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1.
Expert Rev Hematol ; 13(1): 55-70, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657974

RESUMO

Introduction: Historically, the majority of childhood cancers, including acute lymphoblastic leukemia (ALL), were not thought to have a hereditary basis. However, recent germline genomic studies have revealed that at least 5 - 10% of children with cancer (and approximately 3 - 4% of children with ALL) develop the disease due to an underlying genetic predisposition.Areas covered: This review discusses several recently identified ALL predisposing conditions and provides updates on other more well-established syndromes. It also covers topics related to the evaluation and management of children and family members at increased ALL risk.Expert opinion: Germline predisposition is gaining recognition as an important risk factor underlying the development of pediatric ALL. The challenge now lies in how best to capitalize on germline genetic information to improve ALL diagnosis, treatment, and perhaps even prevention.

2.
Pediatr Blood Cancer ; 67(2): e28047, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31736278

RESUMO

PURPOSE: To estimate the absolute number of adult survivors of childhood cancer in the U.S. population who carry a pathogenic or likely pathogenic variant in a cancer predisposition gene. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Program, we estimated the number of childhood cancer survivors on December 31, 2016 for each childhood cancer diagnosis, multiplied this by the proportion of carriers of pathogenic/likely pathogenic variants in the St. Jude Lifetime Cohort (SJLIFE) study, and projected the resulting number onto the U.S. RESULTS: Based on genome sequence data, 11.8% of 2450 SJLIFE participants carry a pathogenic/likely pathogenic variant in one of 156 cancer predisposition genes. Given this information, we estimate that 21 800 adult survivors of childhood cancer in the United States carry a pathogenic/likely pathogenic variant in one of these genes. The highest estimated absolute number of variant carriers are among survivors of central nervous system tumors (n = 4300), particularly astrocytoma (n = 1800) and other gliomas (n = 1700), acute lymphoblastic leukemia (n = 4300), and retinoblastoma (n = 3500). The most frequently mutated genes are RB1 (n = 3000), NF1 (n = 2300), and BRCA2 (n = 800). CONCLUSION: Given the increasing number of childhood cancer survivors in the United States, clinicians should counsel survivors regarding their potential genetic risk, consider referral for genetic counseling and testing, and, as appropriate, implement syndrome-specific cancer surveillance or risk-reducing measures.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31710506

RESUMO

RATIONALE: Interleukin (IL) 18 is a member of the IL-1 cytokine family and elevated blood IL-18 concentrations associate with disease activity in Macrophage Activation Syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions. OBJECTIVE: While recent investigations provide mechanistic evidence for a contribution of IL-18 to (hyper)inflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression. METHODS: Samples from in vivo and in vitro endotoxin re-challenge experiments, inflammatory disease patients and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT-inhibition was analyzed in two MAS mouse models as well as a patient with recurrent MAS. MEASUREMENTS AND MAIN RESULTS: Peripheral blood as well as monocytic IL-18 expression escaped lipopolysacharide (LPS)-induced immunoparalysis. LPS-stimulated primary human monocytes revealed a specific IL-18 expression kinetics controlled by IFNα/ß-signaling. JAK/STAT-inhibition or IFNß-neutralization during LPS-stimulation blunted cytokine expression. Similarly, microtubule destabilizing drugs abrogated LPS-induced IL18 expression, which could be fully reversed by addition of IFNα/ß. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I interferon score and IL18 expression, while JAK/STAT-inhibition in two MAS mouse models as well as a patient with recurrent MAS strongly reduced IL-18 serum levels. CONCLUSION: Our data indicate that IL-18 (but not IL-1ß) production from human monocytes requires cooperate toll-like receptor and IFNα/ß-signaling. Interference with IFNα/ß-expression or signaling following JAK/STAT-inhibition may control catastrophic hyperinflammation in MAS. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

4.
Int J Mol Sci ; 20(19)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569599

RESUMO

Invariant natural killer T (iNKT) cells are a unique T cell lineage that develop in the thymus and emerge with a memory-like phenotype. Accordingly, following antigenic stimulation, they can rapidly produce copious amounts of Th1 and Th2 cytokines and mediate activation of several immune cells. Thus, it is not surprising that iNKT cells play diverse roles in a broad range of diseases. Given their pivotal roles in host immunity, it is crucial that we understand the mechanisms that govern iNKT cell development and effector functions. Over the last two decades, several studies have contributed to the current knowledge of iNKT cell biology and activity. Collectively, these studies reveal that the thymic development of iNKT cells, their lineage expansion, and functional properties are tightly regulated by a complex network of transcription factors and signaling molecules. While prior studies have clearly established the importance of the SLAM-SAP-Fyn signaling axis in iNKT cell ontogenesis, recent studies provide exciting mechanistic insights into the role of this signaling cascade in iNKT cell development, lineage fate decisions, and functions. Here we summarize the previous literature and discuss the more recent studies that guide our understanding of iNKT cell development and functional responses.

