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| 7. |
- Hagey, DW, et al.
(författare)
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Myeloid cells from Langerhans cell histiocytosis patients exhibit increased vesicle trafficking and an altered secretome capable of activating NK cells
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 108:9, s. 2422-2434
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Tidskriftsartikel (refereegranskat)abstract
- Langerhans cell histiocytosis (LCH) is a potentially life-threatening inflammatory myeloid neoplasia linked to paediatric neurodegeneration, whereby transformed LCH cells form agglomerated lesions in various organs. Although MAP-kinase pathway mutations have been identified in LCH cells, the functional consequences of these mutations and the mechanisms that cause the pathogenic behaviour of LCH cells are not well understood. In our study, we used an in vitro differentiation system and RNA-sequencing to compare monocyte-derived dendritic cells from LCH patients to those derived from healthy controls or patients with Crohn’s disease, a non-histiocytic inflammatory disease. We observed that Interferon-γ treatment exacerbated intrinsic differences between LCH patient and control cells, including strikingly increased endoand exocytosis gene activity in LCH patients. We validated these transcriptional patterns in lesions and functionally confirmed that LCH cells exhibited increased endo- and exocytosis. Furthermore, RNA-sequencing of extracellular vesicles (EV) revealed the enrichment of pathological transcripts involved in cell adhesion, MAP-kinase pathway, vesicle trafficking and T-cell activation in LCH patients. Thus, we tested the effect of the LCH secretome on lymphocyte activity and found significant activation of NK cells. These findings implicate EVs in the pathology of LCH for the first time, in line with their established roles in the formation of various other tumour niches. Thus, we describe novel traits of LCH patient cells and suggest a pathogenic mechanism of potential therapeutic and diagnostic importance.
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| 8. |
- Hagey, DW, et al.
(författare)
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Myeloid cells from Langerhans cell histiocytosis patients exhibit increased vesicle trafficking and an altered secretome capable of activating NK cells
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 108:9, s. 2422-2434
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Tidskriftsartikel (refereegranskat)abstract
- Langerhans cell histiocytosis (LCH) is a potentially life-threatening inflammatory myeloid neoplasia linked to paediatric neurodegeneration, whereby transformed LCH cells form agglomerated lesions in various organs. Although MAP-kinase pathway mutations have been identified in LCH cells, the functional consequences of these mutations and the mechanisms that cause the pathogenic behaviour of LCH cells are not well understood. In our study, we used an in vitro differentiation system and RNA-sequencing to compare monocyte-derived dendritic cells from LCH patients to those derived from healthy controls or patients with Crohn’s disease, a non-histiocytic inflammatory disease. We observed that Interferon-γ treatment exacerbated intrinsic differences between LCH patient and control cells, including strikingly increased endoand exocytosis gene activity in LCH patients. We validated these transcriptional patterns in lesions and functionally confirmed that LCH cells exhibited increased endo- and exocytosis. Furthermore, RNA-sequencing of extracellular vesicles (EV) revealed the enrichment of pathological transcripts involved in cell adhesion, MAP-kinase pathway, vesicle trafficking and T-cell activation in LCH patients. Thus, we tested the effect of the LCH secretome on lymphocyte activity and found significant activation of NK cells. These findings implicate EVs in the pathology of LCH for the first time, in line with their established roles in the formation of various other tumour niches. Thus, we describe novel traits of LCH patient cells and suggest a pathogenic mechanism of potential therapeutic and diagnostic importance.
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| 12. |
- Kvedaraite, E, et al.
(författare)
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Human dendritic cells in cancer
- 2022
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Ingår i: Science immunology. - 2470-9468. ; 7:70, s. eabm9409-
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Tidskriftsartikel (refereegranskat)
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| 13. |
- Kvedaraite, E, et al.
(författare)
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Human dendritic cells in cancer
- 2022
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Ingår i: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 7:70, s. eabm9409-
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) are professional antigen-presenting cells, orchestrating innate and adaptive immunity during infections, autoimmune diseases, and malignancies. Since the discovery of DCs almost 50 years ago, our understanding of their biology in humans has increased substantially. Here, we review both antitumor and tolerogenic DC responses in cancer and discuss lineage-specific contributions by their functionally specialized subsets, including the conventional DC (cDC) subsets cDC1 and cDC2, the newly described DC3, and the plasmacytoid DCs (pDCs), focusing on the human setting. In addition, we review the lineage-unrestricted “mature DCs enriched in immunoregulatory molecules” (mregDC) state recently described across different human tumors.
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| 14. |
- Kvedaraite, Egle, et al.
(författare)
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Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142−/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142−/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
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| 15. |
- Kvedaraite, E, et al.
(författare)
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Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 118:6
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Tidskriftsartikel (refereegranskat)abstract
- While broad efforts toward getting an overview of immune cell and soluble factor alterations in COVID-19 are under way, a deep and comprehensive understanding of the mononuclear phagocyte system, including circulating progenitors, is still largely lacking. This study provides a reference for the mononuclear phagocyte response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.
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| 17. |
- Kvedaraite, E, et al.
(författare)
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Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology
- 2022
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Ingår i: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 7:78, s. eadd3330-
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Tidskriftsartikel (refereegranskat)abstract
- Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
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| 26. |
- Medina, LMP, et al.
