , Doença de Erdheim-Chester/patologia , Feminino , Células Espumosas/imunologia , Células Espumosas/patologia , Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Células-Tronco Hematopoéticas/imunologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Humanos , Imunofenotipagem , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Masculino , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Monócitos/imunologia , Monócitos/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/imunologia , Receptores Notch/genética , Receptores Notch/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
13.
Biol Blood Marrow Transplant ; 23(5): 805-812, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28212937

RESUMO

Alemtuzumab conditioning is highly effective at reducing the incidence of acute and chronic graft-versus-host disease (GVHD) in reduced-intensity fludarabine and melphalan transplantation with cyclosporine monotherapy. Less frequent and lower dose scheduling may be used with sibling donors, but an optimal regimen for matched unrelated donors has not been defined. In this retrospective observational study of 313 patients, the incidence and severity of GVHD was compared in patients receiving 3 different dose schedules: the standard 100-mg regimen (20 mg on days -7 to -3), 60 mg (30 mg on days -4 and -2), or 50 mg (10 mg on days -7 to -3). Patients treated with 100 mg, 60 mg, or 50 mg developed acute GVHD grades I to IV with an incidence of 74%, 65%, and 64%, respectively, whereas 36%, 32%, and 41% developed chronic GHVD. An excess of severe acute grades III/IV GVHD was observed in the 50-mg cohort (15% versus 2% to 6%; P = .016). The relative risk of severe acute grade GVHD remained more than 3-fold higher in the 50-mg cohort compared with the 100-mg cohort after adjustment for differences in HLA match, age, gender mismatch, cytomegalovirus risk, and diagnosis (P = .030). The findings indicate that the 60-mg alemtuzumab schedule was comparable with the 100-mg schedule, but more attenuated schedules may increase the risk of severe grade GVHD.


Assuntos
Alemtuzumab/administração & dosagem , Doença Enxerto-Hospedeiro/tratamento farmacológico , Adulto , Idoso , Aloenxertos/química , Aloenxertos/imunologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Doadores não Relacionados , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto Jovem
14.
Blood ; 129(14): 1927-1939, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28209719

RESUMO

Heterozygous GATA2 mutation is associated with immunodeficiency, lymphedema, and myelodysplastic syndrome. Disease presentation is variable, often coinciding with loss of circulating dendritic cells, monocytes, B cells, and natural killer (NK) cells. Nonetheless, in a proportion of patients carrying GATA2 mutation, NK cells persist. We found that peripheral blood NK cells in symptomatic patients uniformly lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF), as well as expression of intracellular signaling proteins FcεRγ, spleen tyrosine kinase (SYK), and EWS/FLI1-Activated Transcript 2 (EAT-2) in a variegated manner. Moreover, consistent with an adaptive identity, NK cells from patients with GATA2 mutation displayed altered expression of cytotoxic granule constituents and produced interferon-γ upon Fc-receptor engagement but not following combined interleukin-12 (IL-12) and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, GATA-binding protein-2 (GATA-2) was expressed in hematopoietic stem cells, but not in NK-cell progenitors, CD3-CD56bright, canonical, or adaptive CD3-CD56dim NK cells. Peripheral blood NK cells from individuals with GATA2 mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients with GATA2 mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.


Assuntos
Proliferação de Células , Fator de Transcrição GATA2 , Células-Tronco Hematopoéticas/imunologia , Células Matadoras Naturais/imunologia , Mutação , Adolescente , Adulto , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/imunologia , Criança , Feminino , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/imunologia , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Masculino , Pessoa de Meia-Idade , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Receptores de IgE/genética , Receptores de IgE/imunologia , Quinase Syk/genética , Quinase Syk/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
15.
J Clin Invest ; 127(1): 306-320, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27893462

RESUMO

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8-/-, but not Irf8+/-, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.


Assuntos
Alelos , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença , Fatores Reguladores de Interferon , Células Matadoras Naturais/imunologia , Mutação , Viroses , Animais , Antígeno CD56/genética , Antígeno CD56/imunologia , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Masculino , Camundongos , Camundongos Knockout , Viroses/genética , Viroses/imunologia
16.
Neurol Neuroimmunol Neuroinflamm ; 4(1): e299, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27833932

RESUMO

OBJECTIVE: To identify a treatment-responsive BRAFV600E mutation in brainstem neurohistiocytosis, where no lesional tissue was readily obtainable, using a cell-free DNA approach. METHODS: Cell-free DNA was extracted from urine and allele-specific PCR for the BRAFV600E mutation was performed. Response to conventional treatment (corticosteroids and interferon) and targeted treatment with a BRAF inhibitor was assessed by clinical evaluation, gadolinium-enhanced MRI brain scan, and serial testing of urinary cell-free DNA for mutant alleles. RESULTS: BRAFV600E mutation could be readily identified in urinary cell-free DNA at an allele frequency of 4.2%. Treatment of Erdheim-Chester disease with corticosteroids and interferon was ineffective and associated with disease progression. Treatment with BRAF inhibitors was associated with clinical improvement and near-complete radiologic remission. Following 6 months of BRAF inhibitor therapy, no enhancing lesions could be detected in the brain and mutant alleles were cleared from the urine. CONCLUSIONS: Analysis of urinary cell-free DNA using allele-specific PCR for BRAFV600E mutations allows rapid noninvasive identification of a highly treatment-responsive pathway, leading to clinical and radiologic remission of disease. Our case demonstrates that this assay may have a particular role in challenging neurohistiocytosis cases, where attempts at obtaining lesional tissue have failed or are not feasible. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence. This is a single observation study without controls.