5.
J Natl Cancer Inst ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31647544

RESUMO

BACKGROUND: We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value. METHODS: The fraction of telomeric reads was determined from whole-genome sequencing data for paired tumor/normal samples from 653 patients with 23 cancer types from the Pediatric Cancer Genome Project (PCGP). Telomere dynamics were characterized as the ratio of telomere fractions between tumor and normal samples. Somatic mutations were gathered, RNA sequencing data for 330 patients were analyzed for gene expression, and Cox regression was used to assess the telomere dynamics on patient survival. RESULTS: Telomere lengthening was observed in 28.7% of solid tumors, 10.5% of brain tumors, and 4.3% of hematological cancers. Among 81 samples with telomere lengthening, 26 had somatic mutations in ATRX, corroborated by a low level of ATRX expression in the subset of tumors with RNA sequencing. TERT amplification and/or activation was observed in 10 tumors with telomere lengthening, including 2 leukemias of the E2A-PBX1 subtype. Among hematological cancers, pathway analysis for genes with expressions most negatively correlated with telomere fractions suggest implication of a gene ontology process of antigen presentation by MHC class II. A higher ratio of telomere fractions was statistically significantly associated with poorer survival for patients with brain tumors (hazard ratio = 2.18, 95% confidence interval = 1.37 to 3.46). CONCLUSION: Because telomerase inhibitors are currently being explored as potential agents to treat pediatric cancer, these data are valuable as they identify a subpopulation of patients with reactivation of telomerase who are most likely to benefit from this novel therapeutic option.

6.
Blood Adv ; 3(20): 2962-2979, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648317

RESUMO

Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously classified as benign/likely benign, pathogenic/likely pathogenic, variant of unknown significance (VUS), or conflicting interpretations (CONF) in ClinVar. The application of RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the benefit of gene-specific criteria and sharing internal laboratory data.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31604778

RESUMO

Patients harboring germline pathogenic biallelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in RECQL4, the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer-predisposing condition Rothmund-Thomson syndrome (RTS), are associated with increased risk for childhood cancer. To address this question, we interrogated germline sequence data from 4435 pediatric cancer patients at St. Jude Children's Research Hospital and 1127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and identified 24 (0.43%) who harbored loss-of-function (LOF) RECQL4 variants, including five of 249 (2.0%) with osteosarcoma (OS). These RECQL4 variants were significantly overrepresented in children with OS, the cancer most frequently observed in patients with RTS, as compared to 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = 0.00087, odds ratio [OR] = 7.1, 95% CI, 2.9-17). Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis. Altogether these data expand our understanding of the genetic factors predisposing to childhood cancer and reveal a novel association between heterozygous RECQL4 LOF variants and development of pediatric OS.

8.
Genome Res ; 29(9): 1555-1565, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31439692

RESUMO

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

9.
Pediatr Blood Cancer ; 66(11): e27929, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31339233

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.

12.
Blood ; 133(23): 2465-2477, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-30992265

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Adulto , Feminino , Humanos , Masculino
13.
Blood ; 134(2): 147-159, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31015190

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-γ (IFN-γ). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1 -/-) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-γ, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN-γ signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-γ-neutralizing antibody (αIFN-γ) in 2 murine HLH models. In both models, ruxolitinib and αIFN-γ reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-γ-dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-γ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1 -/- mice exhibited enhanced survival compared with mice in which αIFN-γ was discontinued. This protective effect could be mimicked by transient treatment with αIFN-γ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-γ-dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.


Assuntos
Linfo-Histiocitose Hemofagocítica/imunologia , Neutrófilos/efeitos dos fármacos , Pirazóis/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
14.
Cancer ; 125(14): 2455-2464, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901077

RESUMO

BACKGROUND: Patients with cancer are increasingly offered genomic sequencing, including germline testing for cancer predisposition or other disorders. Such testing is unfamiliar to patients and families, and clear communication is needed to introduce genomic concepts and convey risk and benefit information. METHODS: Parents of children with cancer were offered the opportunity to have their children's tumor and germline examined with clinical genomic sequencing. Families were introduced to the study with a 2-visit informed consent model. Baseline genetic knowledge and self-reported literacy/numeracy were collected before a study introduction visit, during which basic concepts related to genomic sequencing were discussed. Information was reinforced during a second visit, during which informed consent was obtained and a posttest was administered. RESULTS: As reflected by the percentage of correct answers on the pretest and posttest assessments, this model increased genetic knowledge by 11.1% (from 77.8% to 88.9%; P < .0001) in 121 parents participating in both the study introduction and consent visits. The percentage of parents correctly identifying the meaning of somatic and germline mutations increased significantly (from 18% to 59% [somatic] and from 31% to 64% [germline]; P < .0001). Nevertheless, these concepts remained unfamiliar to one-third of the parents. No relation was identified between the change in the overall percentage of correct answers and self-reported literacy, numeracy, or demographics. CONCLUSIONS: The use of a 2-visit communication model improved knowledge of concepts relevant to genomic sequencing, particularly differences between somatic and germline testing; however, these areas remained confusing to many participants, and reinforcement may be necessary to achieve complete understanding.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30886117

