uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Nilsson, Gunnar
Alternative names
Publications (10 of 19) Show all publications
Grootens, J., Ungerstedt, J. S., Wu, C., Hamberg Levedahl, K., Nilsson, G. & Dahlin, J. S. (2020). CD203c distinguishes the erythroid and mast cell-basophil differentiation trajectories among human Fc epsilon RI+ bone marrow progenitors [Letter to the editor]. Allergy. European Journal of Allergy and Clinical Immunology, 75(1), 211-214
Open this publication in new window or tab >>CD203c distinguishes the erythroid and mast cell-basophil differentiation trajectories among human Fc epsilon RI+ bone marrow progenitors
Show others...
2020 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 75, no 1, p. 211-214Article in journal, Letter (Other academic) Published
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-409453 (URN)10.1111/all.13981 (DOI)000479803400001 ()31306485 (PubMedID)
Funder
Swedish Research CouncilMagnus Bergvall Foundation
Available from: 2020-04-22 Created: 2020-04-22 Last updated: 2020-04-22Bibliographically approved
Hallgren, J., Hellman, L., Maurer, M., Nilsson, G. P., Wernersson, S., Åbrink, M. & Pejler, G. (2020). Novel aspects of mast cell and basophil function: Highlights from the 9th meeting of the European Mast Cell and Basophil Research Network (EMBRN)-A Marcus Wallenberg Symposium [Letter to the editor]. Allergy. European Journal of Allergy and Clinical Immunology, 75(3), 707-708
Open this publication in new window or tab >>Novel aspects of mast cell and basophil function: Highlights from the 9th meeting of the European Mast Cell and Basophil Research Network (EMBRN)-A Marcus Wallenberg Symposium
Show others...
2020 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 75, no 3, p. 707-708Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2020
National Category
Immunology in the medical area Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-406838 (URN)10.1111/all.14065 (DOI)000518758900027 ()31557323 (PubMedID)
Funder
Swedish Cancer SocietySwedish Asthma and Allergy AssociationMarcus Wallenbergs Foundation for International Scientific CollaborationWenner-Gren FoundationsSwedish Research Council
Available from: 2020-03-12 Created: 2020-03-12 Last updated: 2020-04-07Bibliographically approved
Maric, J., Ravindran, A., Mazzurana, L., Van Acker, A., Rao, A., Kokkinou, E., . . . Mjosberg, J. (2019). Cytokine-induced endogenous production of prostaglandin D-2 is essential for human group 2 innate lymphoid cell activation. Journal of Allergy and Clinical Immunology, 143(6), 2202-2214.e5
Open this publication in new window or tab >>Cytokine-induced endogenous production of prostaglandin D-2 is essential for human group 2 innate lymphoid cell activation
Show others...
2019 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 6, p. 2202-2214.e5Article in journal (Refereed) Published
Abstract [en]

Objective: We set out to examine PG production in human ILC2s and the implications of such endogenous production on ILC2 function. Methods: The effects of the COX-1/2 inhibitor flurbiprofen, the hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2s were determined by assessing receptor and transcription factor expression, cytokine production, and gene expression with flow cytometry, ELISA, and quantitative RT-PCR, respectively. Concentrations of lipid mediators were measured by using liquid chromatography-tandem mass spectrometry and ELISA. Results: We show that ILC2s constitutively express HPGDS and upregulate COX-2 upon IL-2, IL-25, and IL-33 plus thymic stromal lymphopoietin stimulation. Consequently, PGD2 and its metabolites can be detected in ILC2 supernatants. We reveal that endogenously produced PGD2 is essential in cytokine-induced ILC2 activation because blocking of the COX-1/2 or HPGDS enzymes or the CRTH2 receptor abolishes ILC2 responses. Conclusion: PGD2 produced by ILC2s is, in a paracrine/autocrine manner, essential in cytokine-induced ILC2 activation. Hence we provide the detailed mechanism behind how CRTH2 antagonists represent promising therapeutic tools for allergic diseases by controlling ILC2 function.