17.
EBioMedicine ; 14: 65-73, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27913155

RESUMO

High-risk primary biliary cholangitis (PBC), defined by inadequate response at one year to Ursodeoxycholic acid (UDCA), is associated with disease progression and liver transplantation. Stratifying high-risk patients early would facilitate improved approaches to care. Using long-term follow-up data to define risk at presentation, 6 high-risk PBC patients and 8 low-risk patients were identified from biopsy, transplant and biochemical archival records. Formalin-fixed paraffin-embedded (FFPE) liver biopsies taken at presentation were graded (Scheuer and Nakanuma scoring) and gene expression analysed using the NanoString® nCounter PanCancer Immunity 770-gene panel. Principle component analysis (PCA) demonstrated discrete gene expression clustering between controls and high- and low-risk PBC. High-risk PBC was characterised by up-regulation of genes linked to T-cell activation and apoptosis, INF-γ signalling and leukocyte migration and down-regulation of those linked to the complement pathway. CDKN1a, up-regulated in high-risk PBC, correlated with significantly increased expression of its gene product, the senescence marker p21WAF1/Cip, by biliary epithelial cells. Our findings suggest high- and low-risk PBC are biologically different from disease outset and senescence an early feature in high-risk disease. Identification of a high-risk 'signal' early from standard FFPE tissue sections has clear clinical utility allowing for patient stratification and second-line therapeutic intervention.


Assuntos
Colangite/genética , Colangite/patologia , Perfilação da Expressão Gênica , Transcriptoma , Adulto , Idoso , Biomarcadores , Biópsia , Colangite/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Curr Opin Allergy Clin Immunol ; 16(6): 530-540, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27755182

RESUMO

PURPOSE OF REVIEW: Dendritic cells are specialized antigen-presenting cells which link innate and adaptive immunity, through recognition and presentation of antigen to T cells. Although the importance of dendritic cells has been demonstrated in many animal models, their contribution to human immunity remains relatively unexplored in vivo.Given their central role in infection, autoimmunity, and malignancy, dendritic cell deficiency or dysfunction would be expected to have clinical consequences. RECENT FINDINGS: Human dendritic cell deficiency disorders, related to GATA binding protein 2 (GATA2) and interferon regulatory factor 8 (IRF8) mutations, have highlighted the importance of dendritic cells and monocytes in primary immunodeficiency diseases and begun to shed light on their nonredundant roles in host defense and immune regulation in vivo. The contribution of dendritic cell and monocyte dysfunction to the pathogenesis of primary immunodeficiency disease phenotypes is becoming increasingly apparent. However, dendritic cell analysis is not yet a routine part of primary immunodeficiency disease workup. SUMMARY: Widespread uptake of dendritic cell/monocyte screening in clinical practice will facilitate the discovery of novel dendritic cell and monocyte disorders as well as advancing our understanding of human dendritic cell biology in health and disease.


Assuntos
Células Dendríticas/fisiologia , Fator de Transcrição GATA2/genética , Síndromes de Imunodeficiência/imunologia , Fatores Reguladores de Interferon/genética , Monócitos/fisiologia , Imunidade Adaptativa , Animais , Apresentação do Antígeno , Autoimunidade , Humanos , Síndromes de Imunodeficiência/genética , Mutação/genética , Linfócitos T/imunologia
19.
Microbiol Spectr ; 4(5)2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27780016

RESUMO

The maintenance of monocytes, macrophages, and dendritic cells (DCs) involves manifold pathways of ontogeny and homeostasis that have been the subject of intense study in recent years. The concept of a peripheral mononuclear phagocyte system continually renewed by blood-borne monocytes has been modified to include specialized DC pathways of development that do not involve monocytes, and longevity through self-renewal of tissue macrophages. The study of development remains difficult owing to the plasticity of phenotypes and misconceptions about the fundamental structure of hematopoiesis. However, greater clarity has been achieved in distinguishing inflammatory monocyte-derived DCs from DCs arising in the steady state, and new concepts of conjoined lymphomyeloid hematopoiesis more easily accommodate the shared lymphoid and myeloid phenotypes of some DCs. Cross-species comparisons have also yielded coherent systems of nomenclature for all mammalian monocytes, macrophages, and DCs. Finally, the clear relationships between ontogeny and functional specialization offer information about the regulation of immune responses and provide new tools for the therapeutic manipulation of myeloid mononuclear cells in medicine.


Assuntos
Células Dendríticas/citologia , Células Dendríticas/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Monócitos/citologia , Monócitos/imunologia , Animais , Humanos , Modelos Animais
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