RESUMO
The concept of functional specialization is fundamental to the immune system but has not been previously observed in human Langerhans cells. In this issue of Immunity, Liu et al. use single-cell approaches to define two distinct epidermal subsets converging on a common activation and migration pathway.
Assuntos
Células de Langerhans , Pele , Epiderme , HumanosRESUMO
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.
Assuntos
Antígenos CD34/metabolismo , Células Dendríticas/citologia , Hematopoese/fisiologia , Fatores Reguladores de Interferon/metabolismo , Animais , Antígenos CD1/metabolismo , Linhagem Celular , Linhagem da Célula/imunologia , Células Dendríticas/imunologia , Glicoproteínas/metabolismo , Células-Tronco Hematopoéticas/citologia , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Camundongos , Receptores Imunológicos/metabolismoRESUMO
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. This article provides protocols with top ticks and pitfalls for preparation and successful generation of mouse and human DC from different cellular sources, such as murine BM and HoxB8 cells, as well as human CD34+ cells from cord blood, BM, and peripheral blood or peripheral blood monocytes. We describe murine cDC1, cDC2, and pDC generation with Flt3L and the generation of BM-derived DC with GM-CSF. Protocols for human DC generation focus on CD34+ cell culture on OP9 cell layers for cDC1, cDC2, cDC3, and pDC subset generation and DC generation from peripheral blood monocytes (MoDC). Additional protocols include enrichment of murine DC subsets, CRISPR/Cas9 editing, and clinical grade human DC generation. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
Assuntos
Células Dendríticas , Monócitos , Animais , Camundongos , Humanos , Antígenos CD34 , Fenótipo , Diferenciação CelularRESUMO
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.
Assuntos
Proteína de Leucina Linfoide-Mieloide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Epigênese Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Genes Reguladores , CromatinaRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.
Assuntos
Bronquiectasia , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Bronquiectasia/etiologia , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Adulto JovemRESUMO
PURPOSE: X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton's tyrosine kinase (BTK). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients. METHODS: XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes. RESULTS: In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50-95%), and the 1-year discontinuation rate of IgRT was 89%. CONCLUSION: Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage.
Assuntos
Agamaglobulinemia , Doenças Genéticas Ligadas ao Cromossomo X , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/terapia , Agamaglobulinemia/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças Genéticas Ligadas ao Cromossomo X/etiologia , Melfalan , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/etiologiaRESUMO
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⺠CLEC9A⺠DCs and CD1c⺠DCs are murine CD103⺠DCs and CD64⻠CD11b⺠DCs. In addition, human tissues also contain CD14⺠cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⺠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⺠monocytes and dermal CD14⺠cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⺠cells are CD11b⺠CD64⺠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.
Assuntos
Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/imunologia , Pele/imunologia , Animais , Antígeno CD11b/biossíntese , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Movimento Celular/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Humanos , Memória Imunológica/imunologia , Camundongos , Camundongos Transgênicos , Receptores de IgG/biossíntese , Pele/citologia , Linfócitos T/imunologiaRESUMO
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/imunologiaRESUMO
We present a case of complete deficiency of the interferon alpha/beta receptor alpha chain (IFNAR1) in a child with fatal systemic hyperinflammation, apparently provoked by live-attenuated viral vaccination. Such pathologic hyperinflammation, fulfilling criteria for hemophagocytic lymphohistiocytosis, is an emerging phenotype accompanying inborn errors of type I interferon immunity.
Assuntos
Linfo-Histiocitose Hemofagocítica , Homozigoto , Humanos , Interferon-alfa/uso terapêutico , Linfo-Histiocitose Hemofagocítica/genética , Receptor de Interferon alfa e beta/genéticaRESUMO
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.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/patologia , Humanos , Tolerância Imunológica , Imunidade , SíndromeRESUMO
Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8(+) T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141(hi) DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c(+) and CD14(+) tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141(hi) DCs were closely related to blood CD141(+) DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.
Assuntos
Antígenos CD/metabolismo , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Cadeias alfa de Integrinas/metabolismo , Animais , Antígenos/imunologia , Movimento Celular/imunologia , Quimiocina CXCL10/biossíntese , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Pele/imunologia , Transcriptoma , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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.
Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndromes de Imunodeficiência/mortalidade , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemRESUMO
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/imunologiaRESUMO
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/imunologiaRESUMO
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.
Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Fatores Reguladores de Interferon/genética , Células Dendríticas/patologia , Humanos , Masculino , Monócitos/patologia , MutaçãoRESUMO
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 , Fator 4 Semelhante a Kruppel , Fenótipo , Transdução de SinaisRESUMO
The human mononuclear phagocyte network comprises dendritic cells (DCs), monocytes and macrophages with a range of immune functions including antigen presentation linking innate and adaptive immunity. A number of DC, monocyte and macrophage subsets have been described in lymphoid and non-lymphoid tissues of mouse and human, with increased understanding of their distinct functional properties and genetic and cellular pathways of development. More recently, through comparative biology studies, a unified nomenclature of mononuclear phagocytes has begun to emerge with the identification of homologous subsets in several species. In this review, we discuss the current classification of human mononuclear phagocytes and the parallel organization of this network in the mouse. We also review the genetic control and developmental pathway of human mononuclear phagocytes and the immunological functions of the distinct subsets in health and inflammation.
Assuntos
Macrófagos/imunologia , Monócitos/imunologia , Sistema Fagocitário Mononuclear/imunologia , Imunidade Adaptativa/imunologia , Animais , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Humanos , Macrófagos/citologia , Camundongos , Modelos Imunológicos , Monócitos/citologia , Sistema Fagocitário Mononuclear/citologiaRESUMO
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.