Place, publisher, year, edition, pages
MOSBY-ELSEVIER, 2019
Keywords
Group 2 innate lymphoid cells, prostaglandin D-2, chemoattractant receptor-homologous molecule expressed on T(H)2 cells, allergy
National Category
Immunology Immunology in the medical area Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-387922 (URN)10.1016/j.jaci.2018.10.069 (DOI)000470113200024 ()30578872 (PubMedID)
Funder
Swedish Research Council, 521-2013-2791Swedish Foundation for Strategic Research , ICA120023Swedish Research CouncilSwedish Foundation for Strategic Research Swedish Cancer Society, 130396Swedish Society for Medical Research (SSMF)German Research Foundation (DFG)Swedish Heart Lung Foundation, HLF 20150640; HLF 20140469
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Rönnberg, E., Ghaib, A., Ceriol, C., Enoksson, M., Arock, M., Säfholm, J., . . . Nilsson, G. (2019). Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions. Frontiers in Immunology, 10, Article ID 1361.
Open this publication in new window or tab >>Divergent Effects of Acute and Prolonged Interleukin 33 Exposure on Mast Cell IgE-Mediated Functions
Show others...
2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1361Article in journal (Refereed) Published
Abstract [en]

Background: Epithelial cytokines, including IL-33 and Thymic stromal lymphopoietin (TSLP), have attracted interest because of their roles in chronic allergic inflammation-related conditions such as asthma. Mast cells are one of the major targets of IL-33, to which they respond by secreting cytokines. Most studies performed thus far have investigated the acute effects of IL-33 on mast cells. In the current study, we investigated how acute vs. prolonged exposure of mast cells to IL-33 and TSLP affects mediator synthesis and IgE-mediated activation.

Methods: Human lung mast cells (HLMCs), cord blood-derived mast cells (CBMCs), and the ROSA mast cell line were used for this study. Receptor expression and the levels of mediators were measured after treatment with IL-33 and/or TSLP.

Results: IL-33 induced the release of cytokines. Prolonged exposure to IL-33 increased while TSLP reduced intracellular levels of tryptase. Acute IL-33 treatment strongly potentiated IgE-mediated activation. In contrast, 4 days of exposure to IL-33 decreased IgE-mediated activation, an effect that was accompanied by a reduction in Fc epsilon RI expression.

Conclusion: We show that IL-33 plays dual roles in mast cells, in which its acute effects include cytokine release and the potentiation of IgE-mediated degranulation, whereas prolonged exposure to IL-33 reduces IgE-mediated activation. We conclude that mast cells act quickly in response to the alarmin IL-33 to initiate an acute inflammatory response, whereas extended exposure to IL-33 during prolonged inflammation reduces IgE-mediated responses. This negative feedback effect suggests the presence of a novel regulatory pathway that modulates IgE-mediated human mast cell responses.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
Fc epsilon RI, IgE, IL-33, mast cells, TSLP
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390195 (URN)10.3389/fimmu.2019.01361 (DOI)000472212500001 ()31275312 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research AstraZenecaSwedish Heart Lung FoundationTore Nilsons Stiftelse för medicinsk forskningLars Hierta Memorial FoundationSwedish Society for Medical Research (SSMF)Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-08Bibliographically approved
Nilsson, G. & Dahlin, J. S. (2019). New insights into the origin of mast cells [Letter to the editor]. Allergy. European Journal of Allergy and Clinical Immunology, 74(4), 844-845
Open this publication in new window or tab >>New insights into the origin of mast cells
2019 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 4, p. 844-845Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
WILEY, 2019
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-382019 (URN)10.1111/all.13668 (DOI)000462915600026 ()30427067 (PubMedID)
Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-18Bibliographically approved
Grootens, J., Ungerstedt, J. S., Ekoff, M., Rönnberg, E., Klimkowska, M., Amini, R.-M., . . . Dahlin, J. S. (2019). Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis. EBioMedicine, 43, 150-158
Open this publication in new window or tab >>Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis
Show others...
2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 43, p. 150-158Article in journal (Refereed) Published
Abstract [en]

