Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing.

Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased levels of cGAMP and enhanced IFN-I signature. To identify disease mechanisms and potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients.

DAMPening sterile inflammation of the kidney.

Renal ischemia reperfusion injury (IRI) is a serious cause of acute kidney injury (AKI). Danger-associated-molecular pattern molecules (DAMPs) are thought to promote IRI by initiating immune cell infiltration and driving disease progression, but the underlying pathophysiological mechanisms are mainly unclear. Poluzzi et al.

The multifaceted role of the renal mononuclear phagocyte system.

The kidney contains a large and complex network of mononuclear phagocytes, which includes dendritic cells (DCs) and macrophages (MØs). The distinction between these cell types is traditionally based on the expression of molecular markers and morphology. However, several classification systems are used in parallel to identify DCs and MØs, leading to considerable uncertainty about their identity and functional roles.

Plasmacytoid dendritic cells: important players in human kidney allograft rejection.

Plasmacytoid dendritic cells are a unique dendritic cell subset that bridges innate and adaptive immune responses. They release high amounts of type I interferons in response to viral and bacterial infection. Plasmacytoid dendritic cells are thought to act as key players in renal allograft rejection, but the underlying mechanisms are unclear.

Opposing Roles of Dendritic Cell Subsets in Experimental GN.

Dendritic cells (DCs) are thought to form a dendritic network across barrier surfaces and throughout organs, including the kidney, to perform an important sentinel function. However, previous studies of DC function used markers, such as CD11c or CX3CR1, that are not unique to DCs. Here, we evaluated the role of DCs in renal inflammation using a CD11c reporter mouse line and two mouse lines with DC-specific reporters, -GFP and -GFP.

Correlation of BCR/ABL transcript variants with patients' characteristics in childhood chronic myeloid leukaemia.

Background And Objective: The characteristic chromosomal translocation t(9;22)(q34;q11) in chronic myeloid leukaemia (CML) mainly results in the two different BCR/ABL fusion transcripts b2a2 or b3a2. Both transcript variants can occur simultaneously due to alternative splicing of the b3a2 transcript. Conflicting results have been reported on the influence of the transcripts on haematological findings at diagnosis and the course of the disease in adults while data concerning these topics on childhood CML are still missing.

Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma.

Clinical and histopathological characteristics have limited prognostic value for children with anaplastic large-cell lymphoma (ALCL). We evaluated the presence, extent, and prognostic impact of circulating tumor cells in bone marrow (BM) and peripheral blood (PB) of children and adolescents with NPM-ALK-positive ALCL at diagnosis using qualitative and quantitative polymerase chain reaction (PCR) for NPM-ALK. Numbers of NPM-ALK transcripts were normalized to 10(4) copies ABL (NCNs).

Minimal residual disease analysis in children with t(12;21)-positive acute lymphoblastic leukemia: comparison of Ig/TCR rearrangements and the genomic fusion gene.

Quantification of minimal residual disease (MRD) based on clonotypic immunoglobulin/ T-cell receptor (Ig/TCR) gene rearrangements is widely used as an independent prognostic parameter in childhood acute lymphoblastic leukemia (ALL). In this study we compared MRD by quantification of Ig/TCR targets and genomic ETV6-RUNX1 specific sequences. In ten of twelve patients with t(12;21)+ ALL we observed concordance with rapid blast reduction in nine, and high-level persistence in one case.

NQO1 C609T polymorphism in distinct entities of pediatric hematologic neoplasms.

Background And Objectives: NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that protects cells against mutagenicity from free radicals and toxic oxygen metabolites. The gene coding for NQO1 is subject to a genetic polymorphism at nucleotide position 609 (C-->T) of the human NQO1 cDNA. Heterozygous individuals (C/T) have intermediate activity and homozygotes for the variant allele (T/T) are deficient in NQO1 activity.

Gene expression patterns associated with recurrent chromosomal translocations in acute lymphoblastic leukemia.

We obtained a global view of gene expression in both cell lines and pediatric acute lymphoblastic leukemia (ALL) samples that harbor one of several selected chromosomal abnormalities. When the cell lines were studied alone, we found that these chromosomal abnormalities were associated with the predominant variation in transcriptional programs across the set of cell lines studied. When cell lines and clinical samples were studied together, we found that each chromosomal abnormality (TEL/AML1, BCR/ABL, or MLL abnormalities) was associated with a characteristic gene expression signature that was shared by both cell lines and clinical samples.

The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype.

The family of multidrug resistance-associated proteins (MRPs) belongs to the superfamily of adenosine triphosphate-binding-cassette (ABC) transporters, which have the ability to function as outward pumps for chemotherapeutic drugs and therefore might be involved in drug resistance. In this study the expression of the MRP2, MRP3, MRP4, MRP5, and SMRP genes was measured using TaqMan real-time polymerase chain reaction (PCR) in 103 children with previously untreated acute lymphoblastic leukemia (ALL) (precursor B-cell ALL [B-ALL], n = 71; T-cell ALL [T-ALL], n = 32). All 5 genes were expressed with a great variability.

Analysis of t(9;11) chromosomal breakpoint sequences in childhood acute leukemia: almost identical MLL breakpoints in therapy-related AML after treatment without etoposides.

The translocation t(9;11)(p22;q23) is a recurring chromosomal abnormality in acute myeloid leukemia (AML) fusing two genes designated as MLL and AF9. Within MLL, almost all rearrangements cluster in an 8.3-kb restricted region and fuse 5' portions of MLL to a variety of heterologous genes in various 11q23 translocations.

Cryptic chromosomal aberrations leading to an AML1/ETO rearrangement are frequently caused by small insertions.

The translocation t(8;21)(q22;q22), which results in the fusion of the AML1 (RUNX1) and ETO (CBFA2T1) genes, is a recurrent aberration in acute myeloid leukemia (AML), preferentially correlated with FAB M2, and has the highest incidence in childhood AML. Because of the favorable prognosis, the evidence of the t(8;21) or the AML1/ETO fusion gene is mandatory in most of the therapy trials, allowing the stratification of the patients to the correct risk group in terms of treatment. Here we present six out of 59 children with AML who were positive for AML1/ETO by RT-PCR, but showed no evidence of the classical t(8;21)(q22;q22) by conventional cytogenetics.

PRAME gene expression in childhood acute lymphoblastic leukemia.

The gene PRAME (preferentially expressed antigen of melanoma) was found to be expressed at high levels in a large fraction of different tumors and adult leukemias. Since PRAME is only expressed at low levels in a few normal tissues and encodes an antigen recognized by autologous cytolytic T lymphocytes, it might be a good candidate for tumor immunotherapy. In this study, quantitative reverse transcriptase polymerase chain reaction was used to measure PRAME gene expression in 50 children with newly diagnosed acute lymphoblastic leukemia (ALL).

Clinical implications of PRAME gene expression in childhood acute myeloid leukemia.

The expression of the PRAME gene (preferentially expressed antigen of melanoma) was measured by quantitative reverse transcriptase polymerase chain reaction in 50 children with newly diagnosed acute myeloid leukemia (AML), three samples of CD34(+) stem cells, six bone marrow samples, and 10 peripheral blood samples of healthy donors, as well as three AML cell-lines (KG-1, U937, and HL-60). Eight patients were also analyzed in relapse. Contrary to previous reports, we could show that the PRAME gene is expressed by CD34(+) stem cells.