RESUMO

Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by heterozygous germline mutations in the TP53 gene. Although more than 200 missense and null TP53 mutations are well established as disease-causing, little is known about the pathogenicity and cancer risks associated with small in-frame deletions. This leads to challenges in variant classification and subsequent difficulty making a molecular diagnosis. We report the genetic testing process for a pediatric patient diagnosed with an undifferentiated high-grade brain tumor following his mother's diagnosis of early-onset bilateral breast cancer. Sequential testing revealed that both harbored a heterozygous three-nucleotide deletion in exon 7 of TP53 (c.764_766delTCA; I255del), which was classified as a variant of uncertain significance. Because the maternal family history was void of any other LFS spectrum tumors, additional information was needed to effectively classify the variant. Targeted TP53 testing of the patient's maternal grandparents confirmed that neither carried the variant; this new de novo data upgraded the variant classification to likely pathogenic. To assess the impact of this mutation on the encoded p53 protein, additional in vitro analyses were performed. Structural modeling predicted that the deletion of isoleucine at codon 255 would disrupt the architecture of the DNA-binding domain, suggesting that it might negatively impact p53 function. Consistent with this notion, the I255del mutant protein exhibited significantly impaired transcriptional activity and greatly reduced growth suppressive properties, similar to more well-characterized LFS-associated p53 mutants. This report illustrates the importance of seeking additional evidence to assign proper pathogenicity classification, which enables optimal genetic counseling and medical management of individuals with LFS and their at-risk relatives.

16.
Nat Med ; 25(4): 597-602, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833747

RESUMO

Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents, and ranges on the spectrum of malignancy from low grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF1,2. However, in approximately 50% of cases no genetic driver has been established2. Clinical whole-genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine-threonine kinase that activates MEK3,4. The patient, who had exhausted all other therapeutic options, was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations of MAP3K8 in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements-uncovered by comprehensive clinical sequencing of a single case-are the most common genetic event in spitzoid melanoma, are present in adult melanomas and could be amenable to MEK inhibition.


Assuntos
Genoma Humano , MAP Quinase Quinase Quinases/genética , Melanoma/genética , Proteínas Proto-Oncogênicas/genética , Análise de Sequência de DNA , Animais , Criança , Éxons/genética , Humanos , Masculino , Camundongos , Mutação/genética , Células NIH 3T3 , Proteínas de Fusão Oncogênica/genética
17.
Blood Adv ; 3(5): 813-824, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30858151

RESUMO

Invariant natural killer T (iNKT) cells comprise a unique lineage of CD1d-restricted lipid-reactive T lymphocytes that potently kill tumor cells and exhibit robust immunostimulatory functions. Optimal tumor-directed iNKT cell responses often require expression of the antigen-presenting molecule CD1d on tumors; however, many tumor cells downregulate CD1d and thus evade iNKT cell recognition. We generated a soluble bispecific fusion protein designed to direct iNKT cells to the site of B-cell cancers in a tumor antigen-specific but CD1d-independent manner. This fusion protein is composed of a human CD1d molecule joined to a single chain antibody FV fragment specific for CD19, an antigen widely expressed on B-cell cancers. The CD1d-CD19 fusion protein binds specifically to CD19-expressing, but not CD19-negative cells. Once loaded with the iNKT cell lipid agonist α-galactosyl ceramide (αGC), the CD1d-CD19 fusion induces robust in vitro activation of and cytokine production by human iNKT cells. iNKT cells stimulated by the αGC-loaded CD1d-CD19 fusion also strongly transactivate T-, B-, and NK-cell responses and promote dendritic cell maturation. Importantly, the αGC-loaded fusion induces robust lysis of CD19+CD1d- Epstein-Barr virus immortalized human B-lymphoblastoid cell lines that are otherwise resistant to iNKT cell killing. Consistent with these findings; administration of the αGC-loaded fusion protein controlled the growth of CD19+CD1d- tumors in vivo, suggesting that it can "link" iNKT cells and CD19+CD1d- targets in a therapeutically beneficial manner. Taken together, these preclinical studies demonstrate that this B cell-directed fusion protein can be used to effectively induce iNKT cell antitumor responses in vitro and in vivo.