Background: Systemic mastocytosis (SM) is a haematological disease characterised by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34(+) haematopoietic progenitors can carry the mutation: however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34(+) bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc epsilon RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2019
Keywords
Systemic Mastocytosis, Single-cell, Mast cell, Mast cell progenitor, CD45RA, Haematopoiesis, Haematopoietic stem cells, KIT D816V
National Category
Cell and Molecular Biology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-387962 (URN)10.1016/j.ebiom.2019.03.089 (DOI)000470091600028 ()30975542 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Cancer Research Funds of RadiumhemmetMagnus Bergvall FoundationTore Nilsons Stiftelse för medicinsk forskningStockholm County Council
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2020-06-05Bibliographically approved
Tebroke, J., Lieverse, J. E., Säfholm, J., Schulte, G., Nilsson, G. & Rönnberg, E. (2019). Wnt-3a Induces Cytokine Release in Human Mast Cells. CELLS, 8(11), Article ID 1372.
Open this publication in new window or tab >>Wnt-3a Induces Cytokine Release in Human Mast Cells
Show others...
2019 (English)In: CELLS, ISSN 2073-4409, Vol. 8, no 11, article id 1372Article in journal (Refereed) Published
Abstract [en]

Mast cells are well known for their detrimental effects in allergies and asthma, and Wnt signaling has recently been implicated in asthma and other airway diseases. However, it is not known if or how Wnts affect human mast cells. Since Wnt expression is elevated in individuals with asthma and is linked to a Th2 profile, we hypothesized that mast cells could be affected by Wnts in the context of asthma. We therefore sought to investigate the role of Wnt signaling in human mast cell development and activation. We first examined the expression of the 10 main Wnt receptors, Frizzled 1-10 (FZD(1-10)), and found expression of several FZDs in human mast cells. Treatment with purified recombinant Wnt-3a or Wnt-5a did not affect the proliferation or maturation of CD34(+) progenitors into mast cells, as indicated by cellular expression of CD117 and Fc epsilon RI, activation by Fc epsilon RI crosslinking, and histamine and tryptase release. Furthermore, Wnt treatment did not change the phenotype from MCT to MCTC, since MrgX2 expression, compound 48/80-mediated activation, and carboxypeptidase A3 content were not affected. However, Wnt-3a activated WNT/beta-catenin signaling in mature human mast cells, as revealed by stabilization of beta-catenin, upregulation of IL-8 and CCL8 mRNA expression, and release of IL-8 protein. Thus, our data suggest that Wnt-3a activation of mast cells could contribute to the recruitment of immune cells in conditions associated with increased Wnt-3a expression, such as asthma.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
mast cells, Wnt signaling, Wnt-3a, Frizzled, IL-8, CCL8, asthma
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-402237 (URN)10.3390/cells8111372 (DOI)000502266700070 ()31683769 (PubMedID)
Funder
Swedish Research Council, 2017-04676Swedish Heart Lung FoundationSwedish Foundation for Strategic Research Tore Nilsons Stiftelse för medicinsk forskningLars Hierta Memorial FoundationSwedish Society for Medical Research (SSMF)AstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Cancer Society, CAN2017/561
Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-16Bibliographically approved
Ravindran, A., Rönnberg, E., Dahlin, J. S., Mazzurana, L., Säfholm, J., Orre, A.-C., . . . Nilsson, G. (2018). An Optimized Protocol for the Isolation and Functional Analysis of Human Lung Mast Cells. Frontiers in Immunology, 9, Article ID 2193.
Open this publication in new window or tab >>An Optimized Protocol for the Isolation and Functional Analysis of Human Lung Mast Cells
Show others...
2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2193Article in journal (Refereed) Published
Abstract [en]

Background: Mast cells are tissue-resident inflammatory cells defined by their high granularity and surface expression of the high-affinity IgE receptor, Fc + RI, and CD117/KIT, the receptor for stem cell factor (SCF). There is a considerable heterogeneity among mast cells, both phenotypically and functionally. Human mast cells are generally divided into two main subtypes based on their protease content; the mucosa-associated MCT (tryptase positive and chymase negative mast cell) and the connective tissue associated-residing MCTC (tryptase and chymase positive mast cell). Human lung mast cells exhibit heterogeneity in terms of cellular size, expression of cell surface receptors, and secreted mediators. However, knowledge about human lung mast cell heterogeneity is restricted to studies using immunohistochemistry or purified mast cells. Whereas the former is limited by the number of cellular markers that can be analyzed simultaneously, the latter suffers from issues related to cell yield.