(författare)
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Targeted plasma proteomics reveals signatures discriminating COVID-19 from sepsis with pneumonia
- 2023
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Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X. ; 24:1, s. 62-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCOVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features.MethodsWe measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients.ResultsWe identified a core response to infection consisting of 42 proteins altered in both COVID-19 and sepsis, although higher levels of cytokine storm-associated proteins were evident in sepsis. Furthermore, microbiologic etiology and clinical endotypes were linked to unique signatures. Finally, through machine learning, we identified biomarkers, such as TRIM21, PTN and CASP8, that accurately differentiated COVID-19 from CAP-sepsis with higher accuracy than standard clinical markers.ConclusionsThis study extends the understanding of host responses underlying sepsis and COVID-19, indicating varying disease mechanisms with unique signatures. These diagnostic and severity signatures are candidates for the development of personalized management of COVID-19 and sepsis.
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| 28. |
- Mitchell, J, et al.
(författare)
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Altered Populations of Unconventional T Cell Lineages in Patients with Langerhans Cell Histiocytosis
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 16506-
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Tidskriftsartikel (refereegranskat)abstract
- Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of γδ T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies.
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| 29. |
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| 30. |
- Mitchell, J, et al.
(författare)
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Plasma Signaling Factors in Patients With Langerhans Cell Histiocytosis (LCH) Correlate With Relative Frequencies of LCH Cells and T Cells Within Lesions
- 2022
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Ingår i: Frontiers in pediatrics. - : Frontiers Media SA. - 2296-2360. ; 10, s. 872859-
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Tidskriftsartikel (refereegranskat)abstract
- Langerhans cell histiocytosis (LCH) lesions contain an inflammatory infiltrate of immune cells including myeloid-derived LCH cells. Cell-signaling proteins within the lesion environment suggest that LCH cells and T cells contribute majorly to the inflammation. Foxp3+ regulatory T cells (Tregs) are enriched in lesions and blood from patients with LCH and are likely involved in LCH pathogenesis. In contrast, mucosal associated invariant T (MAIT) cells are reduced in blood from these patients and the consequence of this is unknown. Serum/plasma levels of cytokines have been associated with LCH disease extent and may play a role in the recruitment of cells to lesions. We investigated whether plasma signaling factors differed between patients with active and non-active LCH. Cell-signaling factors (38 analytes total) were measured in patient plasma and cell populations from matched lesions and/or peripheral blood were enumerated. This study aimed at understanding whether plasma factors corresponded with LCH cells and/or LCH-associated T cell subsets in patients with LCH. We identified several associations between plasma factors and lesional/circulating immune cell populations, thus highlighting new factors as potentially important in LCH pathogenesis. This study highlights plasma cell-signaling factors that are associated with LCH cells, MAIT cells or Tregs in patients, thus they are potentially important in LCH pathogenesis. Further study into these associations is needed to determine whether these factors may become suitable prognostic indicators or therapeutic targets to benefit patients.
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| 33. |
- Strunz, B., et al.
(författare)
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Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy
- 2021
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Ingår i: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 6:56
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Tidskriftsartikel (refereegranskat)abstract
- Immune cell differentiation is critical for adequate tissue-specific immune responses to occur. Here, we studied differentiation of human uterine natural killer cells (uNK cells). These cells reside in a tissue undergoing constant regeneration and represent the major leukocyte population at the maternal-fetal interface. However, their physiological response during the menstrual cycle and in pregnancy remains elusive. By surface proteome and transcriptome analysis as well as using humanized mice, we identify a differentiation pathway of uNK cells in vitro and in vivo with sequential acquisition of killer cell immunoglobulin-like receptors and CD39. uNK cell differentiation occurred continuously in response to the endometrial regeneration and was driven by interleukin-15. Differentiated uNK cells displayed reduced proliferative capacity and immunomodulatory function including enhanced angiogenic capacity. By studying human uterus transplantation and monozygotic twins, we found that the uNK cell niche could be replenished from circulation and that it was under genetic control. Together, our study uncovers a continuous differentiation pathway of human NK cells in the uterus that is coupled to profound functional changes in response to local tissue regeneration and pregnancy.
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| 35. |
- Sveijer, M., et al.
(författare)
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Screening for neurodegeneration in Langerhans cell histiocytosis with neurofilament light in plasma
- 2022
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 198:4, s. 721-728
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Tidskriftsartikel (refereegranskat)abstract
- Patients with Langerhans cell histiocytosis (LCH) may develop progressive neurodegeneration in the central nervous system (ND-CNS-LCH). Neurofilament light protein (NFL) in cerebrospinal fluid (CSF) is a promising biomarker to detect and monitor ND-CNS-LCH. We compared paired samples of NFL in plasma (p-NFL) and CSF in 10 patients (19 samples). Nine samples had abnormal CSF-NFL (defined as >= 380 ng/l) with corresponding p-NFL >= 2 ng/l. Ten samples had CSF-NFL < 380 ng/l; eight (80%) with p-NFL < 2 ng/l (p < 0.001; Fisher's exact test). Thus, our results suggest that p-NFL may be used to screen for ND-CNS-LCH. Further studies are encouraged, including the role of p-NFL for monitoring of ND-CNS-LCH.
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