18.
Front Immunol ; 10: 119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774631

RESUMO

Synonymous with secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome (MAS) is a term used by rheumatologists to describe a potentially life-threatening complication of systemic inflammatory disorders, most commonly systemic juvenile idiopathic arthritis (sJIA) and systemic lupus erythematosus (SLE). Clinical and laboratory features of MAS include sustained fever, hyperferritinemia, pancytopenia, fibrinolytic coagulopathy, and liver dysfunction. Soluble interleukin-2 receptor alpha chain (sCD25) and sCD163 may be elevated, and histopathology often reveals characteristic increased hemophagocytic activity in the bone marrow (and other tissues), with positive CD163 (histiocyte) staining. A common hypothesis as to the pathophysiology of many cases of MAS proposes a defect in lymphocyte cytolytic activity. Specific heterozygous gene mutations in familial HLH-associated cytolytic pathway genes (e.g., PRF1, UNC13D) have been linked to a substantial subset of MAS patients. In addition, the pro-inflammatory cytokine environment, particularly IL-6, has been shown to decrease NK cell cytolytic function. The inability of NK cells and cytolytic CD8 T cells to lyse infected and otherwise activated antigen presenting cells results in prolonged cell-to-cell (innate and adaptive immune cells) interactions and amplification of a pro-inflammatory cytokine cascade. The cytokine storm results in activation of macrophages, causing hemophagocytosis, as well as contributing to multi-organ dysfunction. In addition to macrophages, dendritic cells likely play a critical role in antigen presentation to cytolytic lymphocytes, as well as contributing to cytokine expression. Several cytokines, including tumor necrosis factor, interferon-gamma, and numerous interleukins (i.e., IL-1, IL-6, IL-18, IL-33), have been implicated in the cytokine cascade. In addition to broadly immunosuppressive therapies, novel cytokine targeted treatments are being explored to dampen the overly active immune response that is responsible for much of the pathology seen in MAS.


Assuntos
Síndrome de Ativação Macrofágica/imunologia , Animais , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Humanos , Macrófagos/imunologia
19.
JCI Insight ; 4(1)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30626747

RESUMO

Host-commensal interactions are critical for the generation of robust inflammatory responses, yet the mechanisms leading to this effect remain poorly understood. Using a murine model of cytokine storm, we identified that host microbiota are required to sustain systemic TLR-driven immune responses. Mice treated with broad-spectrum antibiotics or raised in germ-free conditions responded normally to an initial TLR signal but failed to sustain production of proinflammatory cytokines following administration of repeated TLR signals in vivo. Mechanistically, host microbiota primed JAK signaling in myeloid progenitors to promote TLR-enhanced myelopoiesis, which is required for the accumulation of TLR-responsive monocytes. In the absence of TLR-enhanced monocytopoiesis, antibiotic-treated mice lost their ability to respond to repeated TLR stimuli and were protected from cytokine storm-induced immunopathology. These data reveal priming of TLR-enhanced myelopoiesis as a microbiota-dependent mechanism that regulates systemic inflammatory responses and highlight a role for host commensals in the pathogenesis of cytokine storm syndromes.

20.
Nat Rev Clin Oncol ; 16(4): 227-240, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30546053

RESUMO

Advances in genomic research and risk-directed therapy have led to improvements in the long-term survival and quality of life outcomes of patients with childhood acute lymphoblastic leukaemia (ALL). The application of next-generation sequencing technologies, especially transcriptome sequencing, has resulted in the identification of novel molecular subtypes of ALL with prognostic and therapeutic implications, as well as cooperative mutations that account for much of the heterogeneity in clinical responses observed among patients with specific ALL subtypes. In addition, germline genetic variants have been shown to influence the risk of developing ALL and/or the responses of non-malignant and leukaemia cells to therapy; shared pathways for drug activation and metabolism are implicated in treatment-related toxicity and drug sensitivity or resistance, depending on whether the genetic changes are germline, somatic or both. Indeed, although once considered a non-hereditary disease, genomic investigations of familial and sporadic ALL have revealed a growing number of genetic alterations or conditions that predispose individuals to the development of ALL and treatment-related second cancers. The identification of these genetic alterations holds the potential to direct genetic counselling, testing and possibly monitoring for the early detection of ALL and other cancers. Herein, we review these advances in our understanding of the genomic landscape of childhood ALL and their clinical implications.


Assuntos
Biomarcadores Tumorais/genética , Genômica/métodos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Variantes Farmacogenômicos , Medicina de Precisão , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Sequenciamento Completo do Exoma
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