Aim: To develop a protocol that enables isolation of human lung mast cells at high yields for analysis of functional properties and detailed analysis using single-cell based analyses of protein (flow cytometry) or RNA (RNA-sequencing) expression.

Methods: Mast cells were isolated from human lung tissue by a sequential combination of washing, enzymatic digestion, mechanical disruption, and density centrifugation using Percoll (WEMP). As a comparison, we also isolated mast cells using a conventional enzyme-based protocol. The isolated cells were analyzed by flow cytometry.

Results: We observed a significant increase in the yield of total human lung CD45(+) immune cells and an even more pronounced increase in the yield of CD117(+) mast cells with the WEMP protocol in comparison to the conventional protocols. In contrast, the frequency of the rare lymphocyte subset innate lymphoid cells group 2 (ILC2) did not differ between the two methods.

Conclusion: The described WEMP protocol results in a significant increase in the yield of human lung mast cells compared to a conventional protocol. Additionally, the WEMP protocol enables simultaneous isolation of different immune cell populations such as lymphocytes, monocytes, and granulocytes while retaining their surface marker expression that can be used for advanced single-cell analyses including multi-color flow cytometry and RNA-sequencing.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
mast cells, lung, enzymatic digestion protocols, human mast cells, mast cell isolation
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-367035 (URN)10.3389/fimmu.2018.02193 (DOI)000446444600001 ()30344519 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Swedish Heart Lung FoundationAstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Karolinska Institutet's Research Foundation
Available from: 2018-11-29 Created: 2018-11-29 Last updated: 2018-11-29Bibliographically approved
Halova, I., Rönnberg, E., Draberova, L., Vliagoftis, H., Nilsson, G. P. & Draber, P. (2018). Changing the threshold-Signals and mechanisms of mast cell priming. Immunological Reviews, 282(1), 73-86
Open this publication in new window or tab >>Changing the threshold-Signals and mechanisms of mast cell priming
Show others...
2018 (English)In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 282, no 1, p. 73-86Article in journal (Refereed) Published
Abstract [en]

Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2, sphingosine-1-phosphate, and β-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
cell priming, chemokines, cytokine receptors, cytokines, high-affinity IgE receptor, mast cell
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-343008 (URN)10.1111/imr.12625 (DOI)000424876400006 ()29431203 (PubMedID)
Funder
Swedish Research Council, K2012-57X-13029-14-6
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-05-15Bibliographically approved
Grootens, J., Ungerstedt, J. S., Nilsson, G. & Dahlin, J. S. (2018). Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells. BLOOD ADVANCES, 2(17), 2273-2281
Open this publication in new window or tab >>Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells
2018 (English)In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, no 17, p. 2273-2281Article, review/survey (Refereed) Published
Abstract [en]

Hematopoietic stem cells differentiate into all types of blood cells, including peripheral tissue-resident mast cells. The early mast cell differentiation takes place in the bone marrow, after which the progenitor cells enter the circulation and mature once reaching their target organ. Early results from single-cell culture experiments and colony-forming assays have produced the classic hierarchical tree model of hematopoiesis. The introduction of high-throughput, single-cell RNA sequencing is now revolutionizing our understanding of the differentiation process, questioning the classic tree-based models. By integrating the results from early cell culture experiments with single-cell transcriptomics, we present a differentiation landscape model of hematopoiesis and discuss it with focus on mast cells. The review also describes how the hematologic neoplasm systemic mastocytosis can be used to model human hematopoiesis using naturally occurring cell barcoding by means of the common KIT D816V mutation.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY, 2018
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-367138 (URN)10.1182/bloodadvances.2018019539 (DOI)000444247300012 ()30206100 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyTore Nilsons Stiftelse för medicinsk forskningMagnus Bergvall Foundation
Available from: 2018-11-29 Created: 2018-11-29 Last updated: 2018-11-29Bibliographically approved
Organisations

Search in DiVA

Show all publications