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1.  Mutations in CECR1 associated with a neutrophil signature in peripheral blood 
Background
A reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis.
Methods
Considering the phenotypic overlap of ADA2 deficiency with the type I interferonopathy Aicardi-Goutières syndrome due to mutations in SAMHD1, we looked for the presence of an interferon signature in the peripheral blood of two newly ascertained ADA2-deficient patients.
Results
We identified biallelic CECR1 mutations in two patients consistent with ADA2 deficiency. Both patients demonstrated an upregulation of interferon stimulated gene transcripts in peripheral blood. More strikingly however, genome-wide analysis revealed a marked overexpression of neutrophil-derived genes, suggesting that the vasculitis seen in ADA2 deficiency may be an indirect effect resulting from chronic and marked activity of neutrophils.
Conclusions
We hypothesise that ADA2 may act as a regulator of neutrophil activation, and that a reduction of ADA2 activity results in significant endothelial damage via a neutrophil-driven process.
Electronic supplementary material
The online version of this article (doi:10.1186/1546-0096-12-44) contains supplementary material, which is available to authorized users.
doi:10.1186/1546-0096-12-44
PMCID: PMC4181355  PMID: 25278816
Adenosine deaminase; ADA2; CECR1; Neutrophil signature; Type I interferon; Aicardi-Goutières syndrome; SAMHD1
3.  T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow 
Mutually exclusive expression of T-bet and Eomes drives the development of distinct NK cell lineages with complementary functions.
Trail+DX5−Eomes− natural killer (NK) cells arise in the mouse fetal liver and persist in the adult liver. Their relationships with Trail−DX5+ NK cells remain controversial. We generated a novel Eomes-GFP reporter murine model to address this question. We found that Eomes− NK cells are not precursors of classical Eomes+ NK cells but rather constitute a distinct lineage of innate lymphoid cells. Eomes− NK cells are strictly dependent on both T-bet and IL-15, similarly to NKT cells. We observed that, in the liver, expression of T-bet in progenitors represses Eomes expression and the development of Eomes+ NK cells. Reciprocally, the bone marrow (BM) microenvironment restricts T-bet expression in developing NK cells. Ectopic expression of T-bet forces the development of Eomes− NK cells, demonstrating that repression of T-bet is essential for the development of Eomes+ NK cells. Gene profile analyses show that Eomes− NK cells share part of their transcriptional program with NKT cells, including genes involved in liver homing and NK cell receptors. Moreover, Eomes− NK cells produce a broad range of cytokines, including IL-2 and TNF in vitro and in vivo, during immune responses against vaccinia virus. Thus, mutually exclusive expression of T-bet and Eomes drives the development of different NK cell lineages with complementary functions.
doi:10.1084/jem.20131560
PMCID: PMC3949572  PMID: 24516120
4.  Monitoring NK cell activity in patients with hematological malignancies 
Oncoimmunology  2013;2(9):e26011.
Natural killer (NK) cells are lymphocytes of the innate immune system that can recognize and kill various types of malignant cells. Monitoring the activity of peripheral NK cells in patients affected by hematological malignancies may provide prognostic information or unveil ongoing tumor-specific immune responses. Moreover, further insights into the biology of NK cells might also promote the development of novel strategies for stimulating their anticancer activity. Here, we review the main methods to monitor phenotypic and functional NK cell properties in cancer patients, focusing on individuals affected by multiple myeloma, a hematological malignancy currently treated with immunomodulatory drugs.
doi:10.4161/onci.26011
PMCID: PMC3850490  PMID: 24327939
Lenalidomide; cytotoxicity; flow cytometry; multiple myeloma; natural killer cells
5.  Regulation of Mouse NK Cell Development and Function by Cytokines 
Natural Killer (NK) cells are innate lymphocytes with an important role in the early defense against intracellular pathogens and against tumors. Like other immune cells, almost every aspects of their biology are regulated by cytokines. Interleukin (IL)-15 is pivotal for their development, homeostasis, and activation. Moreover, numerous other activating or inhibitory cytokines such as IL-2, IL-4, IL-7, IL-10, IL-12, IL-18, IL-21, Transforming growth factor-β (TGFβ) and type I interferons regulate their activation and their effector functions at different stages of the immune response. In this review we summarize the current understanding on the effect of these different cytokines on NK cell development, homeostasis, and functions during steady-state or upon infection by different pathogens. We try to delineate the cellular sources of these cytokines, the intracellular pathways they trigger and the transcription factors they regulate. We describe the known synergies or antagonisms between different cytokines and highlight outstanding questions in this field of investigation. Finally, we discuss how a better knowledge of cytokine action on NK cells could help improve strategies to manipulate NK cells in different clinical situations.
doi:10.3389/fimmu.2013.00450
PMCID: PMC3859915  PMID: 24376448
natural killer cells; cytotoxicity; interferons; signal transduction; interleukin-15; interleukin-12; interleukin-18; TGF-beta
6.  Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling 
Genome Biology  2008;9(1):R17.
Genome-wide expression profiling of mouse and human leukocytes reveal conserved transcriptional programs of plasmacytoid or conventional dendritic cell subsets.
Background
Dendritic cells (DCs) are a complex group of cells that play a critical role in vertebrate immunity. Lymph-node resident DCs (LN-DCs) are subdivided into conventional DC (cDC) subsets (CD11b and CD8α in mouse; BDCA1 and BDCA3 in human) and plasmacytoid DCs (pDCs). It is currently unclear if these various DC populations belong to a unique hematopoietic lineage and if the subsets identified in the mouse and human systems are evolutionary homologs. To gain novel insights into these questions, we sought conserved genetic signatures for LN-DCs and in vitro derived granulocyte-macrophage colony stimulating factor (GM-CSF) DCs through the analysis of a compendium of genome-wide expression profiles of mouse or human leukocytes.
Results
We show through clustering analysis that all LN-DC subsets form a distinct branch within the leukocyte family tree, and reveal a transcriptomal signature evolutionarily conserved in all LN-DC subsets. Moreover, we identify a large gene expression program shared between mouse and human pDCs, and smaller conserved profiles shared between mouse and human LN-cDC subsets. Importantly, most of these genes have not been previously associated with DC function and many have unknown functions. Finally, we use compendium analysis to re-evaluate the classification of interferon-producing killer DCs, lin-CD16+HLA-DR+ cells and in vitro derived GM-CSF DCs, and show that these cells are more closely linked to natural killer and myeloid cells, respectively.
Conclusion
Our study provides a unique database resource for future investigation of the evolutionarily conserved molecular pathways governing the ontogeny and functions of leukocyte subsets, especially DCs.
doi:10.1186/gb-2008-9-1-r17
PMCID: PMC2395256  PMID: 18218067

Results 1-6 (6)